OncoTargets and Therapy (Jul 2019)
MicroRNA-936 targets FGF2 to inhibit epithelial ovarian cancer aggressiveness by deactivating the PI3K/Akt pathway
Abstract
Cuihong Li,1,* Shunrui Yu,1,* Shanshan Wu,2 Ying Ni,3 Zixuan Pan41Department of Gynecology and Obstetrics, Yidu Central Hospital of Weifang, Weifang 262500, People’s Republic of China; 2Department of Emergency, Yidu Central Hospital of Weifang, Weifang 262500, People’s Republic of China; 3Department of Oral, Weifang Nursing Vocational College, Weifang 262000, People’s Republic of China; 4Department of Gynecology, The Affiliated Hospital of Weifang Medical University, Weifang 261031, People’s Republic of China*These authors contributed equally to this workPurpose: MicroRNA-936 (miR-936) was previously reported to be dysregulated and involved in the development of non-small cell lung cancer and glioma. However, the functional roles of miR-936 in epithelial ovarian cancer (EOC) remain unclear. In this study, we aimed to evaluate miR-936 expression in EOC and investigate its regulatory role in EOC cell behavior.Methods: The expression of miR-936 in EOC was measured by RT-qPCR. Cell proliferation, apoptosis, migration, and invasion in vitro, as well as tumor growth in vivo, were determined by CCK-8, flow cytometry, migration and invasion assays, and xenograft models in nude mice, respectively. Bioinformatics analysis, luciferase reporter assays, RT-qPCR, and Western blot analysis were performed to investigate the relationship between miR-936 and fibroblast growth factor 2 (FGF2).Results: miR-936 expression was significantly downregulated in EOC tissues and cell lines. Low miR-936 expression was found to be correlated with the tumor size, FIGO stage, and lymphatic metastasis in EOC patients. Functional experiments indicated that ectopic miR-936 expression suppressed EOC cell proliferation, migration, and invasion; promoted cell apoptosis; and decreased tumor growth in vivo. In addition, the FGF2 gene was verified to be a direct target of miR-936 in EOC cells. FGF2 expression levels were upregulated in EOC tissues and were inversely correlated with miR-936 expression. Furthermore, effects of FGF2 silencing were similar to those of miR-936 overexpression in EOC cells. Recovered FGF2 expression rescued the miR-936-induced inhibitory effects in EOC cells. Notably, miR-936 was able to deactivate the PI3K/Akt signaling pathway in EOC cells by regulating FGF2 both in vitro and in vivo.Conclusion: Altogether, our findings provided initial evidence that miR-936 inhibits the aggressiveness of EOC cells in vitro and in vivo, at least partially, by targeting FGF2-mediated suppression of the PI3K/Akt pathway. Therefore, the miR-936/FGF2/PI3K/Akt pathway is a promising therapeutic target for the treatment of EOC patients.Keywords: epithelial ovarian cancer, microRNA-936, fibroblast growth factor 2, PI3K/Akt pathway
