miRNA-181a-5p Enhances the Sensitivity of Cells to Cisplatin in Esophageal Adenocarcinoma by Targeting CBLB

Song Yang,1,* Peng Wang,1,* Songhua Wang,1 Aihua Cong,1 Qi Zhang,1 Wenhao Shen,1 Xiangyi Li,2 Wei Zhang,3 Gaohua Han1 1Department of Oncology, Taizhou People’s Hospital, Taizhou, Jiangsu 225300, People’s Republic of China; 2Department of Endocrinology, Taizhou People’s Hospital, Taizhou, Jiangsu 225300, People’s Republic of China; 3Department of Infectious Diseases, Taizhou People’s Hospital, Taizhou 225300, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Zhang; Gaohua Han Email tgc6nl@163.com; y0ztiin@163.comBackground: Cisplatin (CDDP) is extensively used for esophageal adenocarcinoma (EAC) chemotherapy, while cisplatin resistance is getting worse. microRNA-181a-5p (miR-181a-5p) has been reported to play an important role in various human cancers. However, the effect and underlying mechanism of miR-181a-5p in cisplatin resistance of EAC remain unclear.Methods: Cisplatin-resistant EAC cells OE19/CDDP and parental sensitive OE19 cells were applied for experiments in vitro. The expressions of miR-181a-5p and CBLB were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. The cisplatin resistance of cells was expressed by cell viability, IC50 and apoptosis rate by using CCK-8 assay or flow cytometry. The interaction between miR-181a-5p and CBLB was evaluated by luciferase reporter assay and RIP assay. In vivo experiments were conducted via the murine xenograft model.Results: miR-181a-5p was highly expressed while CBLB was lowly expressed in OE19 cell lines compared with OE19/CDDP cells. In cisplatin-resistant OE19/CDDP cells, miR-181a-5p up-regulation or CBLB knockdown inhibited cell viability and inducted apoptosis. In cisplatin-sensitive OE19 cells, miR-181a-5p inhibition or CBLB overexpression promoted cell viability and suppressed apoptosis. CBLB was confirmed to be a target of miR-181a-5p, and rescue assay showed CBLB overexpression reversed the suppression of OE19/CDDP cell viability induced by miR-181a-5p up-regulation, and its down-regulation attenuated miR-181a-5p-inhibition-mediated enhancement of OE19 cell viability. In addition, miR-181a-5p up-regulation enhanced the cytotoxicity of cisplatin in EAC in vivo.Conclusion: miR-181a-5p enhanced the sensitivity of cells to cisplatin in EAC by targeting CBLB, indicating a promising sensitizer of cisplatin therapy in clinical esophageal cancer.Keywords: EAC, cisplatin resistance, miR-181a-5p, CBLB