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Frontiers in Oncology

Gastrointestinal Cancers

REVIEW article

Front. Oncol., 25 February 2021 | https://doi.org/10.3389/fonc.2021.641343

The Emerging Landscape of Long Non-Coding RNAs in Colorectal Cancer Metastasis

Zhiming Liao1†, Hui Nie1†, Yutong Wang1, Jingjing Luo2, Jianhua Zhou1,3* and Chunlin Ou1,3*
  • 1Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
  • 2Teaching and Research Room of Biochemistry and Molecular Biology, Medical School of Hunan University of Traditional Chinese Medicine, Changsha, China
  • 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers, with extremely high rates of morbidity and mortality. The main cause of death in CRC is distant metastasis; it affects patient prognosis and survival and is one of the key challenges in the treatment of CRC. Long non-coding RNAs (lncRNAs) are a group of non-coding RNA molecules with more than 200 nucleotides. Abnormal lncRNA expression is closely related to the occurrence and progression of several diseases, including cancer. Recent studies have shown that numerous lncRNAs play pivotal roles in the CRC metastasis, and reversing the expression of these lncRNAs through artificial means can reduce the malignant phenotype of metastatic CRC to some extent. This review summarizes the major mechanisms of lncRNAs in CRC metastasis and proposes lncRNAs as potential therapeutic targets for CRC and molecular markers for early diagnosis.

Introduction

Colorectal cancer (CRC) is currently the third most common malignant tumor worldwide. Approximately 1.8 million new cases and nearly 900,000 deaths are reported worldwide each year. The high incidence and high mortality of CRC are serious threats to human health (1, 2). The occurrence and development of CRC is a complex process that involves exogenous and endogenous factors, such as Signaling molecules, homeostasis, microenvironment, diet, and lifestyle, which play an important role in the CRC pathogenesis (3, 4). In recent years, the molecular pathological epidemiology (MPE) has showed that the diet and lifestyle are closely related to the tumorigenesis. For example, smoking, eating red and processed meat, excess alcohol intake, and certain drugs (e.g., aspirin) have been confirmed to be related to the occurrence and development of CRC (5). With the rapid progress in clinical treatment, the 5-year survival rates of patients with CRC has improved significantly. However, the treatment outcomes in patients with metastatic CRC are still not ideal, and the 5-year survival rate in such patients is only ~12% (68). Metastasis of CRC is an important factor leading to the CRC recurrence and death. Therefore, elucidating the molecular mechanism of CRC metastasis and identifying molecular markers related to metastasis are critical for improving the treatment outcomes of CRC.

Long non-coding RNAs (lncRNAs) are non-coding RNA molecules that are greater than 200 nucleotides in length. Most of them are transcribed by RNA polymerase II and share similarities with messenger RNAs (mRNAs), although they lack coding ability (9). lncRNAs can be divided into five categories according to their positional relationship with protein-coding genes: sense, antisense, bidirectional, inter-intron, and intergenic lncRNAs (10). Accumulating evidence strongly suggests that lncRNAs are an important class of molecules that regulate genomic processes. The long nucleotide chain of lncRNAs can either form a complex spatial structure and interact with protein factors, or provide a large binding site for the concurrent binding of several molecules that collectively participate in X-chromosome silencing, genomic imprinting, epigenetic regulation, transcriptional activation or interference, nuclear and cytoplasmic trafficking, mRNA splicing and degradation, and genomic imprinting, among others (11). Since lncRNAs play important roles in various aspects of gene expression, the relationship between lncRNAs and tumors has become the focus area of current research. A variety of lncRNAs have been shown to promote or suppress tumorigenesis in different cancers. For instance, Zhuang et al. (12) found that lncRNA GClnc1 promotes the proliferation and invasion of bladder cancer by activating MYC expression. LncRNA PVT1 plays a carcinogenic role in prostate cancer and is a potential diagnostic biomarker (13). In CRC, researchers have found numerous differentially expressed lncRNAs and confirmed their important roles in regulating CRC cell proliferation, apoptosis, invasion, and metastasis as well as sensitivity to radiotherapy and chemotherapy (14). For instance, the HOXB-AS3 peptide encoded by lncRNA HOXB-AS3 has been shown to inhibit the growth of CRC (15). Accumulated evidence indicates that lncRNAs are important markers of CRC metastasis. Yue et al. observed that lncRNA CYTOR can promote the CRC metastasis via the Wnt/β-catenin signaling pathway (16). Therefore, lncRNAs are potential therapeutic targets for CRC.

Characteristics and Roles of lncRNAs

Generally, non-coding RNAs can be divided into long-chain and short-chain non-coding RNAs based on their lengths (17). The first long non-coding RNA transcript sequence discovered in eukaryotes has a length of more than 200 nt and an mRNA-like structure. After splicing, a 7mC cap is usually added at the 5′end of the lncRNA sequence, and a polyA tail is sometimes added to the 3′end (18, 19). Studies have shown that for some lncRNAs, corresponding DNA regions are located between genes or introns, some overlap with protein-coding genes, while some lncRNAs encode a small number of functional short peptides (20, 21). While the primary structure of an lncRNA is its nucleotide sequence, its functional activity depends on base pairing but it is less conserved than its higher-order structure (22, 23). The secondary and tertiary structures of lncRNAs determine their functions. The secondary structures mainly include double helices and hairpins, whereas the tertiary structures are more diverse, such as sarcin-ricin loops. The lower conservation of its primary structure is balanced by these higher-order structures (2426).

The main modes of action reported for lncRNAs include: ① interfering with mRNA cleavage by forming complementary double-stranded RNA (27), ② altering the activity of a specific protein through direct binding (28), ③ changing the cytoplasmic localization of a specific protein through direct binding (29), ④ altering the expression of target genes by inhibiting RNA polymerase II, or through chromatin remodeling and histone modification (30), ⑤ interfering with target gene expression by initiating transcription from the promoter region of protein-coding genes (31), ⑥ forming double-stranded RNAs with the transcripts of protein-coding genes and producing endogenous siRNAs through the action of Dicer (32), ⑦ acting as a structural component by forming a nucleic acid-protein complex (33), and ⑧ acting as the precursor of a small RNAs (such as a miRNAs or piRNAs). LncRNAs are mostly expressed in the nucleus and their expression levels are lower compared to those of mRNAs (34). However, lncRNAs are intricately involved in the regulation of various biological activities owing to their tissue-specific expression, and they can also affect disease processes (35). LncRNAs can also regulate the expression of important genes at multiple levels via epigenetic regulation and by modulating transcription, post-transcriptional processes, translation, and protein modification either as an initially transcribed RNA or a mature spliced RNA. Moreover, lncRNAs play important roles in physiological processes including development, tissue differentiation, reproduction, and immunity as well as in the formation and development of tumors.

Mechanism of lncRNA Action in CRC Metastasis

Tumor metastasis is the process wherein malignant cells detach from the primary tumor site and are translocated through the circulatory system to secondary tissues or organs, where they colonize and form secondary tumors (36). Tumor invasion and metastasis are complex, dynamic processes that typically involve changes in the tumor microenvironment, epithelial-mesenchymal transition (EMT), hypoxia, and angiogenesis among other mechanisms (37). Accumulating studies have shown that lncRNAs regulate CRC metastasis mainly by regulating key factors that simultaneously affect multiple signaling pathways that are closely related to tumor metastasis. In other cases, lncRNAs can sponge miRNAs to regulate the expression of target genes. lncRNAs can also bind directly to proteins to induce the protein degradation via affecting their phosphorylation or ubiquitination. Tumor invasion and metastasis affect patient prognosis and survival and are important causes of tumor-related death; hence, blocking these processes remains a critical challenge in cancer treatment (38).

LncRNAs Regulate CRC Metastasis by Regulating Signaling Pathways

Tumor metastasis involves complex regulatory processes and alteration in multiple molecular signaling pathways in the tumor microenvironment (39, 40). Several pathways, including the Wnt/β-catenin (41), PI3K/AKT (42), STAT (43), MAPK (44), and Notch signaling pathways (45) play key roles in the metastasis of different tumors (Table 1).

TABLE 1
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Table 1 LncRNAs and their targeting signaling pathways in the regulation of CRC metastasis.

Several studies have reported that the Wnt/β-catenin signaling pathway is closely related to CRC metastasis. Yue et al. (16) observed that lncRNA CYTOR, which is highly expressed in CRC, forms a positive feed forward loop with β-catenin and participates in the regulation of colon cancer metastasis. In this process, cell receptors bind to cytoplasmic β-catenin and block β-catenin phosphorylation catalyzed by casein kinase 1 (CK1), leading to the accumulation of β-catenin and its nuclear transport. Subsequently, the β-catenin/TCF complex activates the expression of cell receptor encoding genes, thereby forming a positive feed forward loop. LncRNA SLCO4A1-AS1 inhibits the interaction of β-catenin with GSKβ, inhibits β-catenin phosphorylation, and improves β-catenin stability, ultimately promoting the proliferation, migration, and invasion of CRC cells (82). Wu et al. (83) showed that lncRNA JMJD2C promotes CRC metastasis by enhancing the β-catenin signaling pathway and participating in the regulation of histone methylation at the MALAT1 promoter. In addition to directly participating in β-catenin signaling pathway transduction, lncRNAs can also play indirect regulatory roles in this signaling pathway. Research has shown that NEAT1 indirectly activates the Wnt/β-catenin signaling pathway through DDX5, and therefore, exerts its carcinogenic effects are mediated by DDX5 (53).

The PI3K/AKT signaling pathway also plays a key role in CRC metastasis, and several lncRNAs have been shown to modulate this pathway. Song et al. (84) found that the expression of the lncRNA, PlncRNA-1, was significantly higher in CRC tissues, and PlncRNA-1 knockout significantly reduced the spread, migration, and invasion of CRC cells. Further functional analysis showed that PlncRNA-1 affects the growth and metastasis of CRC mainly through the PI3K/AKT signaling pathway. The lncRNA SNHG6 inhibits ETS1 expression by directly targeting its 3′-untranslated region (UTR) and inhibiting the expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/rapamycin mechanical target (mTOR) to activate the CRC invasion (85). In addition, Wang et al. (86) found that lncRNA AB073614 promotes the proliferation and metastasis of CRC cells mainly through the PI3K/AKT signaling pathway. The lncRNA ST3Gal6 antisense 1 (ST3Gal6-AS1) is derived from the promoter region of gene encoding sialyltransferase ST3Gal6, and it mediates α-2,3 sialylation through the ST3Gal6-AS1/ST3Gal6 axis, thereby regulating PI3K/Akt signaling and leading to the nuclear translocation of Foxo1 in CRC cells (87).

Several other signaling pathways have been confirmed to play important roles in CRC metastasis. Functional analysis has shown that the lncRNA FEZF1-AS1, which is upregulated in CRC tissues, can bind to pyruvate kinase 2 (PKM2) protein and improve its stability. Higher cytoplasmic levels of PKM2 promote pyruvate kinase activity and lactate production (aerobic glycolysis), whereas higher nuclear levels of PKM2, induced by FEZF1-AS1, activate STAT3 signaling, which promotes the proliferation and metastasis of CRC cells (88). Zhou et al. (78) found that lncRNA-cCSC1 can modulate the characteristics of CRC stem cells by activating the Hedgehog signaling pathway and thus, plays an important role in CRC metastasis.

The migration and invasion of tumor cells require cytoskeletal rearrangement. Tang et al. (89) reported that lncRNAs can directly regulate the cytoskeleton in a variety of tumors and can alter the cytoskeleton via Rho/ROCK signaling during tumor migration. The lncRNA EPB41L4A-AS1 is overexpressed in CRC tissues and may affect proliferation, invasion, and migration by activating the Rho/ROCK-related protein kinase signaling pathway. Therefore, EPB41L4A-AS1 could be used as a new biomarker for the diagnosis and targeted treatment of CRC (90). Further, Tang et al. (91) studied the specific role of lncRNA-SLCO4A1-AS1 in CRC and found that its effects on cell proliferation, migration, and invasion were mainly associated with regulating the EGFR/MAPK pathway. Studies have shown that 1α, 25-(OH)2D and vitamin D receptor (VDR) in CRC cells stimulate MEG3 expression by directly binding to the promoter of lncRNA MEG3; MEG3 acts as a tumor suppressor by regulating clusterin activity. Therefore, the VDR/lncRNA MEG3/clusterin signaling pathway is a potential therapeutic target and prognostic biomarker for CRC patients (92).

LncRNAs Regulate CRC Metastasis Through Sponging miRNA

In recent years, several studies have shown that since lncRNAs contain several introns, they can sponge miRNAs to form competing endogenous RNA (ceRNA) networks. LncRNAs are transported to target cells via circulation, bind to intracellular miRNAs, sponge them, and limit their ability to interfere with the translation of their target mRNAs; a process important for cancer cell proliferation, invasion, migration, and apoptosis. Thus, the ability to sponge miRNAs is an important mechanism by which lncRNAs regulate CRC metastasis (Figure 1).

