Abstract
Although increasing evidence indicated that deregulation of microRNAs (miRNAs) contributed to tumor initiation and progression, but little is known about the biological role of miR-340 in ovarian cancer (OC). In this study, we found that miR-340 expression was downregulated in OC tissues compared with its expression in normal ovarian epithelium and endometrium, and treatment with 5-aza-2′-deoxycytidine (5-Aza-dC) or trichostatin A (TSA) increased miR-340 expression in OC cells. In addition, ectopic miR-340 expression inhibited OC cell growth and metastasis in vitro and in vivo. Four and a half LIM domains protein 2 (FHL2) was confirmed as a direct target of miR-340 and silencing FHL2 mimicked the effects of miR-340 in OC cells. Further mechanistic study showed that miR-340 inhibited the Wnt/β-catenin pathway by targeting FHL2, as well as downstream cell cycle and epithelial-to-mesenchymal transition (EMT) signals in OC cells. Moreover, the greatest association between miR-340 and FHL2 was found in 481 ovarian serous cystadenocarcinoma tissues via pan-cancer analysis. Finally, we revealed that lower miR-340 or higher FHL2 was associated with poor OC patient outcomes. Our findings indicate that the miR-340-FHL2 axis regulates Wnt/β-catenin signaling and is involved in tumorigenesis in OC. Therefore, manipulating the expression of miR-340 or its target genes is a potential strategy in OC therapy.
Highlights
Human ovarian cancer (OC) is the leading cause of death from gynecologic malignancies[1,2,3]
Treatment with 5-Aza-dC or trichostatin A (TSA) restored the levels of miR-340 in A2780 and SKOV3 cells (Fig. 1d, e), suggesting that downregulation of miR-340 is due to its promoter hypermethylation in OC cells
FHL2 and miR-340 had no effect on the activity of FopFlash, a negative control β-catenin reporter (Fig. 7a, b). These results showed that which ultimatelyWingless/integrated (Wnt)/β-catenin signaling was negatively regulated by miR-340 and positively regulated by FHL2, which offers a plausible explanation for the suppressive effects of the miR-340-FHL2 axis in OC cells
Summary
Human ovarian cancer (OC) is the leading cause of death from gynecologic malignancies[1,2,3]. Worldwide, ~295,400 new cases of OC have been diagnosed and 184,800 women are expected to succumb to the disease in 20184. This case-to-fatality ratio is nearly twice that of breast cancer[4]. The canonical pathway is activated upon Wnt ligand binding to Frizzled receptors and LDL-receptor-related protein (LRP) co-receptors. These interactions disrupt the adenomatous polyposis coli (APC)/Axin/casein kinase 1 alpha (CK1A)/glycogen synthase kinase 3 beta (GSK3β) complex, which results in the translocation and Official journal of the Cell Death Differentiation Association
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