MicroRNA-24 in Cancer: A Double Side Medal With Opposite Properties

MicroRNA-24 (miR-24) has been widely studied in a variety of human cancers, which plays different roles in specific type of cancers. In the present review, we summarized the recent surveys regarding the role of miR-24 in different human cancers. On the one hand, miR-24 was reported to be down-regulated in some types of cancer, indicating its role as a tumor suppressor. On the other hand, it has shown that miR-24 was up-regulated in some other types of cancer, even in the same type of cancer, suggesting the role of miR-24 being as an oncogene. Firstly, miR-24 was dysregualted in human cancers, which is related to the clinical performance of cancer patients. Thus miR-24 could be used as a potential non-invasive diagnostic marker in human cancers. Secondly, miR-24 was associated with the tumor initiation and progression, being as a promoter or inhibitor. Therefore, miR-24 might be an effective prognostic biomarker in different type of cancers. Lastly, the abnormal expression of miR-24 was involved in the chemo- and radio- therapies of cancer patients, indicating the role of miR-24 being as a predictive biomarker to cancer treatment. Totally, miR-24 contributes to tumorigenesis, tumor progression, and tumor therapy, which closely related to clinic. The present review shows that miR-24 plays a double role in human cancers and provides plenty of evidences to apply miR-24 as a potential novel therapeutic target in treating human cancers.


INTRODUCTION
MicroRNAs (miRNAs) are an evolutionarily conserved family of endogenous 19-22nt long noncoding RNAs, which are related with post-transcriptional regulation of gene expression by cleaving the target mRNAs or repressing translation (1). More and more evidences proved that miRNAs contributed to the initiation and progression of many diseases, including cancer. In the year 2002, the first relation between cancer and miRNA deregulation was demonstrated. Since then, a variety of surveys about miRNAs in different human cancers have been performed, showing miRNAs can be used as effective markers and as novel therapeutic targets in human cancers (2). For example, dysregulation of miRNAs has been widely involved in the activation of oncogenes in hepatocellular carcinoma (HCC), showing the potential diagnostic and therapeutic value of miRNAs in HCC (3). MiRNA dysregulation is a causal factor in many cancers, suppressing or promoting the initiation and progression of human cancers. Moreover, miRNA mimics and inhibitors that target miRNAs are promising in pre-clinical development, and several miRNAtargeted therapeutics have reached clinical development (4). Insights into the roles of miRNAs in human cancers have made miRNAs attractive tools and targets for novel therapeutic approaches.
Several clinical evidences have supported the idea that dysregulation of miR-24 is correlated with the clinical features of human cancer. Therefore, the role of miR-24 in human cancer has been explored by numerous clinical, translational, and basic studies. The increasing amount of scientific evidence has confirmed the therapeutic relevance and the biological role of miR-24 in human cancer, for which a critical review is necessary. In the present review, we will summarize the recent advances in the research of miR-24 and provide an overview of its double roles in human cancers. We'll also comprehensively highlight the biological roles of miR-24 in carcinogenesis, cancer progression, metastasis, and drug resistance and discuss the potential application of miR-24 as a diagnostic tool and therapeutic target in human cancers.

Aberrant miR-24 Expression in Cancer
The expression pattern of miR-24 has been extensively studied, by comparing the tumor and non-tumor tissues of human cancer ( Table 1). The up-regulation or down-regulation of miR-24 has been found in the specific cancer type. On the one hand, compared with normal tissues, miR-24 was found to be up-regulated in the following human cancers: lung cancer (LC) (6,44,45), hepatocellular carcinoma (HCC) (7), breast cancer (BC) (8), tongue squamous cell carcinoma (TSCC) (42), bladder cancer (BLC) (46), gastric cancer (GC) (47), acute leukemia (AL) (48), and Hodgkin Lymphoma (HL) (49). On the other hand, miR-24 was found to be down-regulated  (31), and gastric cancer (GC) (32), compared to the normal tissues. Specifically, miR-24 promoted lung cancer progression by regulating the tumor suppressor gene menin (45). While miR-24 was downregulated in both lung adenocarcinoma tissues and cells, and it suppressed the proliferation and migration of LA cells by regulating fibroblast growth factor receptor 3 (FGFR3) (30). Therefore, miR-24 was expressed differentially in different type of cancers, with opposite roles as an oncogene or a tumor suppressor.

