Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation
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Tong-Hong Wang1,2,3, Chi-Hao Wu4, Chau-Ting Yeh3, Shih-Chi Su5, Shih-Min Hsia6, Kung-Hao Liang3, Chin-Chuan Chen1,7, Chuen Hsueh1,8 and Chi-Yuan Chen1,2
1Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
2Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
3Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
4Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan
5Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
6School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan
7Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan, Taiwan
8Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
Chuen Hsueh, email: [email protected]
Chi-Yuan Chen, email: [email protected]
Keywords: melatonin, hepatocellular carcinoma, epithelial-mesenchymal transition, lncRNA-CPS1-IT1, HIF-1α
Received: April 14, 2017 Accepted: June 10, 2017 Published: July 18, 2017
Melatonin is the primary pineal hormone that relays light/dark cycle information to the circadian system. It was recently reported to exert intrinsic antitumor activity in various cancers. However, the regulatory mechanisms underlying the antitumor activity of melatonin are poorly understood. Moreover, a limited number of studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), a major life-threatening malignancy in both sexes in Taiwan. In this study, we investigated the antitumor effects of melatonin in HCC and explored the regulatory mechanisms underlying these effects. We observed that melatonin significantly inhibited the proliferation, migration, and invasion of HCC cells and significantly induced the expression of the transcription factor FOXA2 in HCC cells. This increase in FOXA2 expression resulted in upregulation of lncRNA-CPS1 intronic transcript 1 (CPS1-IT1), which reduced HIF-1α activity and consequently resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo experiments confirmed that melatonin exerts tumor suppressive effects by reducing tumor growth. In conclusion, our findings suggested that melatonin inhibited HCC progression by reducing lncRNA-CPS1-IT1-mediated EMT suppression and indicated that melatonin could be a promising treatment for HCC.
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