FIGURE 1
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Figure 1 LncRNAs regulate CRC metastasis by sponging miRNAs. (A) lncRNA LINC00668 promotes the metastasis and infiltration of CRC cells by sponging miR-188-5p and weakening its inhibiting effect on USP47 expression; (B) lncRNA MALAT1 regulates the miR-106b-5p expression by functioning as a competing endogenous RNA (ceRNA) and regulates the SLAIN2-associated microtubule mobility, leading to the CRC progression; (C) lncRNA TTTY15 functions as the ceRNA to regulate the expression of target gene DVL3 by sponging miR-29a-3p to promote CRC metastasis; (D) lncRNA-SNHG5 influences CRC cell metastasis by modulating the SNHG5/miR-132-3p/CERB5 axis. (E) lncRNA MIR4435-2HG acts as a ceRNA to promote the metastasis of CRC via upregulating YAP1 expression by sponging miR-206.

Yan et al. (93) reported the lncRNA LINC00668, which is encoded on chromosome 18p11.31, as a newly discovered lncRNA associated with cancers. LINC00668 is upregulated in CRC cancer tissues and cells and studies have shown that LINC00668 can bind to miR-188-5p in CRC cells. Therefore, LINC00668 may play a carcinogenic role in CRC by sponging miR-188-5p and upregulating USP 47 expression. Shan et al. (94) found that lncRNA SNHG7 regulates GALT1 levels by activating miR-216b and plays a carcinogenic role in CRC development. Xu et al. (95) reported that MIR17HG promotes CRC by inducing NF-κB/RELA expression and competitively sponging miR-375. LncRNA-SNHG5 has been shown to affect the proliferation, metastasis, and migration of CRC cells by regulating miR-132-3p/CREB5 (96). LncRNA-CRNDE modulates CRC progression and chemotherapy resistance by regulating the expression level of miR-181a-5p and the activity of the Wnt/β-catenin signaling pathway (49). LncRNA HNF1A-AS1, which is upregulated in colon cancer tissues, is closely related to clinical staging, vascular invasion, lymph node metastasis, and distant metastasis. In addition, HNF1A-AS1 regulates the expression of miRNA-34a by acting as a ceRNA, thereby inhibiting the miR-34a/SIRT1/p53 feedback loop and activating the Wnt signaling pathway to promote the development of colon cancer (97). LncRNA MIR4435-2HG was first found in lung cancer tissues where it functions as a ceRNA and sponges miR-206 to upregulate the expression of YAP 1. MIR4435-2HG promotes the CRC growth and metastasis via the miR-206/YAP 1 axis (98). A functional analysis by Yang et al. (99) showed that knocking out lncRNA-FTX significantly inhibited the proliferation, migration, and invasion of CRC cells. Further analysis showed that FTX could directly interact with miR-215 and inhibit its expression, thereby inhibiting the metastasis of CRC. In CRC cells, the expression of lncRNA TUG1 is abnormally high, whereas the expression of miR-600 is downregulated in CRC tissues, cell lines, and metastatic tissues. Moreover, TUG1 inhibits the migration, invasion, and EMT of CRC cells by competing with miR-600 (100).

Li et al. (101) revealed the previously unrecognized role of the lncRNA ZDHHC8P1/miR-34a regulatory axis in regulating the progression and metastasis of CRC and proposed a viable approach to treat late-stage metastatic CRC patients. LncRNA SNHG1 expression is upregulated in human CRC tissues. In the cytoplasm, SNHG1 sponges miR-154-5p, thereby reducing its ability to inhibit the expression of cyclin D2 (CCND2). In the nucleus, SNHG1 directly interacts with polycomb repressive complex 2 (PRC2) and modulates histone methylation at the promoters of Kruppel-like factor 2 (KLF2) and cyclin-dependent kinase inhibitor 2B (CDKN2B) (102). In vivo and in vitro experiments by Zhuang et al. (103) showed that lncRNA MALAT1 promotes CRC metastasis mainly via the lncRNA MALAT1/miR-106b-5p/SLAIN2 axis. LncRNA TTTY15 expression is abnormally upregulated in CRC tissues and it functions as a ceRNA by sponging miR-29a-3p to regulate the expression of the target gene DVL3, which affects the proliferation and metastasis of CRC (104). The results of in vivo and in vitro experiments have shown that a novel oncogenic lncRNA, RP11-757G1.5, which is overexpressed in CRC tissues, regulates the expression of YAP1 by sponging miR-139-5p and inhibiting its activity, thereby promoting the metastasis and invasion in CRC (105).

LncRNAs Regulate CRC Metastasis Through Protein Binding

Similar to molecular chaperones, lncRNAs bind directly to transcription factors and form RNA-protein-DNA ternary complexes that regulate the transcription of downstream target genes involved in the CRC metastasis (Figure 2). LncRNAs act by two main mechanisms, which occur in different parts of the cells. In the nucleus, lncRNAs can coordinate with or antagonize transcription factors, thereby regulating the transcription of metastasis-related genes. In the cytoplasm, lncRNAs can bind to proteins and alter their post-translational modifications to induce the protein degradation; when these proteins are relevant to cancer, these effects can impact tumor metastasis.

FIGURE 2
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Figure 2 LncRNAs regulate CRC metastasis through protein binding. (A) lncRNA RPPH1 interacts with β-III tubulin (TUBB3) to prevent its ubiquitination and induces epithelial-mesenchymal transformation (EMT) of CRC; (B) lncRNA SNHG6 activates the endogenous colorectal cancer invasion pathway by down-regulating the expression of phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/rapamycin mechanical target (mTOR); (C) lncRNA SlCO4a1-AS1 stabilized β-catenin by impairing the interaction of β-catenin with GSKβ, thereby activating Wnt/β-catenin signaling in CRC cells; (D) lncRNA CASC11 promotes CRC cell proliferation and metastasis by interacting with hnRNP-K protein and activating the WNT/β-catenin signaling; (E) lncRNA RP11 is involved in the CRC development by forming the RP11/hnRNPA2B1/mRNA complex, which accelerates the mRNA degradation of two E3 ligases Siah1 and Fbxo45 and prevents the proteasomal degradation of Zeb1 to increase its nuclear accumulation.

The lncRNA SATB2-AS1 is specifically downregulated in CRC tissues. A mechanistic analysis showed that SATB2-AS1 binds directly to WDR5 and GADD45A and cis-activates SATB2 transcription by modulating histone H3 lysine 4 trimethylation (H3K4me3) and DNA demethylation in the SATB2 promoter region (106). A study by Wu et al. (107) showed that in intestinal cancer cells, the lncRNA RP11/hnRNPA2B1 (protein)/mRNA complex accelerated the degradation of Siah1 and Fbxo45 mRNAs, both of which encode ubiquitin E3 ligases, thereby preventing the proteasomal degradation of Zeb1, a transcription factor associated with EMT. This post-translational upregulation of Zeb1 is critical to RP11-induced dissemination of intestinal cancer cells. The lncRNA CPS1-IT can block hypoxia-induced autophagy by inhibiting HIF-1α levels, thereby preventing EMT and metastasis in CRC (108). Recent studies have shown that lncRNA RPPH1 can interact with β-III tubulin (TUBB3) to prevent its ubiquitination, which induces EMT and promotes CRC metastasis (109). The lncRNA LUCAT1 was shown to promote the proliferation, apoptosis, migration, and invasion of CRC cells in vitro and in vivo. Analysis showed that LUCAT1 binds to UBA52, which encodes ubiquitin, and the 60S ribosomal protein L40 (RPL40). By binding to UBA52, LUCAT1 targets the ribosomal protein L40/MDM2/p53 pathway to promote tumorigenesis and induce CRC cell cycle arrest and apoptosis (78). The lncRNA SNHG14, which is highly expressed in CRC, promotes CRC cell proliferation, motility, and EMT in vitro. SNHG14 promotes CRC progression by inhibiting EPHA7-mediated negative regulation through a process dependent on the transcription factor EZH2. SNHG14 enhances the stability of EZH2 mRNA by interacting with the RNA-binding protein FUS and sponging miR-186-5p, thereby mitigating miR-186-5p-induced silencing and increasing EZH2 expression in CRC (110). Ding et al. (111) found that the combination of lncRNA CRNDE and EZH2, a key component of PRC2, inhibited the expression of two downstream target genes dual-specific phosphatase 5 (DUSP5) and CDKN1A, which play important roles in CRC proliferation and metastasis. LINC01413 binds to hnRNP-K and induces nuclear translocation of YAP1 (associated protein 1) TAZ, thus regulating the expression of ZEB1 in CRC cells and promoting cancer metastasis (112). Zhang et al. (54) found that upregulation of lncRNA CASC11 in CRC is correlated with CRC growth and metastasis and that it exerts its effects by interacting with hnRNP-K protein and activating the Wnt/β-catenin pathway. Studies have shown that LINC01354 overexpression in CRC results in the enrichment of genes related to the Wnt/β-catenin signaling pathway. In CRC, LINC01354 mainly interacts with hnRNP-D to regulate the stability of β-catenin mRNA and activate the Wnt/β-catenin signaling pathway (50). The lncRNA ROR is a newly discovered lncRNA and Li et al. (113) demonstrated that knockout of the lncRNA ROR gene significantly increased the protein levels of p53 and its target genes, whereas the overexpression of ROR exerted the opposite effect. Thus, we conclude that the level of p53 protein is negatively correlated with ROR, and ROR may participate in the CRC progression via the p53 signaling pathway.

Clinical Significance of lncRNAs in CRC Metastasis

Several studies have revealed that lncRNAs exert important biological effects in the CRC metastasis. Thus, the most practical application of lncRNAs is that they can be used as markers for early diagnosis of CRC metastasis. To improve the convenience and speed of CRC diagnosis, the differentially expressed lncRNAs can be detected in metastatic and non-metastatic samples (such as blood or urine). In addition, some lncRNAs closely correlate with the sensitivity to radiotherapy and chemotherapy, which may help to design novel therapies with better efficacy for the clinical treatment of metastatic CRC.

One challenge associated with existing diagnostic biomarkers of CRC is that they lack sufficient sensitivity and specificity, which can lead to false positive or false negative results. In recent years, several studies have shown that some lncRNAs can be detected in the blood, urine, serum, and other body fluids of patients with cancer (114). These lncRNAs could be used as biomarkers for the early diagnosis of cancer and prediction of patient prognosis (Table 2) (39, 48, 54, 59, 70, 74, 77, 78, 82, 84, 87, 88, 91, 94, 98221). For example, lncRNA RP11-296E3.2, which is highly expressed in metastatic CRC, is associated with short overall survival (OS). In terms of its sensitivity and specificity of diagnosing CRC metastasis, RP11-296E3.2 was superior to CEA in plasma (113). Xu et al. (222) found that the plasma levels of four lncRNAs, ZFAS1, SNHG11, LINC00909, and LINC00654, were significantly lower in postoperative CRC samples than in preoperative samples. The combination of these four lncRNAs showed high diagnostic performance for early CRC. Studies have shown that lncRNA TINCR can affect the PI3K/Akt/mTOR signaling pathway by sponging miR-7-5p and playing a role in promoting CRC. In addition, compared with healthy controls, plasma levels of lncRNA TINCR were significantly elevated in CRC patients, which suggests its potential for the detecting early CRC (154). A correlation analysis by Pan et al. (223) showed that in patients with early CRC, plasma levels of lncRNA PVT1 are significantly higher than those of CEA, suggesting that PVT1 has great potential as a marker for the diagnosis of early CRC. A decrease in lncRNA-ATB expression significantly affects the progression of colon cancer by altering the expression of epithelial markers such as E-cad. A related clinical analysis showed that the level of plasma lncRNA-ATB was significantly increased in colon cancer patients at 1 month after surgery, suggesting that it may be useful for the early diagnosis of CRC (213). Ye et al. (80) observed that the level of lnc-GNAT1-1 in the plasma of CRC patients is related to tumor node metastasis (TNM) staging, while the receiver operating characteristic curve (ROC) showed that plasma lnc-GNAT1-1 has a moderate to good diagnostic efficiency for CRC.

TABLE 2
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Table 2 The correlation between LncRNAs and clinicopathological features in CRC.

LncRNAs have been shown to play roles in lymph node metastasis, lung metastasis, bone metastasis, and brain metastasis associated with several cancers (224). LncRNA CCAT2 is highly expressed in CRC and its expression is closely related to TNM stage as CCAT2 levels are increased from stages I to IV. High CCAT2 expression is closely associated with poor cell differentiation and depth of tumor invasion, lymph node metastasis, distant metastasis, vascular infiltration, and advanced TNM staging, and may be associated with increased liver metastasis (190). LINC00858 expression levels are significantly higher in CRC tissues than in adjacent tissues, and high LINC00858 expression is related to TNM staging, lymph node metastasis, and histological grade. Silencing of LINC00858 inhibits the proliferation, migration, and invasion of CRC cells and induces apoptosis (150). The expression level of MFI2-AS1 are closely related to tumor histological grade, lymphatic and distant metastasis, TNM staging, and vascular infiltration (225). High expression of lncRNA BANCR in CRC is associated with lymph node metastasis and the OS of patients with high BANCR expression is shorter (76). Chen et al. (226) divided 115 CRC patients into two groups based on the median lncRNA XIST expression level and an analysis of these groups showed that XIST expression was closely correlated with tumor size, histological grade, distant metastasis, and TNM staging. Similarly, the expression of lncRNA SNHG3 was significantly upregulated in CRC tissues, and SNHG3 expression was positively correlated with the advanced clinical stage and distant metastasis (118).

