The Roles of MicroRNA-133 in Gynecological Tumors.

The vital roles of miR-133 have been demonstrated adverse functions, both oncogenic and suppressive functions, in the pathophysiology of cervical cancer. Through microarrays analysis of cervical carcinoma, Qin et al . found that the level of miR-133b expression was progressively elevated throughout advancing stages in cervical carcinoma tissues. Cellular studies showed that the elevation of miR-133b deregulates the Akt1 and ERK signaling pathways through direct effects on the mammalian sterile 20-like kinase 2 (MST2), cell division control protein 42 homolog (CDC42) and as homolog gene family member A (RHOA) genes activities, resulting in enhanced cell proliferation and colony formation in vitro and promoting tumorgenesis and metastasis in nude mice model.[ 29 ] Qin et al . also identified miR-133b was a key prognostic mark through the ceRNA network analysis. They then performed the Kaplan–Meier survival analysis using the TCGA dataset, and the results revealed that the survival ratio was significantly better in the low-expression miR-133b group.[ 30 ] However, two recent studies demonstrated that miR-133b played suppressive function and was reversely regulated by upstream oncogenes Lnc02381 and lncMST1P2 with sponging mechanism, inhibiting cell viability, metastasis and migration in cervical cancer cells[ 31 32 ] and in subcutaneous tumor model of nude mice.[ 31 ] Adversely, some researches verified that miR-133a exhibits opposite suppressor roles in cervical cancer. Yuan et al . reported that the expression level of miR-133a was significantly downregulated both in cervical cancer tissues and cervical tumor cell lines,[ 33 ] Research showed that LncRNA NEAT1 acted as a sponge molecules negatively modulating miR-133a expression by targeting 5'UTR of miR-133a. SOX4 was able to act as a downstream target of miR-133a and silencing of SOX4 can restrain progression of cervical cancer; therefore, NEAT1/miR-133a/SOX4 axis plays a significant role in the progression of cervical cancer.[ 33 ]

As illuminated above, miR-133 is mainly acted on WNT, MAPK, and AKT pathways. Here, we summarize other reported microRNAs impacted on the same pathway in ovarian cancer to predict the potential further functions that may be effected on ovarian cancer [ Figure 2 and Table 1 ]. The overexpression of miR-16 and miR377 can regulate metastatic capability by inhibiting the process of EMT and inactivating the Wnt/β-catenin pathway[ 38 39 ] and restoration of miR-338 will attenuate MACC1 and Met overexpression-induced EMT and activities of Wnt/β-catenin and MEK/ERK signaling in vitro and in vivo .[ 40 ] Adversely restraining the expression of miR-27a that regulating FOXO1 can inhabit cell migration and invasion by inhibiting EMT and inactivating of the Wnt/β-catenin pathway in ovarian cells.[ 41 ] These evidences indicate that the microRNAs-induced activation of the Wnt/β-catenin pathway often promotes the EMT process in OC. Chen et al . found that miR-92a-1 is regulated by STAT3 and targets DKK1 the canonical Wnt pathway antagonist, to inhibit the Wnt pathway. The STAT3-miRNA-92-Wnt signaling pathway regulates cancer stem cell-like characteristics and is related to chemoresistance in ovarian cancer cells.[ 42 ] Majem et al . unveiled miR-654 differentially expressed between short term (overall survival of <3 years) and long term (overall survival of more than 8 years) survival groups. Kaplan–Meier survival curves from HGSC tumors reflected that high miR-654 expression related to poorer survival, suggesting a prognostic role for miR-654 levels in OC. In addition, the results demonstrate that miR-654 promoter region is hypermethylated in both OC cell lines and tissues, which can be responsible in part for the low miR-654 levels and suggests that epigenetic silencing could be one of the possible mechanisms of microRNAs regulation. The overexpression of miR-654 reduces viability in normal OC cell lines and OC patient-derived ascitic cells, sensitizing OC cells to paclitaxel and impairing tumor growth in vivo . Further investigation verified that miR-654 mainly targets CDCP1 and PLAGL2 genes which in turn modulate the MYC, AKT, and Wnt pathways in OC.[ 43 ] Similar function miRNAs in ovarian cancer. Black indicators represent binding, red indicators represent promotion, and green indicators represent inhibition Similar microRNAs roles in ovarian cancer EMT: Epithelial-mesenchymal transition, CSC: Cancer stem cell, ERK: Extracellular regulated kinases,MEK(MAPKK):Mitogen-activated protein kinase kinase, MYC:V-Myc myelocytomatosis viral oncogene homolog

MicroRNAs (miRNAs) are a class of small (18–25 nt) noncoding RNAs encoded by endogenous genes that are involved in the regulation of posttranscriptional gene expression in plants and animals.[ 1 ] The production of mature miRNAs requires several key steps. First, long primary transcripts (pri-miRNAs) are transcribed and further cleaved into pre-miRNAs.[ 2 ] Then, the pre-miRNAs are further cleaved by RNase III family enzymes (Dicer) into miRNAs.[ 3 4 ] MiRNAs bind to the target mRNA with a complementary sequence, playing a regulatory role.[ 5 ] Studies have shown that approximately 70% of mammalian miRNAs are located in the transcription units.[ 6 ] The miRNAs target sequences are located at the 3' untranslated regions (UTRs),[ 1 ] the 5' UTRs[ 7 ] and coding regions[ 8 ] of related mRNA. Studies showed that more than 30% of protein-coding genes are regulated by miRNAs. The dysregulation and dysfunction of miRNAs are related to human diseases, and aberrant miRNA expression is well recognized as a significant process in the development of cancer. The miRNA-133 family, primely classified as myomiRNAs, that consists of miR-133a and miR-133b that only a single nucleotide at the 3' end of them is different, is widely studied in human diseases. MiR-133a can be generated by two different genes: MiR-133a-1 and miR-133a-2 that share identical mature sequences. MiR-133a-1, miR-133a-2, and miR-133b are located on human chromosome 18, 20, 6, and transcribed as bicistronic transcripts together with miR-1-2, miR-1-1, and miR-206, respectively. MiR-133 is first identified in the heart and skeletal muscle,[ 9 ] and it also plays an important role in the oncogenic and suppressive functions in different kinds of cancers,[ 10 ] including ovarian cancer,[ 11 12 13 ] colorectal cancer,[ 14 15 ] osteosarcoma,[ 16 17 ] and recently gastric cancer[ 18 19 ] and so on. MiR-133 recently showed increasing key functions in the initiation and development of gynecological cancers. Now, the roles of miR-133 in gynecological cancers will be summarized in this review.

Increasing evidence shows that miR-133 plays a vital role in the initiation and progression of human malignancies. On the one hand, miR-133 mainly inhibits cell proliferation, invasion, metastasis, and regulates EMT in ovarian cancer and uterine malignant tumors. On the other hand, miR-133 shows the opposite effect in cervical cancer. However, more in-depth researches of miR-133 in fields of gynecological cancers, such as drug sensitivity, epigenetics alterations, prediction role of clinical prognosis, and other clinical implications, have not been reported, and further related researches are expected to provide sufficient evidences to explain the functions of miR-133. Nil. Dr. Zhongping Cheng, an editorial board member at Gynecology and Minimally Invasive Therapy , had no role in the peer review process of or decision to publish this article. The other author declared no conflicts of interest in writing this paper.