Aberrant Expression of miR-1301 in Human Cancer

miR-1301 is a newly discovered miRNA, which is abnormally expressed in 14 types of tumors. miR-1301 inhibits 23 target genes, forms a ceRNA network with 2 circRNAs and 8 lncRNAs, and participates in 6 signaling pathways, thereby affecting tumor cell proliferation, invasion, metastasis, apoptosis, angiogenesis, etc. Abnormal expression of miR-1301 is often associated with poor prognosis of cancer patients. In addition, miR-1301 is related to the anti-tumor effect of epirubicin on osteosarcoma and imatinib on chronic myeloid leukemia(CML) and can enhance the cisplatin sensitivity of ovarian cancer. This work systematically summarizes the abnormal expression and prognostic value of miR-1301 in a variety of cancers, depicts the miR-1301-related signaling pathways and ceRNA network, and provides potential clues for future miR-1301 research.

At present, many studies have shown that miR-1301 is closely related to the occurrence and development of cancer, but there is still a lack of systematic understanding of miR-1301. Therefore, we perform a PUBMED search with the following combination: "((((miR1301) OR (miR-1301)) OR (microRNA-1301)) OR (miRNA-1301)) AND (cancer)", and conduct a comprehensive analysis of the retrieved literature. This work summarizes the diagnostic and prognostic value of miR-1301 in cancers, as well as the ceRNA network and signaling pathways it participates in and looks forward to the future challenges of miR-1301 research.

