MicroRNA-421 regulated by HIF-1α promotes metastasis, inhibits apoptosis, and induces cisplatin resistance by targeting E-cadherin and caspase-3 in gastric cancer

// Xiaoxiao Ge 1, 2, * , Xinyang Liu 3, 4, * , Fengjuan Lin 1, 2, * , Peng Li 4 , Kaiyi Liu 1, 2 , Ruixuan Geng 6 , Congqi Dai 1, 2 , Ying Lin 1, 2 , Wenbo Tang 1, 2 , Zheng Wu 1, 2 , Jinjia Chang 1, 2 , Jianwei Lu 7 , Jin Li 1, 2 1 Department of Medical Oncology, Fudan University, Shanghai Cancer Center, Shanghai, 200000, P.R. China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200000, P.R. China 3 Shanghai Medical College, Fudan University, Shanghai, 200000, P.R. China 4 Harvard T.H. Chan School of Public Health, Boston, MA, 02115, U.S.A 5 Department of Regenerative Medicine and Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 20000, P.R. China 6 International Medical Services, Peking Union Medical College Hospital, Beijing, 100000, P.R. China 7 The Advanced Institute of Translational Medicine and School of Software Engineering, Tongji University, Shanghai, 200073, P.R. China * These authors have contributed equally to this work Correspondence to: Jin Li, e-mail: fudanlijin@163.com Jianwei Lu, e-mail: jianweilu_tongji@sina.com Keywords: gastric cancer, miR-421, HIF-1α, cisplatin resistance, epithelial-mesenchymal transition Received: November 25, 2015     Accepted: March 01, 2016     Published: March 21, 2016 ABSTRACT Hypoxia and dysregulation of microRNAs (miRNAs) have been identified as crucial factors in carcinogenesis. However, the potential mechanisms of HIF-1α and miR-421 in gastric cancer have not been well elucidated. In this study, we found that miR-421 was up-regulated by HIF-1α. Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer in vivo and in vitro . E-cadherin and caspase-3 were identified as targets of miR-421. Besides, relative mRNA expression of miR-421 was significantly increased in gastric cancer tumor tissues compared with non-tumor tissues in a cohort of gastric cancer specimens (n=107). The expression of miR-421 was higher in advanced gastric cancers compared with localized ones. Moreover, Kaplan–Meier analysis illustrated that those patients with low levels of miR-421 had a significant longer overall survival (p = 0.006) and time to relapse (p = 0.007). Therefore, miR-421 could serve as an important prognostic marker and a potential molecular target for therapy in gastric cancer.