OncoTargets and Therapy (Jul 2019)
MiR-34c acts as a tumor suppressor in non-small cell lung cancer by inducing endoplasmic reticulum stress through targeting HMGB1
Abstract
Li Tu,*,1,2 Xiang Long,2 Weidong Song,2 Zhongdong Lv,2 Huadong Zeng,1 Tiezhu Wang,3 Xianglu Liu,2 Juanni Dong,2 Ping Xu*,21Department of Respiratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, People’s Republic of China; 2Department of Respiratory Medicine, Peking University Shenzhen Hospital, Shenzhen 518000, People’s Republic of China; 3Department of Respiratory Medicine, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou 363000, People’s Republic of China*These authors contributed equally to this workObjective: To investigate the role of miR-34c in lung cancer.Methods: The levels of microRNA-34c (miR-34c) expression in non-small cell lung cancer (NSCLC) tissue and cell lines were examined by the qRT-PCR assay. High mobility group box 1 (HMGB1) expression in NSCLC was assessed by immunohistochemical analysis (IHC), qRT-PCR, and Western blot assays. The effects of miR-34c overexpression or HMGB1 knockdown on cell proliferation and apoptosis were evaluated by CCK-8 and flow cytometry analysis, respectively. Cellular reactive oxygen species (ROS) production in NSCLC cells was detected using a ROS kit. The levels of Bax, p-ERK, eIF2α, GADD153, and IRE1α expression in treated NSCLC cells were measured by Western blot assays. In addition, the interaction between miR-34c and HMGB1 was verified by the dual-luciferase reporter assay.Results: miR-34c was only slightly expressed, while HMGB1 was highly expressed in NSCLC tissues and cell lines. Overexpression of miR-34c or knockdown of HMGB1 inhibited cell proliferation, promoted cell apoptosis, and induced ER stress in NSCLC cells. In terms of mechanism, miR-34c negatively regulated HMGB1 expression by directly targeting the 3ʹ-untranslated region (UTR) of HMGB1 mRNA. In addition, we proved that HMGB1 overexpression could block the effects of miR-34c on NSCLC cell proliferation, apoptosis, and ER stress.Conclusion: miR-34c may suppress NSCLC tumors by targeting HMGB1 mRNA, promoting endoplasmic reticulum stress, and increasing ROS levels. Our findings suggest that miR-34c has a role in NSCLC.Keywords: non-small cell lung cancer, microRNA, high mobility group box 1, endoplasmic reticulum stress, ER stress