THE ABERRANT EXPRESSION OF miR-1301 IN CANCER
As shown in Table 1, miR-1301 is aberrantly expressed in 16 cancers. Among them, miR-1301 was down-regulated in 11 cancers, up-regulated in 2 cancers, and there were inconsistent expression results of miR-1301 expression in 3 cancers. miR-1301 is involved in the biological processes of tumor cell proliferation, migration, invasion, and apoptosis by regulating multiple downstream genes ( Figure 1). In all tumor types involved in miR-1301, the abnormal expression of miR-1301 can affect the proliferation of tumor cells by affecting cell cycle and apoptosis (1,7,9,12,16,17,24,(26)(27)(28)(29)(33)(34)(35)(36). Metastasis is characterized by cancer cells invading the basement membrane into the adjacent matrix, then invading and surviving into the circulatory system (including blood and lymphatic tissue), and extravasation to distant tissues. A core step in the process of cancer metastasis is the acquisition of migratory and aggressive phenotypes (37). In 9 types of tumors, the abnormal downregulation of miR-1301 will affect p53, WNT, STAT3, and other signaling pathways, which can promote tumor cell migration and invasion.
In four lung cancer cell lines, the expression of miR-1301 was higher than that of human normal lung epithelial cells (BEAS-2B) (5,21). Thy-1 is a cell surface glycoprotein, which is closely related to idiopathic pulmonary fibrosis (22) and lung cancer (5). Polymerase I and transcript release factor (PTRF) is also known as cavin-1, and its down-regulation has been shown to promote the progression of prostate cancer, breast cancer, and glioblastoma (30). In lung cancer, miR-1301 acts as an oncogene by inhibiting the Thy-1 and PTRF genes (5,21).
The expression of miR-1301 is significantly up-regulated in a variety of breast cancer cell lines and tissues, and it promotes cancer cell proliferation by directly targeting and inhibiting the expression of ICAT (3). In triple-negative breast cancer (TNBC), there is a negative feedback loop between EZH2 and miR-1301. Specifically, EZH2 can promote the expression of miR-1301, thereby inhibiting the expression of EZH2 itself. At the same time, the overexpression of miR-1301 can inhibit the proliferation of TNBC cells and the growth of xenograft tumors in mouse (20). The above evidence indicates that the dual role of miR-1301 may depend on the regulation of upstream factors in different pathological tissues. Compared with 2 primary normal breast epithelial cell lines, miR-1301 is highly expressed in 9 breast cancer cell lines. Inhibitor of b-catenin and TCF4 (ICAT) can suppress the activity of Wnt/b-catenin and play a tumor suppressor effect in a variety of tumors (31,32). miR-1301 can inhibit the expression of ICAT, thereby increasing the risk of breast cancer (3). In addition, analysis of TCGA data showed that miR-1301 is highly expressed in TNBC. Both in vivo and in vitro experiments have shown that miR-1301 overexpression can inhibit breast cancer tumor growth (20). The tumor suppressor ability of miR-1301 may be derived from EZH2, which is a recognized oncogene (14). EZH2 is overexpressed in a variety of human malignancies (14). The overexpression of EZH2 is often associated with the advanced stage and poor prognosis of human cancer (15). It is worth noting that the expression of miR-1301 and EZH2 in TNBC is positively correlated, and the high expression of the two is correlated with poor metastasis-free survival and poor overall survival of TNBC patients (20).
The expression of miR-1301 in the five hepatoma cell lines (Hep3B, Huh-7, HepG2, SMMC-7721, and MHCC97L) was significantly lower than that in LO2, a human fetal hepatocyte line (19,44). In addition, in hepatoma cell line HepG2, the expression of miR-1301 was significantly lower than that in (Continued)  (46). The expression of miR-1301 in 5 prostate cancer cell lines (Tsu-Pr1, PC3, DU145, LNCAP, and 22RV1) was higher than that of normal prostate epithelial cells (34). Similarly, the expression of miR-1301 in prostate cancer tissues was also significantly higher than that in adjacent non-tumor tissues (34,45). However, another study found that the expression of miR-1301 in prostate cancer tissues was significantly lower than that in non-cancerous tissues (35).
SIRT1 is a type III histone deacetylase that relies on nicotinamide and can participate in tumor development (25). The expression levels of miR-1301 in gastric cancer cell lines (MGC-803 and SGC-7901) are higher than that of normal human gastric mucosal cell line GES-1. miR-1301 can inhibit SIRT1, thereby exerting carcinogenic effects (16). However, another study showed that the expression of miR-1301 in gastric cancer cell lines (MGC-803, HGC-27, MKN-45, and BGC-823) was lower than that of normal human gastric mucosal cell line GES-1 (1). And this result might be due to the high expression of CCCTC binding factor (CTCF) in gastric cancer, which can activate the up-regulation of LINC01207 expression, thereby sponge miR-1301 (1).
The inconsistent results of miR-1301 expression in hepatocellular carcinoma, prostate cancer, and gastric cancer may be due to the use of different control cell lines and the presence of tissue-specific upstream regulatory factors of

THE PROGNOSTIC VALUE OF miR-1301 IN CANCER
miR-1301 is highly expressed in non-small cell lung cancer but is low expressed in glioma (4, 5), CRC (6), PTC (7), and osteosarcoma (8). In the 5 tumors, the abnormal expression of miR-1301 is closely related to tumor staging and metastasis and can lead to a poor prognosis for patients with NSCLC, glioma, and osteosarcoma ( Table 3).
In NSCLC, the high expression of miR-1301 is significantly related to the shorter overall survival time of NSCLC patients and is also closely related to the advanced TNM stage of NSCLC and positive lymph node metastasis (5). In contrast, the expression of miR-1301 is decreased in gliomas, and the low expression of miR-1301 is significantly related to the high WHO grade, low KPS, and large tumor size of gliomas. Downregulation of miR-1301 is also related to the decrease in the overall survival rate and disease-specific survival of glioma patients (4). In addition, the expression of miR-1301 in stage-III CRC tissue is lower than that in stage-IV CRC. In addition, the expression of miR-1301 in the serum of patients with metastatic CRC was also significantly lower than that of patients with non-metastatic CRC (6). The expression of miR-1301 decreases significantly in normal thyroid tissue, benign thyroid tumor tissue, and PTC tissue. Compared with T1-stage and N0-stage PTC tumors, miR-1301 in T2-T4-stage and N1stage PTC tumors were decreased significantly, respectively (7). The expression of miR-1301 in osteosarcoma tissues was significantly lower than that in non-tumor tissues. The low expression of miR-1301 is significantly related to the patient's advanced clinical stage and distant metastasis, and the patient's poor overall survival rate (8).