LncRNAs are an important group of molecules in the human transcriptome. LncRNAs play important roles not only in several physiological processes but also in various disease processes including cancer development and metastasis. Many lncRNAs are tumor specific and their expression can alter sensitivity to radiotherapy and chemotherapy. Therefore, they are expected to be useful as new therapeutic targets (227). LncRNA MALAT1, which was first found to be differentially expressed in patients with non-small cell lung cancer, is also significantly overexpressed in CRC. Low MALAT1 expression can inhibit the progression and metastasis of CRC and increase the sensitivity of cancer cells to 5-FU. This provides a new direction for designing novel therapeutic regimens for metastatic CRC (228). In addition, MALAT1 was found to be significantly upregulated in CRC tissues and cells treated with oxaliplatin. It promotes anti-oxidative response mainly via the miR-324-3p/ADAM17 axis and enhances sensitivity to oxaliplatin (229). In an experiment designed to select lncRNAs related to oxaliplatin resistance, Sun et al. (230) observed that the lncRNAs CRNDE, H19, UCA1, and HOTAIR affect the sensitivity to oxaliplatin. High expression of HOTAIR is associated with advanced tumor nodules and metastatic stages and poor prognosis of CRC. Peng et al. (231) observed that downregulation of lncRNA POU5F1P4 reduced the sensitivity of metastatic CRC cells to cetuximab, and could be a potential new treatment for metastatic CRC. Wang et al. (232) showed that the LINC00473 expression level was significantly higher in a group of drug-resistant patients than that in non-drug-resistant patients and knockdown of LINC00473 restored paclitaxel-induced cytotoxicity, inhibited cell viability and colony formation, induced apoptosis, and weakened the ability of tumor cells to migrate or invade.

Discussion

The CRC metastasis is induced by a variety of factors in vivo and in vitro. Among the in vivo factors, changes in the tumor cell adhesion to surrounding cells and extracellular matrix, EMT, and the dysregulation of various motor proteins promote the CRC metastasis. Several signaling pathways such as Wnt/β-Catenin and PI3K/AKT signaling pathway play important roles in the CRC metastasis. LncRNAs also act as ceRNA to regulate the expression of downstream target genes or components of CRC metastasis-associated signaling pathways to impact CRC metastasis. Epidemiological studies have shown that CRC metastasis is closely related to several in vitro factors. For example, tea polyphenols (TPs) can exert anti-inflammatory, anti-oxidant, or pro-oxidant effects to promote apoptosis and act at multiple levels to inhibit CRC growth and metastasis (233). Nicotine upregulates the expression of UCA1 and HIF-1α in CRC cells and promotes the proliferation and metastasis of CRC cells (234). In addition, individuals with a family history of colorectal cancer and inflammatory bowel disease are more likely to develop colorectal cancer than individuals without such a family history of these diseases (4). Exploring the relationship among diet, lifestyle, and the risk of CRC occurrence and metastasis from the perspective of molecular epidemiology, and clarifying the critical exposure duration will help us better understand how these factors affect CRC occurrence and pathogenesis. Understanding the occurrence and development of the disease can help further to understand the clinical outcome (235). Elucidating the effects of in vivo factors, exploring the mechanism specific to colorectal cancer metastasis, identifying the important molecules involved in CRC pathogenesis will help the early clinical diagnosis and optimal treatment of CRC patients.

Few methods are available for CRC screening and most of the biomarkers used to diagnose CRC, such as CA199, are differentially expressed in many cancers. Therefore, CRC diagnosis lacks specificity and sensitivity. Mounting evidence has shown that abnormal expression of lncRNAs in human tissues and serum holds potential for early diagnosis and predicting patient prognosis. For example, expression of DANCR was lower in serum samples of postoperative patients than in patients with recurrence; moreover, serum DANCR expression significantly correlated with TNM staging (236).

Research has significantly advanced our understanding of the mechanisms underlying CRC and the therapeutic outcomes have been improved significantly. However, in metastatic CRC, the treatment outcomes, and mortality rate remain unsatisfactory. Therefore, there is an urgent need to find new therapeutic targets for metastatic CRC. Animal-based studies have shown that lncRNAs play important roles in metastatic CRC and can be used as potential targets for clinical treatment. Upon lncRNA-RI silencing, CRC cells show stronger radiosensitivity, making it a potential therapeutic target for metastatic CRC (237). Wu et al. (238) established a mouse xenograft model and observed that loss of lncRNA PVT1 and overexpression of miR-16-5p can minimize tumor volume. Through the lncRNA PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis, lncRNA PVT1 is directly involved in the progression of CRC and is a potential target for CRC treatment. Animal experiments by Yao et al. (239) showed that MIR600HG can inhibit tumor formation. Compared with lncRNA MIR600HG alone, combination therapy with MIR600HG and oxaliplatin significantly inhibited CRC stem cell metastasis and tumor growth.

Although lncRNAs have shown great potential in clinical applications, following gaps remain in lncRNA research. 1) The specific mechanisms underlying the effects of various lncRNAs in CRC remain unclear, highlighting the need for further research on the occurrence and development of CRC. 2) In terms of their utility as CRC biomarkers, the heterogeneity of lncRNA expression may make it difficult to achieve an accurate diagnosis. 3) Only a few animal experiments have been carried out to confirm treatment outcomes. Thus, limited data make it difficult to confirm the reliability of lncRNAs as diagnostic and therapeutic markers. Therefore, it is imperative to further explore the relationships between lncRNAs and CRC so that a solid foundation can be laid for their future use in CRC diagnosis and treatment. Nonetheless, research on lncRNAs in human cancers is expected to lead to major breakthroughs in terms of early diagnosis, risk detection, and treatment in the near future.

Author Contributions

ZL, HN, JZ, and CO designed/planned the study and wrote the paper. All authors participated in writing the paper. ZL, HN, JZ, and CO performed imaging analysis. All authors contributed to the article and approved the submitted version.

Funding

This study was supported by the National Natural Science Foundation of China (81903032), the China Postdoctoral Science Foundation (2020M672520), the Youth Fund of Xiangya Hospital (2018Q011), and the Mittal Innovative Entrepreneurial Project of Central South University (XCX20190719).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer QL declared a shared affiliation, with no collaboration, with several of the authors ZL, HN, YW, JZ, CO to the handling editor at the time of the review.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin (2020) 70(1):7–30. doi: 10.3322/caac.21590

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Nie H, Wang Y, Liao Z, Zhou J, Ou C. The function and mechanism of circular RNAs in gastrointestinal tumours. Cell Prolif (2020) 53(7):e12815. doi: 10.1111/cpr.12815

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Ogino S, Chan AT, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut (2011) 60(3):397–411. doi: 10.1136/gut.2010.217182

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Hughes LAE, Simons C, van den Brandt PA, van Engeland M, Weijenberg MP. Lifestyle, Diet, and Colorectal Cancer Risk According to (Epi)genetic Instability: Current Evidence and Future Directions of Molecular Pathological Epidemiology. Curr Colorectal Cancer Rep (2017) 13(6):455–69. doi: 10.1007/s11888-017-0395-0

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Ogino S, Nowak JA, Hamada T, Milner DA Jr, Nishihara R. Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology. Annu Rev Pathol (2019) 14:83–103. doi: 10.1146/annurev-pathmechdis-012418-012818

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Niksic M, et al. Global surveillance of trends in cancer survival 2000-14(CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancersfrom 322 population-based registries in 71 countries. Lancet (2018) 391(10125):1023–75. doi: 10.1016/S0140-6736(17)33326-3

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Kalyan A, Kircher S, Shah H, Mulcahy M, Benson A. Updates on immunotherapy for colorectal cancer. J Gastrointest Oncol (2018) 9(1):160–9. doi: 10.21037/jgo.2018.01.17

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Frampton M, Houlston RS. Modeling the prevention of colorectal cancer from the combined impact of host and behavioral risk factors. Genet Med (2017) 19(3):314–21. doi: 10.1038/gim.2016.101

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Marchese FP, Raimondi I, Huarte M. The multidimensional mechanisms of long noncoding RNA function. Genome Biol (2017) 18(1):206. doi: 10.1186/s13059-017-1348-2

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell (2009) 136(4):629–41. doi: 10.1016/j.cell.2009.02.006

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Kopp F, Mendell JT. Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell (2018) 172(3):393–407. doi: 10.1016/j.cell.2018.01.011

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Zhuang C, Ma Q, Zhuang C, Ye J, Zhang F, Gui Y. LncRNA GClnc1 promotes proliferation and invasion of bladder cancer through activation of MYC. FASEB J (2019) 33(10):11045–59. doi: 10.1096/fj.201900078RR

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Yang J, Li C, Mudd A, Gu X. LncRNA PVT1 predicts prognosis and regulates tumor growth in prostate cancer. Biosci Biotechnol Biochem (2017) 81(12):2301–6. doi: 10.1080/09168451.2017.1387048

PubMed Abstract | CrossRef Full Text | Google Scholar

14. He X, Li S, Yu B, Kuang G, Wu Y, Zhang M, et al. Up-regulation of LINC00467 promotes the tumourigenesis in colorectal cancer. J Cancer (2019) 10(25):6405–13. doi: 10.7150/jca.32216

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Huang JZ, Chen M, Chen, Gao XC, Zhu S, Huang H, et al. A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth. Mol Cell (2017) 68(1):171–184 e176. doi: 10.1016/j.molcel.2017.09.015

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Yue B, Liu C, Sun H, Liu M, Song C, Cui R, et al. A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/beta-Catenin Signaling Promotes Metastasis of Colon Cancer. Mol Ther (2018) 26(5):1287–98. doi: 10.1016/j.ymthe.2018.02.024

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. Physiol Rev (2016) 96(4):1297–325. doi: 10.1152/physrev.00041.2015

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Schmitt AM, Chang HY. Long Noncoding RNAs in Cancer Pathways. Cancer Cell (2016) 29(4):452–63. doi: 10.1016/j.ccell.2016.03.010

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Huang G, Zhu H, Wu S, Cui M, Xu T. Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome. Front Genet (2019) 10:446. doi: 10.3389/fgene.2019.00446

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res (2012) 22(9):1775–89. doi: 10.1101/gr.132159.111

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Matsumoto A, Pasut A, Matsumoto M, Yamashita R, Fung J, Monteleone E, et al. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature (2017) 541(7636):228–32. doi: 10.1038/nature21034

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell (2015) 160(4):595–606. doi: 10.1016/j.cell.2015.01.009

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature (2010) 464(7291):1071–6. doi: 10.1038/nature08975

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Mercer TR, Mattick JS. Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol (2013) 20(3):300–7. doi: 10.1038/nsmb.2480

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Qian X, Zhao J, Yeung PY, Zhang QC, Kwok CK. Revealing lncRNA Structures and Interactions by Sequencing-Based Approaches. Trends Biochem Sci (2019) 44(1):33–52. doi: 10.1016/j.tibs.2018.09.012

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Somarowthu S, Legiewicz M, Chillon I, Marcia M, Liu F, Pyle AM. HOTAIR forms an intricate and modular secondary structure. Mol Cell (2015) 58(2):353–61. doi: 10.1016/j.molcel.2015.03.006

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet (2016) 17(1):47–62. doi: 10.1038/nrg.2015.10

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Fang Y, Fullwood MJ. Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer. Genomics Proteomics Bioinf (2016) 14(1):42–54. doi: 10.1016/j.gpb.2015.09.006

CrossRef Full Text | Google Scholar

29. Alvarez-Dominguez JR, Lodish HF. Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis. Blood (2017) 130(18):1965–75. doi: 10.1182/blood-2017-06-788695

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell (2013) 152(6):1298–307. doi: 10.1016/j.cell.2013.02.012

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Schmitz KM, Mayer C, Postepska A, Grummt I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev (2010) 24(20):2264–9. doi: 10.1101/gad.590910

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Djupedal I, Ekwall K. Epigenetics: heterochromatin meets RNAi. Cell Res (2009) 19(3):282–95. doi: 10.1038/cr.2009.13

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science (2010) 329(5992):689–93. doi: 10.1126/science.1192002

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature (2012) 489(7414):101–8. doi: 10.1038/nature11233

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev (2009) 23(13):1494–504. doi: 10.1101/gad.1800909

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Ou C, Sun Z, Li X, Li X, Ren W, Qin Z, et al. MiR-590-5p, a density-sensitive microRNA, inhibits tumorigenesis by targeting YAP1 in colorectal cancer. Cancer Lett (2017) 399:53–63. doi: 10.1016/j.canlet.2017.04.011

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Sun Z, Ou C, Liu J, Chen C, Zhou Q, Yang S, et al. YAP1-induced MALAT1 promotes epithelial-mesenchymal transition and angiogenesis by sponging miR-126-5p in colorectal cancer. Oncogene (2019) 38(14):2627–44. doi: 10.1038/s41388-018-0628-y

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Wang Y, Nie H, He X, Liao Z, Zhou Y, Zhou J, et al. The emerging role of super enhancer-derived noncoding RNAs in human cancer. Theranostics (2020) 10(24):11049–62. doi: 10.7150/thno.49168

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Ou C, Sun Z, He X, Li X, Fan S, Zheng X, et al. Targeting YAP1/LINC00152/FSCN1 Signaling Axis Prevents the Progression of Colorectal Cancer. Adv Sci (Weinh) (2020) 7(3):1901380. doi: 10.1002/advs.201901380

