MicroRNA-421 regulated by HIF-1α promotes metastasis, inhibits apoptosis, and induces cisplatin resistance by targeting E-cadherin and caspase-3 in gastric cancer
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Xiaoxiao Ge1,2,*, Xinyang Liu3,4,*, Fengjuan Lin1,2,*, Peng Li4, Kaiyi Liu1,2, Ruixuan Geng6, Congqi Dai1,2, Ying Lin1,2, Wenbo Tang1,2, Zheng Wu1,2, Jinjia Chang1,2, Jianwei Lu7, Jin Li1,2
1Department of Medical Oncology, Fudan University, Shanghai Cancer Center, Shanghai, 200000, P.R. China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200000, P.R. China
3Shanghai Medical College, Fudan University, Shanghai, 200000, P.R. China
4Harvard T.H. Chan School of Public Health, Boston, MA, 02115, U.S.A
5Department of Regenerative Medicine and Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 20000, P.R. China
6International Medical Services, Peking Union Medical College Hospital, Beijing, 100000, P.R. China
7The 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
Jin Li, e-mail: firstname.lastname@example.org
Jianwei Lu, e-mail: email@example.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
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.
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