CircFAM114A2 Inhibits Bladder Cancer Proliferation and Promotes Cisplatin Sensitivity via the miR-222-3p/P27 and miR-146a-5p/P21 Cascades

Abstract

Background: Circular RNAs (circRNAs) are noncoding RNAs that have the structure of a covalently closed loop. Increasing data has proved that circRNA can influence the development and progression of tumors. CircFAM114A2 is generated from several exons of FAM114A2. However, the function and mechanisms of circFAM114A2 in bladder cancer (BCa) remain unclear. Methods: Here, to elucidate the potential roles of circFAM114A2 in BCa, we conducted RNA-sequencing on 5 pairs of BCa samples and screened for circRNAs. CircRNAs, microRNAs (miRNAs) and mRNAs, as well as levels of P27 and P21, in human cells and tissues were detected by qRT-PCR and western blot, respectively. CircRNA-miRNA interactions and miRNA-downstream mRNAs interactions were investigated by RNA pull-down assay and fluorescence in situ hybridization (FISH) or luciferase reporter assays, respectively. Then, the function of circFAM114A2 in BCa was explored using cell proliferation, cell cycle and tumorigenesis assays in nude mice. Finally, the function of circFAM114A2 in cisplatin chemo-sensitivity in BCa was detected by IC50 and tumor formation of xenograft in cisplatin-treated nude mice. Results: We discovered that circFAM114A2 levels were decreased in BCa cell lines and tissues. According to follow-up data, BCa patients with higher circFAM114A2 expression had better survival. Importantly, the levels of circFAM114A2 were associated with the histological grade of BCa. Overexpression of circFAM114A2 inhibited cell proliferation and increased sensitivity to cisplatin chemotherapy. Mechanistically, circFAM114A2 directly sponged miR-222-3p/miR-146a-5p and subsequently influenced the expression of the downstream target genes P27/P21, which, in turn, inhibited progression of BCa. Conclusion: In conclusion, circFAM114A2 acted as a tumor suppressor through a novel circFAM114A2/miR-222-3p/P27 and circFAM114A2/miR-146a-5p/P21 pathway. CircFAM1142 has therefore great potential as a prognostic biomarker and therapeutic target for BCa.