Clinical Relevance of miR-24 in Cancer
A variety of findings have confirmed that dysregulation of miR-24 is related to the clinical performance of human cancer. Some studies found that the expression of miR-24 in cancer tissues, being as an oncogene, was correlated with a later clinical stage, as well as the extent of metastasis (53). For example, miR-24-3p was discovered to be down-regulated in CRC tissues compared with their corresponding non-cancerous tissues, and its expression was associated with local invasion (P = 0.002), lymph node metastasis (P = 0.0007) and clinical stage (P < 0.001) significantly (10). Another report found that the ratio of miR-21/24 was significantly correlated with the tumor size, TNM (tumor, lymph node, and metastasis) stage, lymph metastasis and histologic differentiation of CRC (54). The above two studies showed that miR-24 could be used as a potential prognostic biomarker and survival risk factor for CRC patients. MiR-24 was found to be significantly associated with survival of patients with glioblastoma (GBM) multiforme, and promoted GBM progression by targeting tumor suppressor sex-determining region Y-box 7 (SOX7) (55,56). MiR-24 was obviously overexpressed in lung carcinoma tissues than that of para-cancerous tissues. And the overall survival (OS) of patients with higher miR-24 expression was remarkably shorter than those with lower expression. They further proved that miR-24 promoted the viability, proliferation and cell cycle of lung carcinoma cells and inhibited cell apoptosis by binding to MAPK7 (mitogen-activated protein kinase 7) (57).
In tongue squamous cell carcinoma, a double role of miR-24 was discovered relating to its role in clinic. A study reported that the decrease of miR-24 expression was correlated with high grade and late stage tumor in TSCC (42). Nevertheless, another study reported that miR-24 was increased in both TSCC tissues and cell lines, and the increase of miR-24 expression was associated with advanced clinical stage and a shorter overall survival of TSCC patients (43). In total, these evidences suggest the significance of miR-24, in terms of its correlation with the staging and survival of patients with cancer, being as a potential prognostic biomarker for human cancer.

miR-24 as a Diagnostic and Prognostic Marker in Cancer
The differential expression of miR-24 in body fluid such as plasma, alone or in combination with a panel of other miRNAs, makes it might be considered as a potential non-invasive marker in cancer diagnosis. Since miRNAs are related to the clinic, detecting and monitoring the dysregulated miRNAs could reveal the stage of cancer. There are many evidences revealed the diagnostic role of miR-24 in cancers (58) (62). A study found that miR-24-3p had excellent diagnostic accuracy for oral squamous cell carcinoma [(AUC) = 0.738; P = 0.02], thus salivary exosomal miR-24-3p could be a potential novel diagnostic biomarker for OSCC (50). In total, the above evidences confirmed the role of miR-24 being as a diagnostic marker in human cancer.
Regarding the differential expression of miR-24 in human cancer, miR-24 is associated with patient survival, indicating it could be a potential prognostic biomarker in cancer. Franchina et al. (6) found that circulating miRNAs including miR-22, miR-24, and miR-34a could function as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer. Researchers discovered that the elevation of serum miR-24-3p could be an independent poor prognostic factor for OS and DFS (disease free survival) of HBV (hepatitis B virus)related HCC patients (59). And in acute leukemia, Kaplan-Meier analysis showed that AL patients with high miR-24 expression tended to have shorter overall survival, and in the multivariate analysis stratified for known prognostic variables, miR-24 was identified as an independent prognostic marker (48). In contrast, CRC patients with low miR-24-3p level had a significantly poorer prognosis than those with high miR-24-3p level. And multivariate analysis revealed that miR-24-3p could be an independent prognostic indicator for OS of CRC patients (10). In breast cancer, miR-24 was identified to be highly predictive of early breast cancer relapse (38). In nasopharyngeal carcinoma, a survey proved that exosomal miR-24-3p could serve as a prognostic biomarker, due to its involvement in tumor pathogenesis by mediating T-cell inhibition (25). And our previous study validated that miR-24 could serve as a prognostic marker for NPC recurrence (24). Therefore, miR-24 is a potential promising diagnostic and prognostic marker in human cancer.

