The Diverse Oncogenic and Tumor Suppressor Roles of microRNA-105 in Cancer

MicroRNAs (miRNAs) are non-coding small RNA molecules that regulate gene expression at the post-transcriptional/translational level. They act a considerable role not only in the normal progress of development but also in aberrant human diseases, including malignancy. With accumulating proofs of miR-105, the complex role of miR-105 during cancer initiation and progression is gradually emerging. miR-105 acts as a tumor suppressor by inhibiting tumor growth and metastasis or as an oncogene by promoting tumor initiation and invasion, depending on particular tumor contexts and base-pairing genes. In this review, we emphasize the characteristics of miR-105 in cancer to elucidate various deadly tumors and discuss transcriptional regulations that may explain fluctuations in miR-105 expression. This review may provide new ideas for applying miR-105 as a diagnostic and prognostic biomarker.

Then, the pre-miRNAs are exported from the nuclei by double-stranded RNA-binding proteins (exportin-5) and then cleaved by RNase III family enzymes (Dicer) into incompletely mature miRNAs (3)(4)(5). The mature miRNA is incorporated into the RNA-induced silenced complex (RISC) (6,7). The active RISC complex then binds to a target mRNA with a complementary sequence to trigger the mRNA for subsequent silencing (8). miRNA genes are involved in the regulation of up to 30% of all protein-coding genes (9,10). Although the scope of miRNA regulation of the human transcriptome is still under investigation, the association of miRNA dysregulation with the occurrence and development of various diseases has been supported by evidence (11).
However, contradictory results were produced through previous research with regard to whether miR-105 is an oncogene or a tumor suppressor and whether it is a positive or negative prognostic biomarker. In this review, we examine the following according to the properties of miR-105: (1) the oncogenic roles of miR-105, (2) miR-105 as a tumor suppressor, (3) the functions miR-05 in cancer-cell-secreted exosome, (4) the regulation mechanisms explaining the aberrant expression of miR-105, and (5) the diagnostic and prognostic value of miR-105 in cancer. The aim of this review is to emphasize the novel and diverse functions of miR-105 and its sense in cancer therapy.

Colorectal Cancer
The vital roles of miRNAs, especially miR-105, in the pathophysiology of colorectal cancer (CRC) have been demonstrated in various studies (30)(31)(32). Through highthroughput sequencing, Hamfjord et al. found that the level of miR-105 expression was upregulated in tumor tissues from eight patients with CRC. Further data confirmed the differences in miRNA expression between adenocarcinomas and neuroendocrine of colon cancer (13). Shen et al. also reported that the miR-105 is overexpressed in CRC tissues and cell lines, and miR-105 expression positively correlates with lymph node invasion, TNM stage, and metastasis. Moreover, miR-105 expression is predominantly stimulated by TNF-α in a timedependent manner. Upregulated miR-105 expression promotes CRC cell metastasis and epithelial-mesenchymal transition (EMT) in vitro and in vivo by directly targeting the 3 ′ UTRs of a Rap2 subfamily of a small GTP-binding protein (RAP2C) through the activation of the NF-κB signaling pathway (14). Thus, miR-105 has an oncogenic role in human CRC. However, the abovementioned researches are relatively superficial, and future studies are needed to confirm the specific mechanism of miR-105 in CRC.

Gastric Cancer
Although several miRNAs have demonstrated their crucial roles in the occurrence and progression of gastric cancer (GC) (33)(34)(35), the exact role of miR-105 in GC remains unclear (17,18). Liu et al. first reported that miR-105 expression is significantly elevated in GC tissues than in normal tissues (17). However, Zhou et al. recently revealed that a highly methylated miR-105 promoter decreases miR-105 expression in GC tissues (18). Overexpressed miR-105 inhibits cell viability and proliferation by Tumor promoter (19,20) directly targeting the Yin Yang 1 (YY1). The miR-105 role in GC is complex and thus must be investigated further.

Hepatocellular Carcinoma
To date, human endogenous miRNA dysregulation has been involved in the carcinogenesis and progression of HCC (37-39). Shen et al. found that HCC cell lines and clinical HCC tissues show significant decrease in their miR-105 expression levels in contrast to normal hepatocytes and adjacent noncancerous tissues. Decreased miR-105 expression promotes the proliferation and tumorigenicity of HCC cells in vitro and in vivo and activates the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway by directly upregulating insulin receptor substrate-1, 3-phosphoinositide-dependent protein kinase-1, and AKT1, leading to decreased cyclin-dependent kinase inhibitors of 1A and 1B (p21 Cip1 and p27 Kip1 ) and increased cyclin D1 expression in HCC (16). Another study showed that miR-105 expression was reduced in HCC tissues (15). The upregulated expression of miR-105 suppresses the proliferation of HCC cells in vitro by targeting the nuclear receptor coactivator 1 (NCOA1). Furthermore, decreased miR-105 correlates with reduced median OS and PFS in patients with HCC. The research on the mechanism of miR-105 loss will help future scholars better understand the tumor transformation in HCC and design new treatment strategies.

