Abstract 3446: Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation

Abstract

Abstract Background: Melatonin, the main pineal hormone that relays light/dark cycle information to the circadian system, was recently reported to have intrinsic antitumor activity in various cancers. However, the detailed regulatory mechanisms associated with antitumor activity of melatonin are not well understood yet. Moreover, limited studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), the major life-threatening malignancy for both sexes in Taiwan. Hence, in this study, we investigated the antitumor activity of melatonin on HCC and explored its regulatory mechanism. Methods: Human hepatoma cell lines HepG2 and Huh7 were treated with melatonin followed by functional assays to dissect antitumor effect of melatonin in HCC. The whole transcriptome sequence analysis was performed to explore the long non-coding RNAs (lncRNAs) involved in the anti-HCC activity of melatonin. Further, quantitative RT-PCR, western blot, immunohistochemistry assays, and in vivo animal model experiments were performed to elucidate the regulatory mechanism of lncRNAs in melatonin-mediated HCC suppression. Results: Melatonin significantly inhibited cell proliferation, migration, and invasion capacity of HCC cell lines, while the expression of transcription factor FOXA2 was significantly induced in cells treated with melatonin. The increase in expression of FOXA2 resulted in upregulation of lncRNA-CPS1-IT1 expression, which in turn reduced binding and activation of Hsp90 with HIF-1α. The inactivation of HIF-1α resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo animal model experiments also validated the tumor-suppressor role of melatonin via a reduction in tumor growth. Conclusions: Taken together, our findings suggested that melatonin inhibited HCC progression by modulating lncRNA-CPS1-IT1-mediated EMT suppression and further supported melatonin as a promising therapeutic agent for the treatment of HCC. Note: This abstract was not presented at the meeting. Citation Format: Tong Hong Wang, Chi Hao Wu, Chau Ting Yeh, Kung Hao Liang, Chuen Hsueh, Chi Yuan Chen. Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3446. doi:10.1158/1538-7445.AM2017-3446