BIOLOGICAL ROLE OF THE miR-24 IN HUMAN CANCER
Carcinogenesis and Progression miR-24 is involved in the initiation and progression of human cancer by regulating the specific gene. On the one hand, miR-24 promotes tumorigenesis in some cancer types. Zhang et al. (63) reported that miR24-1-5p promoted tumorigenesis in ovarian epithelial cells. And hsa-mir-24-2 has been validated to be associated with the metastasis of cervical squamous cell carcinoma (64). In lung squamous cell carcinoma, miR-24-3p was overexpressed and functioned as an onco-miR (51). In mesothelioma, miR-24-3p promoted tumorigenesis by inducing cancer cell growth and regulating Rho-GTP activity positively (65). In hepatocellular carcinoma, miR-24-3p increased cancer cell viability and reduced its cell apoptosis (15). And miR-24 increased cell metastasis and invasion by targeting p53 (7). In lung cancer, miR-24 promoted cancer cell growth and metastasis and inhibited cell apoptosis also by targeting menin, and SOX7 (sex-determining region Y-box 7) (44,45). In colorectal cancer, a study showed that HIF-1α (hypoxia inducible factor-1α)-induced miR-23a∼27a∼24 cluster could promote cancer progression via reprogramming its metabolism (66), suggesting miR-24 might be an onco-miR in CRC. Although a previous study showed that miR-24-3p functioned as a tumor suppressor in CRC (10). Whether miR-24 functioned as a tumor suppressor or an onco-miR, in different cancer types, or even in the same cancer type, depends on its different targets. By targeting specific targets, miR-24 could suppress or promote cancer cell proliferation, metastasis, angiogenesis, autophagy, cell cycle, and cell apoptosis. MiR-24-3p mediated the tumorigenesis promotion and accelerated xenografted tumor growth of breast cancer (39,40). As shown in Figure 1, overexpressing miR-24-3p promoted cell proliferation and inhibited cell apoptosis in breast cancer by targeting p27 Kip1 (8,18). In tongue squamous cell carcinoma, miR-24 promoted its proliferation, migration and invasion through targeting FBXW7 (F-box and WD repeat domain containing 7) (43). In cholangiocarcinoma, miR-24 increased cancer cell proliferation, angiogenesis, migration, and invasion by regulating menin (67). In bladder cancer, miR-24-3p increased cell proliferation and migration ability by targeting DEDD (Asp-Glu-Asp-Asp domain) (46).
On the other hand, however, miR-24 suppresses tumorigenesis in some human cancers. For example, miR-24 was significantly downregulated in gastric cancer tissues compared with matched non-tumor tissues, and it was associated with tumor FIGURE 1 | Role of miR-24 in cancer initiation and progression. MiR-24 functioned as a tumor suppressor or an onco-miR, in different cancer types, even in the same cancer type, by targeting different targets. By targeting specific targets, miR-24 could suppress or inhibit cancer cell proliferation, metastasis, angiogenesis, autophagy, cell cycle, and cell apoptosis. The pink ellipse means the protein in it functions as an onco-protein, and the blue ellipse means the protein in it functions as a tumor suppressor. p27 Kip1 , a key protein in regulating cell cycle; FBXW7, F-box and WD repeat domain containing 7, a substrate-recognition subunit of a ubiquitin ligase complex; menin, the protein product of the MEN1 gene, a ubiquitously expressed protein that lacks homology with other protein families; DEDD, Asp-Glu-Asp-Asp domain, a death effector domain-containing protein; CARM3, CARD-containing MAGUK protein 3, a scaffold protein known to activate NF-κB pathway; FGFR3, fibroblast growth factor receptor 3; XIAP, X-linked inhibitor of apoptosis protein; FSCN1, fascin actin-bundling protein 1, a protein encoded by an actin-bundling protein, FSCN1, which is involved in formation of actin-based structures that contribute to cell migration. differentiation (32). In CRC, miR-24-3p suppressed cancer cell proliferation, cell migration and invasion, functioning as a tumor suppressor (10). And miR-24-1-5p decreased CRC cell proliferation, migration and survival significantly by repressing β-catenin expression (20). Ectopic expression of miR-24 inhibited cell cycle, proliferation, migration, and clonogenic potential of prostate cancer cells, as well as inducing cell apoptosis (27). In pancreatic ductal adenocarcinoma (PDA), miR-24-3p exerted its anti-cancer role by suppressing the expression of Laminin Subunit Beta 3 (LAMB3), an oncogene (34). In retinoblastoma, miR-24 plays a tumor suppressive role by targeting c-Myc (35). Moreover, even in the same type of cancer, miR-24 functions oppositely. For example, in colorectal cancer, overexpression of miR-24-1-5p significantly repressed β-catenin expression, and simultaneously decreased CRC cell migration (20). Michael et al. (68) also confirmed that miR-24 inhibited the cell growth of both lung and colon carcinoma. As shown in Figure 1, in bladder cancer, another study reported that miR-24 inhibited cell proliferation, arrested cell cycle and induced cell apoptosis by targeting CARMA3 (CARD-containing MAGUK protein 3) (31). And In lung adenocarcinoma, miR-24-3p could suppress cell proliferation, migration, and invasion by regulating FGFR3 directly (30). In acute lymphoblastic leukemia, miR-24-3p induced cell apoptosis by regulating XIAP (X-linked inhibitor of apoptosis protein) (69). In NPC, miR-24 suppressed cell prolifearation, migration, and invasion and increased the readiosensitivity of cells to iridiation by targeting SP1 (specificity protein 1), FSCN1 (fascin actin-bundling protein 1), and Jab1 (Jun activation domain-binding protein 1), respectively, funcioning as a tumor suppressor (9,24,26). Therefore, both positive and negative roles of the miR-24, in cancer cell maintenance, were found in different kinds of cancer, even in the same cancer type (Figure 1).