PubMed Abstract | CrossRef Full Text | Google Scholar

40. He X, Yu B, Kuang G, Wu Y, Zhang M, Cao P, et al. Long noncoding RNA DLEU2 affects the proliferative and invasive ability of colorectal cancer cells. J Cancer (2021) 12(2):428–37. doi: 10.7150/jca.48423

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, et al. lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/beta-catenin signaling. Nat Med (2017) 23(11):1331–41. doi: 10.1038/nm.4424

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Huang JL, Cao SW, Ou QS, Yang B, Zheng SH, Tang J, et al. The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma. Mol Cancer (2018) 17(1):93. doi: 10.1186/s12943-018-0841-x

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Xu S, Kong D, Chen Q, Ping Y, Pang D. Oncogenic long noncoding RNA landscape in breast cancer. Mol Cancer (2017) 16(1):129. doi: 10.1186/s12943-017-0696-6

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Peng WX, Huang JG, Yang L, Gong AH, Mo YY. Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol Cancer (2017) 16(1):161. doi: 10.1186/s12943-017-0727-3

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A, et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell (2014) 158(3):593–606. doi: 10.1016/j.cell.2014.05.049

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Bin J, Nie S, Tang Z, Kang A, Fu Z, Hu Y, et al. Long noncoding RNA EPB41L4A-AS1 functions as an oncogene by regulating the Rho/ROCK pathway in colorectal cancer. J Cell Physiol (2021) 236(1):523–35. doi: 10.1002/jcp.29880

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Wang JH, Lu TJ, Kung ML, Yang YF, Yeh CY, Tu YT, et al. The Long Noncoding RNA LOC441461 (STX17-AS1) Modulates Colorectal Cancer Cell Growth and Motility. Cancers (Basel) (2020) 12(11):3171. doi: 10.3390/cancers12113171

CrossRef Full Text | Google Scholar

48. Yu X, Wang D, Wang X, Sun S, Zhang Y, Wang S, et al. CXCL12/CXCR4 promotes inflammation-driven colorectal cancer progression through activation of RhoA signaling by sponging miR-133a-3p. J Exp Clin Cancer Res (2019) 38(1):32. doi: 10.1186/s13046-018-1014-x

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Han P, Li JW, Zhang BM, Lv JC, Li YM, Gu XY, et al. The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/beta-catenin signaling. Mol Cancer (2017) 16(1):9. doi: 10.1186/s12943-017-0583-1

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Li J, He M, Xu W, Huang S. LINC01354 interacting with hnRNP-D contributes to the proliferation and metastasis in colorectal cancer through activating Wnt/beta-catenin signaling pathway. J Exp Clin Cancer Res (2019) 38(1):161. doi: 10.1186/s13046-019-1150-y

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Shan Z, An N, Qin J, Yang J, Sun H, Yang W. Long non-coding RNA Linc00675 suppresses cell proliferation and metastasis in colorectal cancer via acting on miR-942 and Wnt/beta-catenin signaling. BioMed Pharmacother (2018) 101:769–76. doi: 10.1016/j.biopha.2018.02.123

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Sun X, Bai Y, Yang C, Hu S, Hou Z, Wang G. Long noncoding RNA SNHG15 enhances the development of colorectal carcinoma via functioning as a ceRNA through miR-141/SIRT1/Wnt/beta-catenin axis. Artif Cells Nanomed Biotechnol (2019) 47(1):2536–44. doi: 10.1080/21691401.2019.1621328

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Zhang M, Weng W, Zhang Q, Wu Y, Ni S, Tan C, et al. The lncRNA NEAT1 activates Wnt/beta-catenin signaling and promotes colorectal cancer progression via interacting with DDX5. J Hematol Oncol (2018) 11(1):113. doi: 10.1186/s13045-018-0656-7

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Zhang Z, Zhou C, Chang Y, Zhang Z, Hu Y, Zhang F, et al. Long non-coding RNA CASC11 interacts with hnRNP-K and activates the WNT/beta-catenin pathway to promote growth and metastasis in colorectal cancer. Cancer Lett (2016) 376(1):62–73. doi: 10.1016/j.canlet.2016.03.022

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Du YL, Liang Y, Shi GQ, Cao Y, Qiu J, Yuan L, et al. LINC00689 participates in proliferation, chemoresistance and metastasis via miR-31-5p/YAP/beta-catenin axis in colorectal cancer. Exp Cell Res (2020) 395(1):112176. doi: 10.1016/j.yexcr.2020.112176

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Gao Q, Zhou R, Meng Y, Duan R, Wu L, Li R, et al. Long noncoding RNA CMPK2 promotes colorectal cancer progression by activating the FUBP3-c-Myc axis. Oncogene (2020) 39(19):3926–38. doi: 10.1038/s41388-020-1266-8

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Gu LQ, Xing XL, Cai H, Si AF, Hu XR, Ma QY, et al. Long non-coding RNA DILC suppresses cell proliferation and metastasis in colorectal cancer. Gene (2018) 666:18–26. doi: 10.1016/j.gene.2018.03.100

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Liu B, Pan S, Xiao Y, Liu Q, Xu J, Jia L. LINC01296/miR-26a/GALNT3 axis contributes to colorectal cancer progression by regulating O-glycosylated MUC1 via PI3K/AKT pathway. J Exp Clin Cancer Res (2018) 37(1):316. doi: 10.1186/s13046-018-0994-x

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Feng W, Li B, Wang J, Zhang H, Liu Y, Xu D, et al. Long Non-coding RNA LINC00115 Contributes to the Progression of Colorectal Cancer by Targeting miR-489-3p via the PI3K/AKT/mTOR Pathway. Front Genet (2020) 11:567630. doi: 10.3389/fgene.2020.567630

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Li Y, Zeng C, Hu J, Pan Y, Shan Y, Liu B, et al. Long non-coding RNA-SNHG7 acts as a target of miR-34a to increase GALNT7 level and regulate PI3K/Akt/mTOR pathway in colorectal cancer progression. J Hematol Oncol (2018) 11(1):89. doi: 10.1186/s13045-018-0632-2

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Pei Q, Liu GS, Li HP, Zhang Y, Xu XC, Gao H, et al. Long noncoding RNA SNHG14 accelerates cell proliferation, migration,invasion and suppresses apoptosis in colorectal cancer cells by targeting miR-944/KRAS axis throughPI3K/AKT pathway. Eur Rev Med Pharmacol Sci (2019) 23(22):9871–81. doi: 10.26355/eurrev_201911_19551

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Pan S, Liu Y, Liu Q, Xiao Y, Liu B, Ren X, et al. HOTAIR/miR-326/FUT6 axis facilitates colorectal cancer progression through regulating fucosylation of CD44 via PI3K/AKT/mTOR pathway. Biochim Biophys Acta Mol Cell Res (2019) 1866(5):750–60. doi: 10.1016/j.bbamcr.2019.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Liang C, Zhao T, Li H, He F, Zhao X, Zhang Y, et al. Long Non-coding RNA ITIH4-AS1 Accelerates the Proliferation and Metastasis of Colorectal Cancer by Activating JAK/STAT3 Signaling. Mol Ther Nucleic Acids (2019) 18:183–93. doi: 10.1016/j.omtn.2019.08.009

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Liu B, Liu Q, Pan S, Huang Y, Qi Y, Li S, et al. The HOTAIR/miR-214/ST6GAL1 crosstalk modulates colorectal cancer procession through mediating sialylated c-Met via JAK2/STAT3 cascade. J Exp Clin Cancer Res (2019) 38(1):455. doi: 10.1186/s13046-019-1468-5

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Zhang L, Ye F, Zuo Z, Cao D, Peng Y, Li Z, et al. Long noncoding RNA TPT1-AS1 promotes the progression and metastasis of colorectal cancer by upregulating the TPT1-mediated FAK and JAK-STAT3 signalling pathways. Aging (Albany NY) (2021) 12. doi: 10.18632/aging.202339

CrossRef Full Text | Google Scholar

66. Luo Y, Ouyang J, Zhou D, Zhong S, Wen M, Ou W, et al. Long Noncoding RNA GAPLINC Promotes Cells Migration and Invasion in Colorectal Cancer Cell by Regulating miR-34a/c-MET Signal Pathway. Dig Dis Sci (2018) 63(4):890–9. doi: 10.1007/s10620-018-4915-9

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Pan K, Xie Y. LncRNA FOXC2-AS1 enhances FOXC2 mRNA stability to promote colorectal cancer progression via activation of Ca(2+)-FAK signal pathway. Cell Death Dis (2020) 11(6):434. doi: 10.1038/s41419-020-2633-7

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Xu J, Shao T, Song M, Xie Y, Zhou J, Yin J, et al. MIR22HG acts as a tumor suppressor via TGFbeta/SMAD signaling and facilitates immunotherapy in colorectal cancer. Mol Cancer (2020) 19(1):51. doi: 10.1186/s12943-020-01174-w

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Takahashi Y, Sawada G, Kurashige J, Uchi R, Matsumura T, Ueo H, et al. Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br J Cancer (2014) 110(1):164–71. doi: 10.1038/bjc.2013.698

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Luo K, Geng J, Zhang Q, Xu Y, Zhou X, Huang Z, et al. LncRNA CASC9 interacts with CPSF3 to regulate TGF-beta signaling in colorectal cancer. J Exp Clin Cancer Res (2019) 38(1):249. doi: 10.1186/s13046-019-1263-3

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Wang X, Lai Q, He J, Li Q, Ding J, Lan Z, et al. LncRNA SNHG6 promotes proliferation, invasion and migration in colorectal cancer cells by activating TGF-beta/Smad signaling pathway via targeting UPF1 and inducing EMT via regulation of ZEB1. Int J Med Sci (2019) 16(1):51–9. doi: 10.7150/ijms.27359

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Wu N, Jiang M, Liu H, Chu Y, Wang D, Cao J, et al. LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-beta/SMAD2/3 signaling pathway. Cell Death Differ (2021) 28(1):219–32. doi: 10.1038/s41418-020-0596-y

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Xu J, Wu G, Zhao Y, Han Y, Zhang S, Li C, et al. Long Noncoding RNA DSCAM-AS1 Facilitates Colorectal Cancer Cell Proliferation and Migration via miR-137/Notch1 Axis. J Cancer (2020) 11(22):6623–32. doi: 10.7150/jca.46562

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Yang MH, Zhao L, Wang L, Ou-Yang W, Hu SS, Li WL, et al. Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin beta3 transcriptional activating and MAPK/AKT signalling. Mol Cancer (2019) 18(1):31. doi: 10.1186/s12943-019-0955-9

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Yang W, Redpath RE, Zhang C, Ning N. Long non-coding RNA H19 promotes the migration and invasion of colon cancer cells via MAPK signaling pathway. Oncol Lett (2018) 16(3):3365–72. doi: 10.3892/ol.2018.9052

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Guo Q, Zhao Y, Chen J, Hu J, Wang S, Zhang D, et al. BRAF-activated long non-coding RNA contributes to colorectal cancer migration by inducing epithelial-mesenchymal transition. Oncol Lett (2014) 8(2):869–75. doi: 10.3892/ol.2014.2154

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Jiang H, Wang Y, Ai M, Wang H, Duan Z, Wang H, et al. Long noncoding RNA CRNDE stabilized by hnRNPUL2 accelerates cell proliferation and migration in colorectal carcinoma via activating Ras/MAPK signaling pathways. Cell Death Dis (2017) 8(6):e2862. doi: 10.1038/cddis.2017.258

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Zhou H, Xiong Y, Peng L, Wang R, Zhang H, Fu Z. LncRNA-cCSC1 modulates cancer stem cell properties in colorectal cancer via activation of the Hedgehog signaling pathway. J Cell Biochem (2020) 121(3):2510–24. doi: 10.1002/jcb.29473

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Zhou Q, Hou Z, Zuo S, Zhou X, Feng Y, Sun Y, et al. LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40-MDM2-p53 pathway through binding with UBA52. Cancer Sci (2019) 110(4):1194–207. doi: 10.1111/cas.13951

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Ye C, Shen Z, Wang B, Li Y, Li T, Yang Y, et al. A novel long non-coding RNA lnc-GNAT1-1 is low expressed in colorectal cancer and acts as a tumor suppressor through regulating RKIP-NF-kappaB-Snail circuit. J Exp Clin Cancer Res (2016) 35(1):187. doi: 10.1186/s13046-016-0467-z

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Chen B, Dragomir MP, Fabris L, Bayraktar R, Knutsen E, Liu X, et al. The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling. Gastroenterology (2020) 159(6):2146–62 e2133. doi: 10.1053/j.gastro.2020.08.018

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Yu J, Han Z, Sun Z, Wang Y, Zheng M, Song C. LncRNA SLCO4A1-AS1 facilitates growth and metastasis of colorectal cancer through beta-catenin-dependent Wnt pathway. J Exp Clin Cancer Res (2018) 37(1):222. doi: 10.1186/s13046-018-0896-y

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Wu X, Li R, Song Q, Zhang C, Jia R, Han Z, et al. JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing beta-catenin signaling pathway. J Exp Clin Cancer Res (2019) 38(1):435. doi: 10.1186/s13046-019-1439-x

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Song W, Mei JZ, Zhang M. Long Noncoding RNA PlncRNA-1 Promotes Colorectal Cancer Cell Progression by Regulating the PI3K/Akt Signaling Pathway. Oncol Res (2018) 26(2):261–8. doi: 10.3727/096504017X15031557924132