miR-1301 AND THE TREATMENT OF CANCER DRUGS
Currently, EPI and IM are used for the clinical treatment of osteosarcoma (9) and CML (10), respectively. Although the treatment of ovarian cancer has been improving, the treatment effect has been poor due to the prone to chemotherapy resistance of ovarian cancer (11). miR-1301 is related to the anti-tumor effects of EPI and IM (9, 10), and miR-1301 can also inhibit the cisplatin resistance of ovarian cancer through the NF-kB signaling pathway (11). The research progress of miR-1301 can provide new hints for the treatment of osteosarcoma and CML, and also help further study the mechanism of drug resistance in ovarian cancer (Figure 2).

EPI Plays an Anti-Tumor Effect in
Osteosarcoma Through the miR-1301/ TRIAP1 Axis EPI has been widely used in the treatment of various cancers, and the resistance of tumors to EPI is related to the enhancement of the bioenergetics of mitochondria (47). TP53-regulated inhibitor of apoptosis 1 (TRIAP1) is overexpressed in many cancers and has been shown to act as an oncogene in tumorigenesis (9). In osteosarcoma, the expression of miR-1301 is down-regulated, while EPI can up-regulate the expression of miR-1301, which can play an anti-osteosarcoma effect by targeting inhibition of TRIAP1 (9).

IM Exerts an Anti-Tumor Effect in CML Through the miR-1301/RanGAP1 Axis
IM is a 2-phenylaminopyrimidine-based tyrosine kinase inhibitor (48). Although IM is the first-line drug for the treatment of CML at this stage, it is not only expensive but also induces various side effects (10). IM can induce apoptosis of CML cell lines and reduce cell viability. Down-regulation of RanGTPase activating protein 1 (RanGAP1) can enhance the effects of IM (10). By targeting RanGAP1, miR-1301 can disrupt the extranuclear transport of BCR-ABL and induce P73dependent apoptosis, thereby improving the therapeutic effect of IM for CML (10). The expression of miR-1301 is downregulated in CML, so the combined use of the ectopic expression of miR-1301 and low-concentration IM can not only achieve a therapeutic effect similar to that of high-concentration IM but also reduce the side effects of IM (10).

The Molecular Mechanism of miR-1301 and Cisplatin Resistance in Ovarian Cancer
The drug resistance of ovarian cancer can induce tumor cell proliferation and invasion, leading to poor prognosis and even death of patients (11). The expression of miR-1301 is increased in SKOV3/DDP anti-cisplatin ovarian cancer cell line, thereby inhibiting the expression of autophagy genes ATG5 and Beclin1, increasing the expression of EMT-related proteins Snail and Slug, and promoting tumor cell invasion and metastasis (11). miR-1301 can promote autophagy and EMT by activating the NF-kB signaling pathway, while down-regulating miR-1301 can inhibit the NF-kB signaling pathway, thereby preventing the occurrence and development of drug-resistant ovarian cancer (11).

