MicroRNA-130b functions as a tumor suppressor by regulating RUNX3 in epithelial ovarian cancer.

To evaluate the clinical significance of microRNA (miR)-130b-Runt domain transcription factor (RUNX3) axis and its effects on oncogenic phenotypes of human epithelial ovarian cancer (EOC). QRT-PCR was performed to detect the expression of miR-130b and RUNX3 mRNA in 100 EOC and 20 normal ovarian tissues. The associations between miR-130b and/or RUNX3 expression and various clinicopathological features of EOC patients were statistically analyzed. Then, the effects of miR-130b-RUNX3 axis on migration and invasion of EOC cells were assessed in vitro. miR-130b expression was downregulated, while RUNX3 mRNA was upregulated, in EOC tissues compared to normal ovarian tissues (both P=0.001). Importantly, the expression level of miR-130b in EOC tissues was negatively correlated with that of RUNX3 mRNA significantly. Additionally, miR-130b-low and/or RUNX3-high expression were all closely correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage (all P<0.05). Moreover, overexpression of miR-130b reduced the expression of RUNX3 and inhibited cancer cell migration and invasion of EOC cells, whereas knockdown of miR-130b increased the expression of RUNX3 and promoted cancer cell migration and invasion of EOC cells. After that, the impaired motility of the miR-130b overexpression cells was recovered partly by the expression of RUNX3. Furthermore, the knockdown of RUNX3 also gave rise to a decrease in cell migration and invasion. Our data reveal that the dysregulation of miR-130b-RUNX3 axis may play important roles in EOC development and progression, and the loss of miR-130b may contribute to the malignant biological behavior of EOC cells via regulating the expression of RUNX3, implying their potentials as promising markers for predicting EOC progression and as candidate targets for gene therapy.

Paudel D ，Zhou W ，Ouyang Y ，Dong S ，Huang Q ，Giri R ，Wang J ，Tong X ... -  《-》

MiR-205 promotes motility of ovarian cancer cells via targeting ZEB1.

To investigate the clinical significance of microRNA-205 (miR-205) and zinc finger E-box binding homeobox 1 (ZEB1) in epithelial ovarian cancer (EOC) and the underlying mechanisms by which they are involved into tumorigenesis. Expression levels of miR-205 and ZEB1 mRNA in EOC tissues were detected by quantitative real-time PCR. Their associations with clinicopathological features of EOC patients were statistically analyzed. Luciferase reporter assay was used to confirm target associations between miR-205 and ZEB1. After that, the functions of miR-205-ZEB1 axis on cell migration and invasion were further determined by transwell assay in vitro. Expression levels of miR-205 (P=0.0001) and ZEB1 mRNA (P<0.0001) in clinical EOC tissues were significantly higher and lower than those in normal tissues, respectively. Interestingly, there was a negative correlation between miR-205 and ZEB1 mRNA expression in EOC tissues (P=0.01). Additionally, miR-205-upregulation and/or ZEB1-downregulation were significantly associated with high pathological grade and advanced clinical stage of EOC patients (all P<0.05). Meantime, luciferase reporter assays identified ZEB1 as a direct target of miR-205 in EOC cells. Moreover, miR-205 blockage inhibited, whereas miR-205 mimics promoted the motility of EOC cells in vitro. Importantly, all the alterations of the above cellular phenotypes by blocking or enhancing of miR-205 could be alleviated by subsequent suppression or re-introduction of its target ZEB1, respectively. MiR-205, acting as an oncogenic miRNA, may promote the clinical progression of EOC patients and enhance the cellular motility in vitro by directly and negatively regulating ZEB1, providing a potential therapeutic strategy for suppression of EOC metastasis.

Niu K ，Shen W ，Zhang Y ，Zhao Y ，Lu Y ... -  《-》

Long non-coding RNA CCAT1 promotes metastasis and poor prognosis in epithelial ovarian cancer.

In this study, we reported that long non-coding RNA (lncRNA) CCAT1 was upregulated in epithelial ovarian cancer (EOC) tissues, and was associated with FIGO stage, histological grade, lymph node metastasis and poor survival of EOC patients. Multivariate Cox regression analysis showed that CCAT1 was an independent prognostic indicator. While CCAT1 downregulation inhibited EOC cell epithelial-mesenchymal transition (EMT), migration and invasion, CCAT1 upregulation promoted EOC cell EMT, migration and invasion. We further identified and confirmed that miR-152 and miR-130b were the targets of CCAT1, and CCAT1 functioned by targeting miR-152 and miR-130b. Subsequently, ADAM17 and WNT1, and STAT3 and ZEB1 were confirmed to be the targets of miR-152 and miR-130b, respectively, and could be regulated by CCAT1 in EOC cells. Knockdown of anyone of these four proteins inhibited EOC cell EMT, migration and invasion. Taken together, our study first revealed a critical role of CCAT1-miR-152/miR-130b-ADAM17/WNT1/STAT3/ZEB1 regulatory network in EOC cell metastasis. These findings provide great insights into EOC initiation and progression, and novel potential therapeutic targets and biomarkers for diagnosis and prognosis for EOC.

Cao Y ，Shi H ，Ren F ，Jia Y ，Zhang R ... -  《-》

Cytidine monophosphate kinase is inhibited by the TGF-β signalling pathway through the upregulation of miR-130b-3p in human epithelial ovarian cancer.

Cytidine monophosphate kinase (CMPK), a member of the nucleoside monophosphate kinase family, plays an important role in the biosynthesis of nucleoside metabolism, DNA repair and tumour development. In this study, we demonstrated for the first time that CMPK was overexpressed in human ovarian epithelial borderline and malignant tumours using tissue microarray. Knockdown of CMPK significantly inhibited epithelial ovarian cancer (EOC) cell proliferation, migration and invasion. Furthermore, CMPK-shRNA inhibited PCNA, MMP-2, MMP-9 and vimentin expression, increased E-cadherin expression and arrested cell cycle at the G2/M phase. Suppression of CMPK resulted in a decrease of EOC cell microtissue formation and colony formation in vitro. Overexpression of miR-130b-3p decreased CMPK expression, whereas anti-miR-130b-3p increased CMPK expression. Moreover, TGF-β1 inhibited the expression of CMPK, which was blocked in the presence of a TGF-β type I receptor, SB431542, and was abolished by the inhibitor of miR-130b-3p, indicating that CMPK is regulated by the TGF-β signalling pathway through the upregulation of miR-130b-3p. Thus, our data identify that overexpression of CMPK occurs in EOC and reveal a mechanism underlying the regulation of CMPK by the TGF-β signalling pathway. We could consider CMPK as an EOC biomarker and targeting CMPK by decreasing its expression may be beneficial in patients with EOC.

Zhou D ，Zhang L ，Sun W ，Guan W ，Lin Q ，Ren W ，Zhang J ，Xu G ... -  《-》

MicroRNA-150 predicts a favorable prognosis in patients with epithelial ovarian cancer, and inhibits cell invasion and metastasis by suppressing transcriptional repressor ZEB1.

Jin M ，Yang Z ，Ye W ，Xu H ，Hua X ... -  《PLoS One》