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Meng S, Jian Z, Yan X, Li J, Zhang R. LncRNA SNHG6 inhibits cell proliferation and metastasis by targeting ETS1 via the PI3K/AKT/mTOR pathway in colorectal cancer. Mol Med Rep (2019) 20(3):2541–8. doi: 10.3892/mmr.2019.10510

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Wang Y, Kuang H, Xue J, Liao L, Yin F, Zhou X. LncRNA AB073614 regulates proliferation and metastasis of colorectal cancer cells via the PI3K/AKT signaling pathway. BioMed Pharmacother (2017) 93:1230–7. doi: 10.1016/j.biopha.2017.07.024

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Hu J, Shan Y, Ma J, Pan Y, Zhou H, Jiang L, et al. LncRNA ST3Gal6-AS1/ST3Gal6 axis mediates colorectal cancer progression by regulating alpha-2,3 sialylation via PI3K/Akt signaling. Int J Cancer (2019) 145(2):450–60. doi: 10.1002/ijc.32103

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Bian Z, Zhang J, Li M, Feng Y, Wang X, Zhang J, et al. LncRNA-FEZF1-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling. Clin Cancer Res (2018) 24(19):4808–19. doi: 10.1158/1078-0432.CCR-17-2967

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Tang Y, He Y, Zhang P, Wang J, Fan C, Yang L, et al. LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis. Mol Cancer (2018) 17(1):77. doi: 10.1186/s12943-018-0825-x

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Bin J, Nie S, Tang Z, Kang A, Fu Z, Hu Y, et al. Long noncoding RNA EPB41L4A-AS1 functions as an oncogene byregulating the Rho/ROCK pathway in colorectal cancer. J Cell Physiol (2020) 236(1):523–35. doi: 10.1002/jcp.29880

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Tang R, Chen J, Tang M, Liao Z, Zhou L, Jiang J, et al. LncRNA SLCO4A1-AS1 predicts poor prognosis and promotes proliferation and metastasis via the EGFR/MAPK pathway in colorectal cancer. Int J Biol Sci (2019) 15(13):2885–96. doi: 10.7150/ijbs.38041

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Zhu Y, Chen P, Gao Y, Ta N, Zhang Y, Cai J, et al. MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin. EBio Medicine (2018) 30:148–57. doi: 10.1016/j.ebiom.2018.03.032

CrossRef Full Text | Google Scholar

93. Yan S, Yue Y, Wang J, Li W, Sun M, Gu C, et al. LINC00668 promotes tumorigenesis and progression through sponging miR-188-5p and regulating USP47 in colorectal cancer. Eur J Pharmacol (2019) 858:172464. doi: 10.1016/j.ejphar.2019.172464

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Shan Y, Ma J, Pan Y, Hu J, Liu B, Jia L. LncRNA SNHG7 sponges miR-216b to promote proliferation and liver metastasis of colorectal cancer through upregulating GALNT1. Cell Death Dis (2018) 9(7):722. doi: 10.1038/s41419-018-0759-7

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Xu J, Meng Q, Li X, Yang H, Xu J, Gao N, et al. Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p. Cancer Res (2019) 79(19):4882–95. doi: 10.1158/0008-5472.CAN-18-3880

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Zhang M, Li Y, Wang H, Yu W, Lin S, Guo J. LncRNA SNHG5 affects cell proliferation, metastasis and migration of colorectal cancer through regulating miR-132-3p/CREB5. Cancer Biol Ther (2019) 20(4):524–36. doi: 10.1080/15384047.2018.1537579

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Fang C, Qiu S, Sun F, Li W, Wang Z, Yue B, et al. Long non-coding RNA HNF1A-AS1 mediated repression of miR-34a/SIRT1/p53 feedback loop promotes the metastatic progression of colon cancer by functioning as a competing endogenous RNA. Cancer Lett (2017) 410:50–62. doi: 10.1016/j.canlet.2017.09.012

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Dong X, Yang Z, Yang H, Li D, Qiu X. Long Non-coding RNA MIR4435-2HG Promotes Colorectal Cancer Proliferation and Metastasis Through miR-206/YAP1 Axis. Front Oncol (2020) 10:160. doi: 10.3389/fonc.2020.00160

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Yang Y, Zhang J, Chen X, Xu X, Cao G, Li H, et al. LncRNA FTX sponges miR-215 and inhibits phosphorylation of vimentin for promoting colorectal cancer progression. Gene Ther (2018) 25(5):321–30. doi: 10.1038/s41434-018-0026-7

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Sun J, Hu J, Wang G, Yang Z, Zhao C, Zhang X, et al. LncRNA TUG1 promoted KIAA1199 expression via miR-600 to accelerate cell metastasis and epithelial-mesenchymal transition in colorectal cancer. J Exp Clin Cancer Res (2018) 37(1):106. doi: 10.1186/s13046-018-0771-x

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Li C, Liu T, Zhang Y, Li Q, Jin LK. LncRNA-ZDHHC8P1 promotes the progression and metastasis ofcolorectal cancer by targeting miR-34a. Eur Rev Med Pharmacol Sci (2019) 23(4):1476–86. doi: 10.26355/eurrev_201902_17105

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Xu M, Chen X, Lin K, Zeng K, Liu X, Pan B, et al. The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p. Mol Cancer (2018) 17(1):141. doi: 10.1186/s12943-018-0894-x

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Zhuang M, Zhao S, Jiang Z, Wang S, Sun P, Quan J, et al. MALAT1 sponges miR-106b-5p to promote the invasion and metastasis of colorectal cancer via SLAIN2 enhanced microtubules mobility. EBio Medicine (2019) 41:286–98. doi: 10.1016/j.ebiom.2018.12.049

CrossRef Full Text | Google Scholar

104. Zheng XY, Cao MZ, Ba Y, Li YF, Ye JL. LncRNA testis-specific transcript, Y-linked 15 (TTTY15) promotes proliferation, migration and invasion of colorectal cancer cells via regulating miR-29a-3p/DVL3 axis. Cancer Biomark (2020). doi: 10.3233/CBM-201709

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Zhu X, Bu F, Tan T, Luo Q, Zhu J, Lin K, et al. Long noncoding RNA RP11-757G1.5 sponges miR-139-5p and upregulates YAP1 thereby promoting the proliferation and liver, spleen metastasis of colorectal cancer. J Exp Clin Cancer Res (2020) 39(1):207. doi: 10.1186/s13046-020-01717-5

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Xu M, Xu X, Pan B, Chen X, Lin K, Zeng K, et al. LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2. Mol Cancer (2019) 18(1):135. doi: 10.1186/s12943-019-1063-6

PubMed Abstract | CrossRef Full Text | Google Scholar

107. Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, et al. m(6)A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer (2019) 18(1):87. doi: 10.1186/s12943-019-1014-2

PubMed Abstract | CrossRef Full Text | Google Scholar

108. Zhang W, Yuan W, Song J, Wang S, Gu X. LncRNA CPS1-IT1 suppresses EMT and metastasis of colorectal cancer by inhibiting hypoxia-induced autophagy through inactivation of HIF-1alpha. Biochimie (2018) 144:21–7. doi: 10.1016/j.biochi.2017.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Liang ZX, Liu HS, Wang FW, Xiong L, Zhou C, Hu T, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization. Cell Death Dis (2019) 10(11):829. doi: 10.1038/s41419-019-2077-0

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Di W, Weinan X, Xin L, Zhiwei Y, Xinyue G, Jinxue T, et al. Long noncoding RNA SNHG14 facilitates colorectal cancer metastasis through targeting EZH2-regulated EPHA7. Cell Death Dis (2019) 10(7):514. doi: 10.1038/s41419-019-1707-x

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Ding J, Li J, Wang H, Tian Y, Xie M, He X, et al. Long noncoding RNA CRNDE promotes colorectal cancer cell proliferation via epigenetically silencing DUSP5/CDKN1A expression. Cell Death Dis (2017) 8(8):e2997. doi: 10.1038/cddis.2017.328

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Ji L, Li X, Zhou Z, Zheng Z, Jin L, Jiang F. LINC01413/hnRNP-K/ZEB1 Axis Accelerates Cell Proliferation and EMT in Colorectal Cancer via Inducing YAP1/TAZ1 Translocation. Mol Ther Nucleic Acids (2020) 19:546–61. doi: 10.1016/j.omtn.2019.11.027

PubMed Abstract | CrossRef Full Text | Google Scholar

113. Li H, Jiang X, Niu X. Long Non-Coding RNA Reprogramming (ROR) Promotes Cell Proliferation in Colorectal Cancer via Affecting P53. Med Sci Monit (2017) 23:919–28. doi: 10.12659/MSM.903462

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Sarfi M, Abbastabar M, Khalili E. Long noncoding RNAs biomarker-based cancer assessment. J Cell Physiol (2019) 234(10):16971–86. doi: 10.1002/jcp.28417

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Cheng Y, Wu J, Qin B, Zou BC, Wang YH, Li Y. CREB1-induced lncRNA LEF1-AS1 contributes to colorectal cancer progression via the miR-489/DIAPH1 axis. Biochem Biophys Res Commun (2020) 526(3):678–84. doi: 10.1016/j.bbrc.2020.03.153

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Shi Q, He Y, Zhang X, Li J, Cui G, Zhang X, et al. Two Novel Long Noncoding RNAs - RP11-296E3.2 and LEF1-AS1can - Separately Serve as Diagnostic and Prognostic Bio-Markers of Metastasis in Colorectal Cancer. Med Sci Monit (2019) 25:7042–51. doi: 10.12659/MSM.916314

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Zhu Y, Li B, Liu Z, Jiang L, Wang G, Lv M, et al. Up-regulation of lncRNA SNHG1 indicates poor prognosis and promotes cell proliferation and metastasis of colorectal cancer by activation of the Wnt/beta-catenin signaling pathway. Oncotarget (2017) 8(67):111715–27. doi: 10.18632/oncotarget.22903

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Dacheng W, Songhe L, Weidong J, Shutao Z, Jingjing L, Jiaming Z. LncRNA SNHG3 promotes the growth and metastasis of colorectal cancer by regulating miR-539/RUNX2 axis. BioMed Pharmacother (2020) 125:110039. doi: 10.1016/j.biopha.2020.110039

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Yao X, Lan Z, Lai Q, Li A, Liu S, Wang X. LncRNA SNHG6 plays an oncogenic role in colorectal cancer and can be used as a prognostic biomarker for solid tumors. J Cell Physiol (2020) 235(10):7620–34. doi: 10.1002/jcp.29672

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Yu C, Sun J, Leng X, Yang J. Long noncoding RNA SNHG6 functions as a competing endogenous RNA by sponging miR-181a-5p to regulate E2F5 expression in colorectal cancer. Cancer Manag Res (2019) 11:611–24. doi: 10.2147/CMAR.S182719

PubMed Abstract | CrossRef Full Text | Google Scholar

121. Zhang P, Shi L, Song L, Long Y, Yuan K, Ding W, et al. and lncRNA SNHG7 are Promising Biomarkers for Prognosis in Synchronous Colorectal Liver Metastasis Following Hepatectomy. Cancer Manag Res (2020) 12:1681–92. doi: 10.2147/CMAR.S233147

PubMed Abstract | CrossRef Full Text | Google Scholar

122. Huang L, Lin H, Kang L, Huang P, Huang J, Cai J, et al. Aberrant expression of long noncoding RNA SNHG15 correlates with liver metastasis and poor survival in colorectal cancer. J Cell Physiol (2019) 234(5):7032–9. doi: 10.1002/jcp.27456

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Ma Z, Gu S, Song M, Yan C, Hui B, Ji H, et al. Long non-coding RNA SNHG17 is an unfavourable prognostic factor and promotes cell proliferation by epigenetically silencing P57 in colorectal cancer. Mol Biosyst (2017) 13(11):2350–61. doi: 10.1039/C7MB00280G

PubMed Abstract | CrossRef Full Text | Google Scholar

124. Ding Y, Feng W, Ge JK, Dai L, Liu TT, Hua XY, et al. Serum level of long noncoding RNA B3GALT5-AS1 as a diagnostic biomarker of colorectal cancer. Future Oncol (2020) 16(13):827–35. doi: 10.2217/fon-2019-0820

PubMed Abstract | CrossRef Full Text | Google Scholar

125. Wang L, Wei Z, Wu K, Dai W, Zhang C, Peng J, et al. Long noncoding RNA B3GALT5-AS1 suppresses colon cancer liver metastasis via repressing microRNA-203. Aging (Albany NY) (2018) 10(12):3662–82. doi: 10.18632/aging.101628

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Hong S, Yan Z, Song Y, Bi M, Li S. LncRNA AGAP2-AS1 augments cell viability and mobility, and confers gemcitabine resistance by inhibiting miR-497 in colorectal cancer. Aging (Albany NY) (2020) 12(6):5183–94. doi: 10.18632/aging.102940

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Shen MY, Zhou GR, Z YZ. LncRNA MIR4435-2HG contributes into colorectal cancer developmentand predicts poor prognosis. Eur Rev Med Pharmacol Sci (2020) 24(4):1771–7. doi: 10.26355/eurrev_202002_20354