The Wnt/b-Catenin Signaling Pathway
The classic Wnt/b-catenin signaling pathway includes the following key components: WNT, Frizzled, low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), and bcatenin (50). b-catenin is a signal transduction transcription activator. Mutations of APC, CTNNB1, and other genes can abnormally activate the Wnt/b-catenin signaling pathway, thereby promoting the occurrence and development of a variety of tumors (51). At the same time, the changes in the expression of downstream target genes of the Wnt/b-catenin signaling pathway (such as cyclinD1, MYC, AXIN2, MMP2, MMP9, etc.) may be related to various biological functions of tumor cells, including stemness, proliferation, differentiation, etc. (52).
Many components in the Wnt/b-catenin signaling pathway have become targets for tumor therapy (19). By participating in the Wnt/b-catenin signaling pathway, miR-1301 can regulate the occurrence and development of bladder cancer (28), hepatocellular carcinoma (19), breast cancer (3), and prostate cancer (45).
Up-regulated miR-1301 inhibits PODXL, activates the Wnt/ b-catenin signaling pathway, and promotes the growth of bladder cancer cells. Knockdown of lncRNA NNT-AS1 can inhibit the expression of related genes in the Wnt/b-catenin signaling pathway, such as CTNNB1, CDK1, AXIN2, cyclinD1, and MYC (28).
BCL9 is overexpressed in a variety of malignant tumors and can activate the Wnt/b-catenin signaling pathway to promote cell proliferation, migration, and invasion (19). In hepatocellular carcinoma, the down-regulation of miR-1301 expression can upregulate the expression of its target gene BCL9 and activate the Wnt/b-catenin signaling pathway, thereby inhibiting the migration, invasion, EMT, and angiogenesis of hepatocellular carcinoma (19).
In breast cancer, the expression of miR-1301 is up-regulated and plays the role of an oncogene. ICAT is an important regulator of the Wnt/b-catenin signaling pathway. miR-1301 directly targets and inhibits ICAT, thereby activating the Wnt/bcatenin signaling pathway and promoting the proliferation of breast cancer cells (3). The p53 Signaling Pathway p53 acts as a sensor and restricts cell reproduction under highlevel pathological conditions, including oncogene signaling, hypoxia, ribosome dysfunction, DNA damage, and nutritional deficiencies. Under low levels of stress, p53 provides pro-survival and protective responses. When cells are exposed to strong stress signals, p53 triggers irreversible senescence or apoptosis programs (53). Ubiquitination factor E4B (UBE4B) is an E3 and E4 ubiquitin ligase that can target phosphorylated p53 and mediate p53 degradation (35). miR-1301 is significantly underexpressed in prostate cancer and can target UBE4B to enhance the function of p53 (49). miR-1301 mediates NO-induced and p53-dependent cell apoptosis by targeting the anti-apoptotic proteins Survivin and MET, thereby participating in colitisrelated carcinogenesis (49).

The mTOR Signaling Pathway
The mammalian target of the rapamycin (mTOR) pathway is involved in many key cellular functions, including protein synthesis, cell cycle progression, apoptosis, and drug resistance (54). mTOR has been widely confirmed as an important downstream molecule of AKT1. The AKT/mTOR signaling pathway mediates tumor metabolic homeostasis and can promote tumor growth and metastasis (33). RHEB is a conserved small GTPase belonging to the Ras superfamily.
RHEB is an important upstream regulator of mammalian mTOR signal transduction (33). In cervical cancer, the mTOR signaling pathway is activated and promotes tumorigenesis and development. Inhibition of the MYLK/miR-1301 axis can lead to down-regulation of mTOR pathway-related genes, such as RHEB, EIF5, and mTORC1 (33). In addition, inhibiting the expression of ABHD11-AS1 can increase the levels of p-PI3K, p-AKT, and p-mTOR (26).

The Ras Signaling Pathway
RAS sarcoma (Ras) protein is a highly homologous small G protein with GTPase activity. RAS sarcoma (Ras) protein is the most frequently activated oncogene in human cancers. N-Ras is involved in cancer and plays a role in the growth, survival, migration, invasion, and angiogenesis of cancer cells (24). In GBM, the expression of miR-1301 is down-regulated, which leads to the activation of the Ras signaling pathway. In glioma cells, overexpression of miR-1301 can down-regulate N-Ras, thereby silencing its downstream MEK-ERK1/2 signaling pathway, inhibiting tumor cell growth, and blocking the G1 phase of the cell cycle (24).

