Abstract
Epithelial ovarian carcinoma (EOC) is the most lethal gynecologic malignancy. However, the molecular mechanisms remain unclear. In this study, we found that miR-146b was downregulated in EOC and its expression level was negatively correlated with the pathological staging. Follow-up functional experiments illustrated that overexpression of miR-146b significantly inhibited cell migration and invasion, and increased cell proliferation, but it also improved the response to chemotherapeutic agents. Mechanistically, we demonstrated that miR-146b exerted its function mainly through inhibiting F-box and leucine-rich repeat protein 10 (FBXL10), and upregulated the Cyclin D1, vimentin (VIM), and zona-occludens-1 (ZO-1) expression in EOC. These findings indicate that miR-146b–FBXL10 axis is an important epigenetic regulation pathway in EOC. Low miR-146b may contribute to cancer progression from primary stage to advanced stage, and may be the promising therapeutic target of EOC.
Highlights
Of all gynecologic malignancies, ovarian cancer is the most lethal gynecologic malignancy[1,2]
Previous studies have indicated that F-box and leucine-rich repeat protein 10 (FBXL10) was a histone lysine demethylase that could target H3K4me[3] or H3K36me[2] for demethylation[15,21]; our results revealed that FBXL10 especially removed methyl groups from H3K4me[3] in ovarian cancer cells (Fig. 5f)
Additional chromatin immunoprecipitation (ChIP) assay revealed a considerable increase in H3K4me[3] levels at the ZO-1 gene promoter with miR146b overexpression (Fig. 7f, g), but no significant changes were observed in H3K4me[3] enrichment at the promoter of VIM. These results demonstrated that ZO-1 and VIM were direct targets of FBXL10, and suggested that FBXL10 regulated the expression of ZO-1 through H3K4me[3] demethylation
Summary
Ovarian cancer is the most lethal gynecologic malignancy[1,2]. Despite recent advances in molecularly targeted therapy and immunotherapy such as anti-PD-1/PD-L1 antibody and CAR-T therapy, the 5-year survival rate of advanced EOC patients falls below 25%4,5. This is primarily because EOC has few early or specific symptoms, and two-thirds of patients had MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression by binding the 3′-untranslated regions (UTR) of mRNAs, inducing direct mRNA degradation, or translation inhibition[7]. The microRNA microarrays indicated that miR-146b was a differentially expressed miRNA in ovarian cancer[14]; the functional role of miR-146b in EOC has rarely been investigated
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