Cancer Therapy Resistance
MiR-24 not only plays a crucial in tumor initiation and progression, but also plays an essential role in cancer therapy, including chemo-and radio-therapies. Drug resistance limits the efficacy of chemotherapy in human cancers. For the role of miR-24 in cancer chemotherapy, a lot of researchers provided evidences. As shown in Figure 2, in colorectal cancer, some reports showed that miR-24 functioned as a tumor suppressor. It was downregulated in colorectal cancer cells and induced cell apoptosis. What's more, ectopic expression of miR-24 could enhance the chemosensitivity of CRC cells to 5-fluorouracil (5-FU) by targeting RNA-binding protein DND1 (dead end protein 1) (70). In gastric cancer, DND1 was a target of miR-24. And miR-24 overexpression suppressed the migration and FIGURE 2 | Role of miR-24 in cancer chemo-and radio-therapies. MiR-24 increased 5-FU sensitivity in both colorectal and gastric cancers. However, miR-24 decreased cisplatin sensitivity in both TSCC and breast cancer. Especially, in breast cancer, miR-24 enhanced tamoxifen senstitivy by targeting Bim. And miR-24 increased sensitivity of cancer cells to radiotherapy, and showed a dual role in chemotherapy. By targeting different targets, miR-24 increased radio-sensitivity in NPC, EC and LSCC. The pink ellipse means the protein in it functions as an onco-protein, and the blue ellipse means the protein in it functions as a tumor suppressor. DND1, dead end protein 1, a RNA-binding protein; FSCN1, fascin actin-bundling protein 1, a protein encoded by an actin-bundling protein, FSCN1, which is involved in formation of actin-based structures that contribute to cell migration. PTEN, phosphatase and tensin homolog, a well-known inhibitor of PI3K/Akt pathway; XIAP, X-linked inhibitor of apoptosis protein; FERMT1, also known as KINDLIN-1, is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation; SP1, specificity protein 1; Jab1, Jun activation domain-binding protein 1, an onco-protein.
invasion of GC. It also enhanced the chemosensitivity of the SNU1 gastric cancer cells (71). In prostate cancer, overexpression of miR-24-3p inhibited survival rate, half maximal inhibitory concentration (IC50) of paclitaxel (PTX) but increased apoptosis in prostate cancer cells after treatment of PTX, via regulating fascin1 (FSCN1) (28). Those researches showed that miR-24 functioned differently after the treatment with chemotherapy, might due to the difference of the specific microenvironment. In human tongue squamous cell carcinoma, miR-24 increased cisplatin resistance by targeting PTEN (phosphatase and tensin homolog) and then acrivating Akt pathway (42). In breast cancer, miR-24-3p functioned as an onco-miR and decreased cisplatin sensitivity by negatively regulating lncRNA (long non-coding RNA) MT1JP (39). Interestingly, another study, published at the same year for the same cancer type, reported that miR-24-3p increased tamoxifen sensitivity by targeting Bim, leading to the induction of breast cancer cell apoptosis, acting as a tumor suppressor (41).
For the role of miR-24 in radiotherapy, Xu et al. (11) showed that miR-24 could increase LSCC radio-sensitivity through enhancing irradiation-induced apoptosis. As shown in Figure 2, in laryngeal squamous cell carcinoma, miR-24 was identified to suppress tumor growth, induce cell apoptosis, and reverse cancer cell radioresistance via targeting XIAP (11). In esophageal cancer, miR-24 could also increase its radio-sensitivity by suppressing FERMT1 (also known as KINDLIN-1) (36). Kang et al. (9) and we previously reported that miR-24 enhanced radio-sensitivity of NPC by targeting SP1, and Jab1 (9,24). Totally, miR-24 plays a crucial role in the radio-and chemo-therapies of cancer (Figure 2).