The NF-kB Signaling Pathway
The NF-kB signaling pathway plays an important role in the processes of autophagy, EMT, cell inflammation, tumor, and immune response (11). NF-kB transcription factor exists in the nucleus and is widely involved in the process of gene transcription (55). The NF-kB family of transcription factors is composed of five different DNA-binding proteins, namely p65 (RELA), p50 (NFKB1), p52 (NFKB2), c-REL, and RELB. They can form up to 15 different homo-or heterodimers (55). The NF-kB signaling pathway is often activated in pathophysiological conditions such as cancer, inflammation, infection, and so on (55). Transfection of cisplatin-resistant strain SKOV3/DDP cell line with miR-1301 mimics can promote the expression of EMTrelated genes Snail and Slug, and inhibit the expression of autophagy genes ATG5 and Beclin1. At the same time, it also promotes the expression of NF-kB and N-cadherin and inhibits the expression of E-cadherin. Targeting miR-1301 can inhibit the NF-kB signaling pathway to reduce the proliferation of cisplatinresistant cells and the development of EMT, thereby preventing the occurrence and development of drug-resistant ovarian cancer (11).

The PI3K/AKT Signaling Pathway
The PI3K/AKT signaling pathway is one of the most active signaling pathways in human tumors and the main signaling pathway downstream of many growth factor receptors. The PI3K/AKT signaling pathway can phosphorylate PI3K and AKT proteins, thereby promoting tumor cell proliferation and malignant transformation, and inhibiting tumor cell apoptosis (56).
In PTC, ABHD11-AS1 can positively regulate the PI3K/AKT signaling pathway and promote the progression of PTC (26). In TNBC, miR-1301, a downstream gene of EZH2, provides a negative feedback inhibition of EZH2 expression. Meanwhile, miR-1301 increases the levels of p21 and p27 proteins downstream of the PI3K/AKT signaling pathway by reducing the levels of p-AKT and Bcl-XL proteins, thereby playing the role of tumor suppressor genes (20). In CRC, miR-1301 can up-regulate AKT1 to promote the proliferation and invasion of CRC cells, and inhibit cell apoptosis (17).

CONCLUSIONS AND PERSPECTIVES
miR-1301 is abnormally expressed in 16 cancers and is related to the clinicopathological characteristics of 5 tumors (NSCLC, PTC, CRC, glioma, and osteosarcoma). Besides, miR-1301 may be related to the chemotherapeutic effects of EPI and IM, and participate in the inhibition of cisplatin resistance in ovarian cancer. miR-1301 can interact with 3 circRNAs and 9 lncRNAs in different cancers. In addition, miR-1301 participates in at least 6 classical signaling pathways.
Although miR-1301 is closely related to the occurrence and development of a variety of tumors, the mechanisms that affect various biological processes of tumor cells have not been fully elucidated. First of all, existing studies have shown that miR-1301 acts as a tumor suppressor in 11 types of tumors. However, miR-1301 is a protumor factor in lung cancer (3,24) and breast cancer (1,29). The mechanism of these differences has not been clarified yet. Secondly, the expression levels of miR-1301 in hepatocellular carcinoma (23,41,42), prostate cancer (20,21,43) and gastric cancer (22,30) tumors are inconsistent. The complex regulation mechanism needs to be further explored in these three cancers. Thirdly, miR-1301 can promote tumor cell metastasis in a variety of tumors, but existing research does not involve the metastasis of cancer cells to secondary sites. In the future, more research on the mechanism of miR-1301 regulating cancer metastasis is needed. Finally, the miR-1301-related ceRNA network described in this work only includes 9 lncRNAs, 3 circRNAs, and 27 mRNAs. Future research needs to focus on discovering more genes and ceRNAs that can interact with miR-1301, which will help further understand the mechanism of miR-1301 in tumors. In addition, the mechanism of miR-1301 in oncogenesis and cancer therapy is also worthy of further research, which will provide a solid theoretical basis for better tumor-targeted therapy and prognosis.
In summary, miR-1301 is a potential tumor target of treatment. More research will focus on the specific molecular mechanism of miR-1301 and its related targets genes in the future. This will lay the foundation for precisely targeted therapy and drug development of related tumors in the future.