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Mo S, Zhang L, Dai W, Han L, Wang R, Xiang W, et al. Antisense lncRNA LDLRAD4-AS1 promotes metastasis by decreasing the expression of LDLRAD4 and predicts a poor prognosis in colorectal cancer. Cell Death Dis (2020) 11(2):155. doi: 10.1038/s41419-020-2338-y

PubMed Abstract | CrossRef Full Text | Google Scholar

129. Chen S, Zhang C, Feng M. Prognostic Value of LncRNA HOTAIR in Colorectal Cancer: A Meta-analysis. Open Med (Wars) (2020) 15:76–83. doi: 10.1515/med-2020-0012

PubMed Abstract | CrossRef Full Text | Google Scholar

130. Wu ZH, Wang XL, Tang HM, Jiang T, Chen J, Lu S, et al. Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. Oncol Rep (2014) 32(1):395–402. doi: 10.3892/or.2014.3186

PubMed Abstract | CrossRef Full Text | Google Scholar

131. Ni X, Ding Y, Yuan H, Shao J, Yan Y, Guo R, et al. Long non-coding RNA ZEB1-AS1 promotes colon adenocarcinoma malignant progression via miR-455-3p/PAK2 axis. Cell Prolif (2020) 53(1):e12723. doi: 10.1111/cpr.12723

PubMed Abstract | CrossRef Full Text | Google Scholar

132. Ni B, Yu X, Guo X, Fan X, Yang Z, Wu P, et al. Increased urothelial cancer associated 1 is associated with tumor proliferation and metastasis and predicts poor prognosis in colorectal cancer. Int J Oncol (2015) 47(4):1329–38. doi: 10.3892/ijo.2015.3109

PubMed Abstract | CrossRef Full Text | Google Scholar

133. Liu X, Liu X, Qiao T, Chen W. Prognostic and clinicopathological significance of long non-coding RNA UCA1 in colorectal cancer: Results from a meta-analysis. Med (Baltimore) (2019) 98(48):e18031. doi: 10.1097/MD.0000000000018031

CrossRef Full Text | Google Scholar

134. Lu C, Xie T, Guo X, Wu D, Li S, Li X, et al. LncRNA DSCAM-AS1 Promotes Colon Cancer Cells Proliferation andMigration via Regulating the miR-204/SOX4 Axis. Cancer Manag Res (2020) 12:4347–56. doi: 10.2147/CMAR.S250670

PubMed Abstract | CrossRef Full Text | Google Scholar

135. Jiang X, Zhu Q, Wu P, Zhou F, Chen J. Upregulated Long Noncoding RNA LINC01234 Predicts Unfavorable Prognosis for Colorectal Cancer and Negatively Correlates With KLF6 Expression. Ann Lab Med (2020) 40(2):155–63. doi: 10.3343/alm.2020.40.2.155

PubMed Abstract | CrossRef Full Text | Google Scholar

136. Zhang H, Lu Y, Wu J, Feng J. LINC00460 Hypomethylation Promotes Metastasis in Colorectal Carcinoma. Front Genet (2019) 10:880. doi: 10.3389/fgene.2019.00880

PubMed Abstract | CrossRef Full Text | Google Scholar

137. Zhang Y, Liu X, Li Q, Zhang Y. lncRNA LINC00460 promoted colorectal cancer cells metastasis via miR-939-5p sponging. Cancer Manag Res (2019) 11:1779–89. doi: 10.2147/CMAR.S192452

PubMed Abstract | CrossRef Full Text | Google Scholar

138. Wang X, Mo FM, Bo H, Xiao L, Chen GY, Zeng PW, et al. Upregulated Expression of Long Non-Coding RNA, LINC00460, Suppresses Proliferation of Colorectal Cancer. J Cancer (2018) 9(16):2834–43. doi: 10.7150/jca.26046

PubMed Abstract | CrossRef Full Text | Google Scholar

139. Lian Y, Yan C, Xu H, Yang J, Yu Y, Zhou J, et al. A Novel lncRNA, LINC00460, Affects Cell Proliferation and Apoptosis by Regulating KLF2 and CUL4A Expression in Colorectal Cancer. Mol Ther Nucleic Acids (2018) 12:684–97. doi: 10.1016/j.omtn.2018.06.012

PubMed Abstract | CrossRef Full Text | Google Scholar

140. Duan Y, Fang Z, Shi Z, Zhang L. Knockdown of lncRNA CCEPR suppresses colorectal cancer progression. Exp Ther Med (2019) 18(5):3534–42. doi: 10.3892/etm.2019.7942

PubMed Abstract | CrossRef Full Text | Google Scholar

141. Li C, Tang T, Wang W. Effect of LncRNA MIAT on Prognosis of Hand-assisted Laparoscopic or Laparoscopic-assisted Colectomy for Colorectal Cancer. Surg Laparosc Endosc Percutan Tech (2019) 29(6):456–61. doi: 10.1097/SLE.0000000000000728

PubMed Abstract | CrossRef Full Text | Google Scholar

142. Zhang XT, Pan SX, Wang AH, Kong QY, Jiang KT, Yu ZB, et al. Non-Coding RNA (lncRNA) X-Inactive Specific Transcript (XIST) Plays a Critical Role in Predicting Clinical Prognosis and Progression of Colorectal Cancer. Med Sci Monit (2019) 25:6429–35. doi: 10.12659/MSM.915329

PubMed Abstract | CrossRef Full Text | Google Scholar

143. Ren Y, Zhao C, He Y, Xu H, Min X. Long non-coding RNA bladder cancer-associated transcript 2 contributes to disease progression, chemoresistance and poor survival of patients with colorectal cancer. Oncol Lett (2019) 18(2):2050–8. doi: 10.3892/ol.2019.10487

PubMed Abstract | CrossRef Full Text | Google Scholar

144. Tian JB, Cao L, Dong GL. Long noncoding RNA DDX11-AS1 induced by YY1 accelerates colorectalcancer progression through targeting miR-873/CLDN7 axis. Eur Rev Med Pharmacol Sci (2019) 23(13):5714–29. doi: 10.26355/eurrev_201907_18309

PubMed Abstract | CrossRef Full Text | Google Scholar

145. Zhong ME, Chen Y, Zhang G, Xu L, Ge W, Wu B. LncRNA H19 regulates PI3K-Akt signal pathway by functioning as a ceRNA and predicts poor prognosis in colorectal cancer: integrative analysis of dysregulated ncRNA-associated ceRNA network. Cancer Cell Int (2019) 19:148. doi: 10.1186/s12935-019-0866-2

PubMed Abstract | CrossRef Full Text | Google Scholar

146. Li CF, Li YC, Wang Y, Sun LB. The Effect of LncRNA H19/miR-194-5p Axis on the Epithelial-Mesenchymal Transition of Colorectal Adenocarcinoma. Cell Physiol Biochem (2018) 50(1):196–213. doi: 10.1159/000493968

PubMed Abstract | CrossRef Full Text | Google Scholar

147. Li M, Wang Q, Xue F, Wu Y. lncRNA-CYTOR Works as an Oncogene Through the CYTOR/miR-3679-5p/MACC1 Axis in Colorectal Cancer. DNA Cell Biol (2019) 38(6):572–82. doi: 10.1089/dna.2018.4548

PubMed Abstract | CrossRef Full Text | Google Scholar

148. Wang X, Chen X, Zhou H, Qian Y, Han N, Tian X, et al. The Long Noncoding RNA, LINC01555, Promotes Invasion and Metastasis of Colorectal Cancer by Activating the Neuropeptide, Neuromedin U. Med Sci Monit (2019) 25:4014–24. doi: 10.12659/MSM.916508

PubMed Abstract | CrossRef Full Text | Google Scholar

149. Wang XD, Lu J, Lin YS, Gao C, Qi F. Functional role of long non-coding RNA CASC19/miR-140-5p/CEMIP axis in colorectal cancer progression in vitro. World J Gastroenterol (2019) 25(14):1697–714. doi: 10.3748/wjg.v25.i14.1697

PubMed Abstract | CrossRef Full Text | Google Scholar

150. Sha QK, Chen L, Xi JZ, Song H. Long non-coding RNA LINC00858 promotes cells proliferation, migration and invasion by acting as a ceRNA of miR-22-3p in colorectal cancer. Artif Cells Nanomed Biotechnol (2019) 47(1):1057–66. doi: 10.1080/21691401.2018.1544143

PubMed Abstract | CrossRef Full Text | Google Scholar

151. Chen G, Gu Y, Han P, Li Z, Zhao JL, Gao MZ. Long noncoding RNA SBF2-AS1 promotes colorectal cancer proliferation and invasion by inhibiting miR-619-5p activity and facilitating HDAC3 expression. J Cell Physiol (2019) 234(10):18688–96. doi: 10.1002/jcp.28509

PubMed Abstract | CrossRef Full Text | Google Scholar

152. Wang Q, He R, Tan T, Li J, Hu Z, Luo W, et al. A novel long non-coding RNA-KAT7 is low expressed in colorectal cancer and acts as a tumor suppressor. Cancer Cell Int (2019) 19:40. doi: 10.1186/s12935-019-0760-y

PubMed Abstract | CrossRef Full Text | Google Scholar

153. Wang YQ, Jiang DM, Hu SS, Zhao L, Wang L, Yang MH, et al. SATB2-AS1 Suppresses Colorectal Carcinoma Aggressiveness by Inhibiting SATB2-Dependent Snail Transcription and Epithelial-Mesenchymal Transition. Cancer Res (2019) 79(14):3542–56. doi: 10.1158/0008-5472.CAN-18-2900

PubMed Abstract | CrossRef Full Text | Google Scholar

154. Yu S, Wang D, Shao Y, Zhang T, Xie H, Jiang X, et al. SP1-induced lncRNA TINCR overexpression contributes to colorectal cancer progression by sponging miR-7-5p. Aging (Albany NY) (2019) 11(5):1389–403. doi: 10.18632/aging.101839

PubMed Abstract | CrossRef Full Text | Google Scholar

155. Jiang X, Li Q, Zhang S, Song C, Zheng P. Long noncoding RNA GIHCG induces cancer progression and chemoresistance and indicates poor prognosis in colorectal cancer. Onco Targets Ther (2019) 12:1059–70. doi: 10.2147/OTT.S192290

PubMed Abstract | CrossRef Full Text | Google Scholar

156. Huang H, Cai L, Li R, Ye L, Chen Z. A novel lncRNA LOC101927746 accelerates progression of colorectal cancer via inhibiting miR-584-3p and activating SSRP1. Biochem Biophys Res Commun (2019) 509(3):734–8. doi: 10.1016/j.bbrc.2018.12.174

PubMed Abstract | CrossRef Full Text | Google Scholar

157. Yan Y, Wang Z, Qin B. A novel long noncoding RNA, LINC00483 promotes proliferation and metastasis via modulating of FMNL2 in CRC. Biochem Biophys Res Commun (2019) 509(2):441–7. doi: 10.1016/j.bbrc.2018.12.090

PubMed Abstract | CrossRef Full Text | Google Scholar

158. Li R, Zhu H, Yang D, Xia J, Zheng Z. Long noncoding RNA lncBRM promotes proliferation and invasion of colorectal cancer by sponging miR-204-3p and upregulating TPT1. Biochem Biophys Res Commun (2019) 508(4):1259–63. doi: 10.1016/j.bbrc.2018.12.053

PubMed Abstract | CrossRef Full Text | Google Scholar

159. Dong Y, Wei MH, Lu JG, Bi CY. Long non-coding RNA HULC interacts with miR-613 to regulate colon cancer growth and metastasis through targeting RTKN. BioMed Pharmacother (2019) 109:2035–42. doi: 10.1016/j.biopha.2018.08.017

PubMed Abstract | CrossRef Full Text | Google Scholar

160. Wang FW, Cao CH, Han K, Zhao YX, Cai MY, Xiang ZC, et al. APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production. J Clin Invest (2019) 129(2):727–43. doi: 10.1172/JCI122478

PubMed Abstract | CrossRef Full Text | Google Scholar

161. Lao Y, Li Q, Li N, Liu H, Liu K, Jiang G, et al. Long noncoding RNA ENST00000455974 plays an oncogenic role through up-regulating JAG2 in human DNA mismatch repair-proficient colon cancer. Biochem Biophys Res Commun (2019) 508(2):339–47. doi: 10.1016/j.bbrc.2018.11.088

PubMed Abstract | CrossRef Full Text | Google Scholar

162. Zhang R, Li JB, Yan XF, Jin K, Li WY, Xu J, et al. Increased EWSAT1 expression promotes cell proliferation, invasionand epithelial-mesenchymal transition in colorectal cancer. Eur Rev Med Pharmacol Sci (2018) 22(20):6801–8. doi: 10.26355/eurrev_201810_16146

PubMed Abstract | CrossRef Full Text | Google Scholar

163. Lei Y, Wang YH, Wang XF, Bai J. LINC00657 promotes the development of colon cancer by activatingPI3K/AKT pathway. Eur Rev Med Pharmacol Sci (2018)22(19):6315–23. doi: 10.26355/eurrev_201810_16042

PubMed Abstract | CrossRef Full Text | Google Scholar

164. Rui Y, Hu M, Wang P, Zhang C, Xu H, Li Y, et al. LncRNA HOTTIP mediated DKK1 downregulation confers metastasis andinvasion in colorectal cancer cells. Histol Histo pathol (2019) 34(6):619–30. doi: 10.14670/HH-18-043

CrossRef Full Text | Google Scholar

165. Ren YK, Xiao Y, Wan XB, Zhao YZ, Li J, Li Y, et al. Association of long non-coding RNA HOTTIP with progression and prognosis in colorectal cancer. Int J Clin Exp Pathol (2015) 8(9):11458–63.