DISCUSSION
Non-coding RNAs (ncRNAs) are important regulators of gene expression in both physiological and pathological conditions, which is critical to finalize the pharmacological application of ncRNAs as either therapeutic tools or as molecular biomarkers in human cancer (72). In the present review, we summarized that miR-24 had opposite functions, even in the same type of cancer (32,47). Firstly, this could be probably due to the inconsistent quality of the studies. Therefore, further large studies are needed to confirm these results, and quality control should be highlighted in future investigations of miR-24 in order to produce consistent and reliable conclusions. Secondly, this could be probably due to the complex regulation network of miR-24. Though miR-24 has promising diagnostic and prognostic value for a variety of human cancers, and its roles in cancer progression suggest that it can be a useful biomarker for therapy, its clinical application remains rare. This is mainly because its toxicity and safety remain unclear. Therefore, further studies are needed to confirm its functions and adverse effects.

CONCLUSIONS
This review highlighted the scientific achievements in the study of miR-24 in human cancer and outlined the biological and clinical insights on the advancements. MiR-24 has been detected as being differentially expressed across different types of cancer, and might predict the survival and treatment response of cancer patients. Its biological functions covered the scenarios of carcinogenesis, cancer progression, metastasis, and drug resistance, suggesting that it might have potential to be used as an emerging targetable entity in cancer treatment. Throughout the present review, we conclude that "microRNA-24 in cancer: a double side medal with opposite properties."

AUTHOR CONTRIBUTIONS
SW was responsible for writing and editing the manuscript. NL was responsible for collecting references and writing the manuscript. QT and HS collected some references. SL and WW were responsible for modifying the manuscript. All authors contributed to the article and approved the submitted version.