MicroRNA-138 enhances TRAIL-induced apoptosis through interferon-stimulated gene 15 downregulation in hepatocellular carcinoma cells
Chaohui Zuo,
Xinyi Sheng,
Zhuo Liu,
Min Ma,
Shuhan Xiong,
Hongyu Deng,
Sha Li,
Darong Yang,
Xiaohong Wang,
Hua Xiao,
Hu Quan,
Man Xia
Affiliations
Chaohui Zuo
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Xinyi Sheng
Graduate School, University of South China, Hengyang, China
Zhuo Liu
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Min Ma
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Shuhan Xiong
School of Public Health, Jilin University, Changchun, China
Hongyu Deng
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Sha Li
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Darong Yang
Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
Xiaohong Wang
Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
Hua Xiao
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Hu Quan
Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Man Xia
Department of Gynecological Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide. TRAIL (tumor necrosis factor–related apoptosis–inducing ligand) is a potential target for cancer therapy. However, many cancer cells are resistant to TRAIL-induced apoptosis and its mechanism is not well understood. In this study, to identify potential therapeutic targets for TRAIL-resistant cancer cells, we compared the expression levels of interferon-stimulated gene 15 in TRAIL-sensitive and TRAIL-resistant hepatocellular carcinoma cell lines. Western blot analysis showed that interferon-stimulated gene 15 expression levels were significantly higher in resistant HLCZ01and Huh7 cells than in sensitive LH86 and SMMC-7721 cells. Interferon-stimulated gene 15 knockdown in resistance cells led to TRAIL sensitivity. Conversely, interferon-stimulated gene 15 overexpression in sensitive cells resulted in TRAIL resistance. Our bioinformatics search detected a putative target sequence for microRNA miR-138 in the 3′ untranslated region of the interferon-stimulated gene 15. Real-time quantitative polymerase chain reaction analysis demonstrated that miR-138 was significantly downregulated in TRAIL-resistant cells compared to TRAIL-sensitive cells. Forced expression of miR-138 in resistant cells decreased both messenger RNA and protein levels of interferon-stimulated gene 15, and when exposed to TRAIL, activated poly(adenosine diphosphate-ribose) polymerase, indicating sensitization to TRAIL. The results suggested that miR-138 regulates the interferon-stimulated gene 15 expression by directly targeting the 3′ untranslated region of interferon-stimulated gene 15 and modulates the sensitivity to TRAIL-induced apoptosis. MiR-138 may be a target for therapeutic intervention in TRAIL-based drug treatments of resistant hepatocellular carcinoma or could be a biomarker to select patients who may benefit from the treatment.