PubMed Abstract | Google Scholar

166. Zhong X, Lu M, Wan J, Zhou T, Qin B. Long noncoding RNA kcna3 inhibits the progression of colorectal carcinoma through down-regulating YAP1 expression. BioMed Pharmacother (2018) 107:382–9. doi: 10.1016/j.biopha.2018.07.118

PubMed Abstract | CrossRef Full Text | Google Scholar

167. Zhou J, Lin J, Zhang H, Zhu F, Xie R. LncRNA HAND2-AS1 sponging miR-1275 suppresses colorectal cancer progression by upregulating KLF14. Biochem Biophys Res Commun (2018) 503(3):1848–53. doi: 10.1016/j.bbrc.2018.07.125

PubMed Abstract | CrossRef Full Text | Google Scholar

168. Cheng K, Zhao Z, Wang G, Wang J, Zhu W. lncRNA GAS5 inhibits colorectal cancer cell proliferation via the miR1825p/FOXO3a axis. Oncol Rep (2018) 40(4):2371–80. doi: 10.3892/or.2018.6584

PubMed Abstract | CrossRef Full Text | Google Scholar

169. Liu L, Meng T, Yang XH, Sayim P, Lei C, Jin B, et al. Prognostic and predictive value of long non-coding RNA GAS5 and mircoRNA-221 in colorectal cancer and their effects on colorectal cancer cell proliferation, migration and invasion. Cancer Biomark (2018) 22(2):283–99. doi: 10.3233/CBM-171011

PubMed Abstract | CrossRef Full Text | Google Scholar

170. Yang Y, Shen Z, Yan Y, Wang B, Zhang J, Shen C, et al. Long non-coding RNA GAS5 inhibits cell proliferation, induces G0/G1 arrest and apoptosis, and functions as a prognostic marker in colorectal cancer. Oncol Lett (2017) 13(5):3151–8. doi: 10.3892/ol.2017.5841

PubMed Abstract | CrossRef Full Text | Google Scholar

171. Li J, Wang Y, Zhang CG, Xiao HJ, Xiao HJ, Hu JM, et al. Effect of long non-coding RNA Gas5 on proliferation, migration, invasion and apoptosis of colorectal cancer HT-29 cell line. Cancer Cell Int (2018) 18:4. doi: 10.1186/s12935-018-0510-6

PubMed Abstract | CrossRef Full Text | Google Scholar

172. Li C, Li W, Zhang Y, Zhang X, Liu T, Zhang Y, et al. Increased expression of antisense lncRNA SPINT1-AS1 predicts a poor prognosis in colorectal cancer and is negatively correlated with its sense transcript. Onco Targets Ther (2018) 11:3969–78. doi: 10.2147/OTT.S163883

PubMed Abstract | CrossRef Full Text | Google Scholar

173. Yu X, Yuan Z, Yang Z, Chen D, Kim T, Cui Y, et al. The novel long noncoding RNA u50535 promotes colorectal cancer growth and metastasis by regulating CCL20. Cell Death Dis (2018) 9(7):751. doi: 10.1038/s41419-018-0771-y

PubMed Abstract | CrossRef Full Text | Google Scholar

174. Jing N, Huang T, Guo H, Yang J, Li M, Chen Z, et al. LncRNA CASC15 promotes colon cancer cell proliferation and metastasis by regulating the miR4310/LGR5/Wnt/betacatenin signaling pathway. Mol Med Rep (2018) 18(2):2269–76. doi: 10.3892/mmr.2018.9191

PubMed Abstract | CrossRef Full Text | Google Scholar

175. Zhang XF, Zhang Y, Shen Z, Yang GG, Wang HD, Li LF, et al. LncRNALUADT1 is overexpressed in colorectal cancer and itsexpression level is related to clinicopathology. Eur Rev Med Pharmacol Sci (2018) 22(8):2282–6. doi: 10.26355/eurrev_201804_14816

PubMed Abstract | CrossRef Full Text | Google Scholar

176. Li X, Zhao X, Yang B, Li Y, Liu T, Pang L, et al. Long non-coding RNA HOXD-AS1 promotes tumor progression and predicts poor prognosis in colorectal cancer. Int J Oncol (2018) 53(1):21–32. doi: 10.3892/ijo.2018.4400

PubMed Abstract | CrossRef Full Text | Google Scholar

177. Wang Y, Lu Z, Wang N, Feng J, Zhang J, Luan L, et al. Long noncoding RNA DANCR promotes colorectal cancer proliferation and metastasis via miR-577 sponging. Exp Mol Med (2018) 50(5):1–17. doi: 10.1038/s12276-018-0082-5

CrossRef Full Text | Google Scholar

178. Liu Y, Zhang M, Liang L, Li J, Chen YX. Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol (2015) 8(9):11480–4.

PubMed Abstract | Google Scholar

179. Wang X, Liu F, Liu X, Wang F, Liao X, Chen Y, et al. Long non-coding RNA expression profiles reveals AK098783 is a biomarker to predict poor prognosis in patients with colorectal cancer. Jpn J Clin Oncol (2018) 48(5):480–4. doi: 10.1093/jjco/hyy037

PubMed Abstract | CrossRef Full Text | Google Scholar

180. Yu X, Zhao J, He Y. Long non-coding RNA PVT1 functions as an oncogene in human colon cancer through miR-30d-5p/RUNX2 axis. J BUON (2018) 23(1):48–54.

PubMed Abstract | Google Scholar

181. Fan H, Zhu JH, Yao XQ. Long non-coding RNA PVT1 as a novel potential biomarker for predicting the prognosis of colorectal cancer. Int J Biol Markers (2018) 33(4):415–22. doi: 10.1177/1724600818777242

PubMed Abstract | CrossRef Full Text | Google Scholar

182. Wang C, Zhu X, Pu C, Song X. Upregulated plasmacytoma variant translocation 1 promotes cell proliferation, invasion and metastasis in colorectal cancer. Mol Med Rep (2018) 17(5):6598–604. doi: 10.3892/mmr.2018.8669

PubMed Abstract | CrossRef Full Text | Google Scholar

183. Feng LM, Zhao DW, Li SJ, Huang J. Association of the upregulation of LncRNA00673 with poor prognosisfor colorectal cancer. Eur Rev Med Pharmacol Sci (2018) 22(3):687–94. doi: 10.26355/eurrev_201802_14294

PubMed Abstract | CrossRef Full Text | Google Scholar

184. Li Y, Zhao L, Zhang Y, Guan L, Zhang H, Zhou H, et al. Downregulation of the long non-coding RNA XLOC_010588 inhibits the invasion and migration of colorectal cancer. Oncol Rep (2018) 39(4):1619–30. doi: 10.3892/or.2018.6260

PubMed Abstract | CrossRef Full Text | Google Scholar

185. Liu XB, Han C, Sun CZ. Long non-coding RNA DLEU7-AS1 promotes the occurrence anddevelopment of colorectal cancer via Wnt/beta-catenin pathway. Eur Rev Med Pharmacol Sci (2018) 22(1):110–7. doi: 10.26355/eurrev-201801-14107

PubMed Abstract | CrossRef Full Text | Google Scholar

186. Li T, Zhu J, Wang X, Chen G, Sun L, Zuo S, et al. Long non-coding RNA lncTCF7 activates the Wnt/beta-catenin pathway to promote metastasis and invasion in colorectal cancer. Oncol Lett (2017) 14(6):7384–90. doi: 10.3892/ol.2017.7154

PubMed Abstract | CrossRef Full Text | Google Scholar

187. Xiong Y, Wang J, Zhu H, Liu L, Jiang Y. Chronic oxymatrine treatment induces resistance and epithelialmesenchymal transition through targeting the long non-coding RNA MALAT1 in colorectal cancer cells. Oncol Rep (2018) 39(3):967–76. doi: 10.3892/or.2018.6204

PubMed Abstract | CrossRef Full Text | Google Scholar

188. Sun ZQ, Chen C, Zhou QB, Liu JB, Yang SX, Li Z, et al. Long non-coding RNA LINC00959 predicts colorectal cancer patient prognosis and inhibits tumor progression. Oncotarget (2017) 8(57):97052–60. doi: 10.18632/oncotarget.21171

PubMed Abstract | CrossRef Full Text | Google Scholar

189. Wu S, Liu J, Wang X, Li M, Chen Z, Tang Y. Aberrant Expression of the Long Non-coding RNA GHRLOS and Its Prognostic Significance in Patients with Colorectal Cancer. J Cancer (2017) 8(19):4040–7. doi: 10.7150/jca.21304

PubMed Abstract | CrossRef Full Text | Google Scholar

190. Zhang J, Jiang Y, Zhu J, Wu T, Ma J, Du C, et al. Overexpression of long non-coding RNA colon cancer-associated transcript 2 is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. Oncol Lett (2017) 14(6):6907–14. doi: 10.3892/ol.2017.7049

PubMed Abstract | CrossRef Full Text | Google Scholar

191. Xie S, Ge Q, Wang X, Sun X, Kang Y. Long non-coding RNA ZFAS1 sponges miR-484 to promote cell proliferation and invasion in colorectal cancer. Cell Cycle (2018) 17(2):154–61. doi: 10.1080/15384101.2017.1407895

PubMed Abstract | CrossRef Full Text | Google Scholar

192. Wang W, Xing C. Upregulation of long noncoding RNA ZFAS1 predicts poor prognosis and prompts invasion and metastasis in colorectal cancer. Pathol Res Pract (2016) 212(8):690–5. doi: 10.1016/j.prp.2016.05.003

PubMed Abstract | CrossRef Full Text | Google Scholar

193. Shen X, Bai Y, Luo B, Zhou X. Upregulation of lncRNA BANCR associated with the lymph node metastasis and poor prognosis in colorectal cancer. Biol Res (2017) 50(1):32. doi: 10.1186/s40659-017-0136-5

PubMed Abstract | CrossRef Full Text | Google Scholar

194. Fu J, Cui Y. Long noncoding RNA ZEB1-AS1 expression predicts progression and poor prognosis of colorectal cancer. Int J Biol Markers (2017) 32(4):e428–33. doi: 10.5301/ijbm.5000303

PubMed Abstract | CrossRef Full Text | Google Scholar

195. Lin J, Tan X, Qiu L, Huang L, Zhou Y, Pan Z, et al. Long Noncoding RNA BC032913 as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3. Mol Ther Nucleic Acids (2017) 8:469–81. doi: 10.1016/j.omtn.2017.07.009

PubMed Abstract | CrossRef Full Text | Google Scholar

196. Zhang JH, Li AY, Wei N. Downregulation of long non-coding RNA LINC01133 is predictive of poor prognosis in colorectal cancer patients. Eur Rev Med Pharmacol Sci (2017) 21(9):2103–7.

PubMed Abstract | Google Scholar

197. Huang FT, Chen WY, Gu ZQ, Zhuang YY, Li CQ, Wang LY, et al. The novel long intergenic noncoding RNA UCC promotes colorectal cancer progression by sponging miR-143. Cell Death Dis (2017) 8(5):e2778. doi: 10.1038/cddis.2017.191

PubMed Abstract | CrossRef Full Text | Google Scholar

198. Gao X, Wen J, Gao P, Zhang G, Zhang G. Overexpression of the long non-coding RNA, linc-UBC1, is associated with poor prognosis and facilitates cell proliferation, migration, and invasion in colorectal cancer. Onco Targets Ther (2017) 10:1017–26. doi: 10.2147/OTT.S129343

PubMed Abstract | CrossRef Full Text | Google Scholar

199. Li X, Wang F, Sun Y, Fan Q, Cui G. Expression of long non-coding RNA PANDAR and its prognostic value in colorectal cancer patients. Int J Biol Markers (2017) 32(2):e218–23. doi: 10.5301/jbm.5000249

PubMed Abstract | CrossRef Full Text | Google Scholar

200. Lu M, Liu Z, Li B, Wang G, Li D, Zhu Y. The high expression of long non-coding RNA PANDAR indicates a poor prognosis for colorectal cancer and promotes metastasis by EMT pathway. J Cancer Res Clin Oncol (2017) 143(1):71–81. doi: 10.1007/s00432-016-2252-y

PubMed Abstract | CrossRef Full Text | Google Scholar

201. Wang Q, Yang L, Hu X, Jiang Y, Hu Y, Liu Z, et al. Upregulated NNT-AS1, a long noncoding RNA, contributes to proliferation and migration of colorectal cancer cells in vitro and in vivo. Oncotarget (2017) 8(2):3441–53. doi: 10.18632/oncotarget.13840

PubMed Abstract | CrossRef Full Text | Google Scholar

202. Zhou DK, Yang XW, Li H, Yang Y, Zhu ZJ, Wu N. Up-regulation of long noncoding RNA CCAL predicts poor patient prognosis and promotes tumor metastasis in osteosarcoma. Int J Biol Markers (2017) 32(1):e108–12. doi: 10.5301/jbm.5000240

PubMed Abstract | CrossRef Full Text | Google Scholar

203. Liu T, Zhang X, Gao S, Jing F, Yang Y, Du L, et al. Exosomal long noncoding RNA CRNDE-h as a novel serum-based biomarker for diagnosis and prognosis of colorectal cancer. Oncotarget (2016) 7(51):85551–63. doi: 10.18632/oncotarget.13465

PubMed Abstract | CrossRef Full Text | Google Scholar

204. Liu T, Zhang X, Yang YM, Du LT, Wang CX. Increased expression of the long noncoding RNA CRNDE-h indicates a poor prognosis in colorectal cancer, and is positively correlated with IRX5 mRNA expression. Onco Targets Ther (2016) 9:1437–48. doi: 10.2147/OTT.S98268

PubMed Abstract | CrossRef Full Text | Google Scholar

205. Yang L, Wei H, Xiao HJ. Long non-coding RNA Loc554202 expression as a prognostic factor in patients with colorectal cancer. Eur Rev Med Pharmacol Sci (2016) 20(20):4243–7.