Other Tumors
Apart from the aforementioned tumors, the miR-105 as a tumor suppressor has been widely studied in other sort of cancer, including prostate cancer and non-small-cell lung cancer (NSCLC  (Figure 2). miR-105 is present in serum-derived exosomes, and the level of miR-105 expression in patients with distant metastasis is higher than in patients who did not develop metastasis (19). These studies provide insights into the regulation of gene expression and cellular components of the tumor microenvironment by exosomally derived miRNAs and indicate that miR-105 has potential clinical applications as a prognostic biomarker and a therapeutic target for BC.

REGULATION MECHANISMS OF miR-105 EXPRESSION
Parallel to protein-encoding genes, the expression of miRNA is regulated not only by different mechanisms at a genetic or epigenetic level but also by the dysregulation of specific transcription factors (52). Similarly, the dysregulation of miR-105 in cancer is involved in some of the aforementioned mechanisms (Figure 1).
Epigenetic regulation is an important mechanism governing miRNA expression (53,54). Zhou    TNF-α in a time-dependent manner through employing RT-qPCR analysis in CRC cells (14). By next-generation sequencing and RT-qPCR, Hsu et al. found that miR-105 expression is upregulated in cells that is treated with CXCL1 secreted from tumor-associated dendritic cells in colon cancer (58).

CLINICAL IMPLICATIONS
Improving the therapeutic result with the early diagnosis and accurate prognosis evaluation of cancer is critical. Cancer cells or tissues may present aberrant miRNA expression profiles, and specific miRNA features can be used not only for diagnosis but also for classifying patients with cancer as subgroups with different prognosis for individualized treatment (59)(60)(61)(62)(63). The role of miR-105 in cancer diagnosis and prognosis is extensively investigated, but it exhibits apparently conflicting outcomes ( Table 2). Zhou et al. demonstrated that patients who later developed distant metastases have higher levels of circulating (exosomal) and tumor miR-105 than patients who did not and had normal mammary tissues, suggesting that cancer-derived miR-105 can serve as a blood-based marker for the early diagnosis of BC metastasis (19). High NCOA1 and low miR-105-1 levels significantly decrease OS (P < 0.001) and PFS (P = 0.002), implying that NCOA1 and miR-105-1 might have a potential prognostic value for patients with HCC (15). Guan et al. found that a decreased miR-105 expression is statistically associated with advanced clinical features and poor OS (P < 0.001) of patients with glioma, suggesting that miR-105 downregulation may be used as a malignant prognostic marker in gliomas (24). Similarly, Yan et al. indicated that low miR-105 expression can be used for identifying patients with a high risk of unfavorable outcomes, particularly as a prognostic marker for patient risk stratification in anaplastic gliomas and secondary and proneural glioblastomas (25). A high level of miR-105 is associated with advanced clinical stages and the increased rates of the distant metastasis of CRC (14). Li et al. found that circulating miR-105/93-3p can act as an early diagnostic biomarker for TNBC, and the levels of miR-105/93-3p are significantly elevated in the plasmas of patients with TNBC relative to the levels in the plasmas of patients without TNBC or healthy controls. As expected, the patients with high miR-105/93-3p levels in TNBC tissues showed a positive correlation with chemoresistance and poor survival (21). Reduced miR-105-1 expression is associated with a larger tumor size, as well as the poor OS and disease-free survival of patients with NSCLC, demonstrating that downregulated miR-105-1 can be used as an independent malignant predictor in patients with NSCLC (22). CONCLUSION miRNAs play a vital role in the initiation and progression of human malignancies. On the one hand, miR-105 facilitates cell proliferation, promotes metastasis and chemoresistance, and initiates EMT in tumorigenesis, as illustrated in Figure 1. On the other hand, miR-105 inhibits proliferation, tumorigenesis, migration, invasion, and drug sensitivity. The role of this miRNA depends on the cellular and histological features of tumors and target mRNAs. The fluctuation of miR-105 expression is correlated with epigenetic alterations, especially the regression of miR-105 in cancer. Nevertheless, further researches are needed to provide sufficient evidence to explain the activation of miR-105 in cancer.

AUTHOR CONTRIBUTIONS
JL, ZZ, and FC contributed to conception and manuscript writing. TH, WP, and QG searched the literature. YS participated in its coordination and modification. All the authors have read and approved the final manuscript.

FUNDING
The work is funded by Jiangsu Key Medical Discipline (General Surgery) (ZDXKA2016005).