PubMed Abstract | Google Scholar

206. Cao D, Ding Q, Yu W, Gao M, Wang Y. Long noncoding RNA SPRY4-IT1 promotes malignant development of colorectal cancer by targeting epithelial-mesenchymal transition. Onco Targets Ther (2016) 9:5417–25. doi: 10.2147/OTT.S111794

PubMed Abstract | CrossRef Full Text | Google Scholar

207. Sun Z, Ou C, Ren W, Xie X, Li X, Li G. Downregulation of long non-coding RNA ANRIL suppresses lymphangiogenesis and lymphatic metastasis in colorectal cancer. Oncotarget (2016) 7(30):47536–55. doi: 10.18632/oncotarget.9868

PubMed Abstract | CrossRef Full Text | Google Scholar

208. Wang F, Ni H, Sun F, Li M, Chen L. Overexpression of lncRNA AFAP1-AS1 correlates with poor prognosis and promotes tumorigenesis in colorectal cancer. BioMed Pharmacother (2016) 81:152–9. doi: 10.1016/j.biopha.2016.04.009

PubMed Abstract | CrossRef Full Text | Google Scholar

209. Yang P, Chen T, Xu Z, Zhu H, Wang J, He Z. Long noncoding RNA GAPLINC promotes invasion in colorectal cancer by targeting SNAI2 through binding with PSF and NONO. Oncotarget (2016) 7(27):42183–94. doi: 10.18632/oncotarget.9741

PubMed Abstract | CrossRef Full Text | Google Scholar

210. Zhou P, Sun L, Liu D, Liu C, Sun L. Long Non-Coding RNA lincRNA-ROR Promotes the Progression of Colon Cancer and Holds Prognostic Value by Associating with miR-145. Pathol Oncol Res (2016) 22(4):733–40. doi: 10.1007/s12253-016-0061-x

PubMed Abstract | CrossRef Full Text | Google Scholar

211. Sun J, Ding C, Yang Z, Liu T, Zhang X, Zhao C, et al. The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition. J Transl Med (2016) 14:42. doi: 10.1186/s12967-016-0786-z

PubMed Abstract | CrossRef Full Text | Google Scholar

212. Chen N, Guo D, Xu Q, Yang M, Wang D, Peng M, et al. Long non-coding RNA FEZF1-AS1 facilitates cell proliferation and migration in colorectal carcinoma. Oncotarget (2016) 7(10):11271–83. doi: 10.18632/oncotarget.7168

PubMed Abstract | CrossRef Full Text | Google Scholar

213. Yue B, Qiu S, Zhao S, Liu C, Zhang D, Yu F, et al. LncRNA-ATB mediated E-cadherin repression promotes the progression of colon cancer and predicts poor prognosis. J Gastroenterol Hepatol (2016) 31(3):595–603. doi: 10.1111/jgh.13206

PubMed Abstract | CrossRef Full Text | Google Scholar

214. Iguchi T, Uchi R, Nambara S, Saito T, Komatsu H, Hirata H, et al. A long noncoding RNA, lncRNA-ATB, is involved in the progression and prognosis of colorectal cancer. Anticancer Res (2015) 35(3):1385–8.

PubMed Abstract | Google Scholar

215. Li Y, Li Y, Chen W, He F, Tan Z, Zheng J, et al. NEAT expression is associated with tumor recurrence and unfavorable prognosis in colorectal cancer. Oncotarget (2015) 6(29):27641–50. doi: 10.18632/oncotarget.4737

PubMed Abstract | CrossRef Full Text | Google Scholar

216. Yue B, Sun B, Liu C, Zhao S, Zhang D, Yu F, et al. Long non-coding RNA Fer-1-like protein 4 suppresses oncogenesis and exhibits prognostic value by associating with miR-106a-5p in colon cancer. Cancer Sci (2015) 106(10):1323–32. doi: 10.1111/cas.12759

PubMed Abstract | CrossRef Full Text | Google Scholar

217. Ye LC, Ren L, Qiu JJ, Zhu DX, Chen T, Chang WJ, et al. Aberrant expression of long noncoding RNAs in colorectal cancer with liver metastasis. Tumour Biol (2015) 36(11):8747–54. doi: 10.1007/s13277-015-3627-4

PubMed Abstract | CrossRef Full Text | Google Scholar

218. Yin DD, Liu ZJ, Zhang E, Kong R, Zhang ZH, Guo RH. Decreased expression of long noncoding RNA MEG3 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Tumour Biol (2015) 36(6):4851–9. doi: 10.1007/s13277-015-3139-2

PubMed Abstract | CrossRef Full Text | Google Scholar

219. Shi D, Zheng H, Zhuo C, Peng J, Li D, Xu Y, et al. Low expression of novel lncRNA RP11-462C24.1 suggests a biomarker of poor prognosis in colorectal cancer. Med Oncol (2014) 31(7):31. doi: 10.1007/s12032-014-0031-7

PubMed Abstract | CrossRef Full Text | Google Scholar

220. Qi P, Xu MD, Ni SJ, Huang D, Wei P, Tan C, et al. Low expression of LOC285194 is associated with poor prognosis in colorectal cancer. J Transl Med (2013) 11:122. doi: 10.1186/1479-5876-11-122

PubMed Abstract | CrossRef Full Text | Google Scholar

221. Ge X, Chen Y, Liao X, Liu D, Li F, Ruan H, et al. Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer. Med Oncol (2013) 30(2):588. doi: 10.1007/s12032-013-0588-6

PubMed Abstract | CrossRef Full Text | Google Scholar

222. Xu W, Zhou G, Wang H, Liu Y, Chen B, Chen W, et al. Circulating lncRNA SNHG11 as a novel biomarker for early diagnosis and prognosis of colorectal cancer. Int J Cancer (2020) 146(10):2901–12. doi: 10.1002/ijc.32747

PubMed Abstract | CrossRef Full Text | Google Scholar

223. Pan X, Cheng R, Zhu X, Cai F, Zheng G, Li J, et al. Prognostic Significance and Diagnostic Value of Overexpressed lncRNAPVT1 in Colorectal Cancer. Clin Lab (2019) 65(12):2279–88. doi: 10.7754/Clin.Lab.2019.190412

CrossRef Full Text | Google Scholar

224. Li Y, Egranov SD, Yang L, Lin C. Molecular mechanisms of long noncoding RNAs-mediated cancer metastasis. Genes Chromosomes Cancer (2019) 58(4):200–7. doi: 10.1002/gcc.22691

PubMed Abstract | CrossRef Full Text | Google Scholar

225. Li C, Tan F, Pei Q, Zhou Z, Zhou Y, Zhang L, et al. Non-coding RNA MFI2-AS1 promotes colorectal cancer cell proliferation, migration and invasion through miR-574-5p/MYCBP axis. Cell Prolif (2019) 52(4):e12632. doi: 10.1111/cpr.12632

PubMed Abstract | CrossRef Full Text | Google Scholar

226. Chen DL, Chen LZ, Lu YX, Zhang DS, Zeng ZL, Pan ZZ, et al. Long noncoding RNA XIST expedites metastasis and modulates epithelial-mesenchymal transition in colorectal cancer. Cell Death Dis (2017) 8(8):e3011. doi: 10.1038/cddis.2017.421

PubMed Abstract | CrossRef Full Text | Google Scholar

227. Bermudez M, Aguilar-Medina M, Lizarraga-Verdugo E, Avendano-Felix M, Silva-Benitez E, Lopez-Camarillo C, et al. LncRNAs as Regulators of Autophagy and Drug Resistance in Colorectal Cancer. Front Oncol (2019) 9:1008. doi: 10.3389/fonc.2019.01008

PubMed Abstract | CrossRef Full Text | Google Scholar

228. Tang D, Yang Z, Long F, Luo L, Yang B, Zhu R, et al. Inhibition of MALAT1 reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer. Cell Signal (2019) 57:21–8. doi: 10.1016/j.cellsig.2019.01.013

PubMed Abstract | CrossRef Full Text | Google Scholar

229. Fan C, Yuan Q, Liu G, Zhang Y, Yan M, Sun Q, et al. Long non-coding RNA MALAT1 regulates oxaliplatin-resistance via miR-324-3p/ADAM17 axis in colorectal cancer cells. Cancer Cell Int (2020) 20:473. doi: 10.1186/s12935-020-01549-5

PubMed Abstract | CrossRef Full Text | Google Scholar

230. Sun F, Liang W, Qian J. The identification of CRNDE, H19, UCA1 and HOTAIR as the key lncRNAs involved in oxaliplatin or irinotecan resistance in the chemotherapy of colorectal cancer based on integrative bioinformatics analysis. Mol Med Rep (2019) 20(4):3583–96. doi: 10.3892/mmr.2019.10588

PubMed Abstract | CrossRef Full Text | Google Scholar

231. Peng K, Liu R, Yu Y, Liang L, Yu S, Xu X, et al. Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer. BioMed Pharmacother (2018) 97:1138–46. doi: 10.1016/j.biopha.2017.11.031

PubMed Abstract | CrossRef Full Text | Google Scholar

232. Wang L, Zhang X, Sheng L, Qiu C, Luo R. LINC00473 promotes the Taxol resistance via miR-15a in colorectalcancer. Biosci Rep (2018) 38(5):BSR20180790. doi: 10.1042/BSR20180790

PubMed Abstract | CrossRef Full Text | Google Scholar

233. Wang ST, Cui WQ, Pan D, Jiang M, Chang B, Sang LX. Tea polyphenols and their chemopreventive and therapeutic effects on colorectal cancer. World J Gastroenterol (2020) 26(6):562–97. doi: 10.3748/wjg.v26.i6.562

PubMed Abstract | CrossRef Full Text | Google Scholar

234. Fu Y, Zhang Y, Cui J, Yang G, Peng S, Mi W, et al. SNP rs12982687 affects binding capacity of lncRNA UCA1 with miR-873-5p: involvement in smoking-triggered colorectal cancer progression. Cell Commun Signal (2020) 18(1):37. doi: 10.1186/s12964-020-0518-0

PubMed Abstract | CrossRef Full Text | Google Scholar

235. Rescigno T, Micolucci L, Tecce MF, Capasso A. Bioactive Nutrients and Nutrigenomics in Age-Related Diseases. Molecules (2017) 22(1):105. doi: 10.3390/molecules22010105

CrossRef Full Text | Google Scholar

236. Shen X, Xue Y, Cong H, Wang X, Fan Z, Cui X, et al. Circulating lncRNA DANCR as a potential auxillary biomarker for thediagnosis and prognostic prediction of colorectal cancer. Biosci Rep (2020) 40(3):BSR20191481. doi: 10.1042/BSR20191481

PubMed Abstract | CrossRef Full Text | Google Scholar

237. Liu R, Zhang Q, Shen L, Chen S, He J, Wang D, et al. Long noncoding RNA lnc-RI regulates DNA damage repair and radiation sensitivity of CRC cells through NHEJ pathway. Cell Biol Toxicol (2020) 36(5):493–507. doi: 10.1007/s10565-020-09524-6

PubMed Abstract | CrossRef Full Text | Google Scholar

238. Wu H, Wei M, Jiang X, Tan J, Xu W, Fan X, et al. lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis. Mol Ther Nucleic Acids (2020) 20:438–50. doi: 10.1016/j.omtn.2020.03.006

PubMed Abstract | CrossRef Full Text | Google Scholar

239. Yao Y, Li N. MIR600HG suppresses metastasis and enhances oxaliplatinchemosensitivity by targeting ALDH1A3 in colorectal cancer. Biosci Rep (2020) 40(4):BSR20200390. doi: 10.1042/BSR20200390

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: colorectal cancer, lncRNAs, cancer metastasis, signaling pathways, markers, therapy

Citation: Liao Z, Nie H, Wang Y, Luo J, Zhou J and Ou C (2021) The Emerging Landscape of Long Non-Coding RNAs in Colorectal Cancer Metastasis. Front. Oncol. 11:641343. doi: 10.3389/fonc.2021.641343

Received: 14 December 2020; Accepted: 29 January 2021;
Published: 25 February 2021.

Edited by:

Zsolt Kovács, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureş, Romania

Reviewed by:

Qianjin Liao, Central South University, China
Shuji Ogino, Brigham and Women’s Hospital and Harvard Medical School, United States

Copyright © 2021 Liao, Nie, Wang, Luo, Zhou and Ou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Chunlin Ou, ouchunlin@csu.edu.cn; Jianhua Zhou, zhoujh15@163.com

These authors have contributed equally to this work and share first authorship