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Int. J. Mol. Sci. 2018, 19(9), 2687; https://doi.org/10.3390/ijms19092687

Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction

1
Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan
2
Graduate 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 33303, Taiwan
3
Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan
4
Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan 33305, Taiwan
5
Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan 33303, Taiwan
6
Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan
7
Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Tao-Yuan 32551, Taiwan
8
Biomedical Engineering Department, Ming Chuan University, Tao-Yuan 33348, Taiwan
*
Authors to whom correspondence should be addressed.
Received: 20 August 2018 / Revised: 6 September 2018 / Accepted: 8 September 2018 / Published: 10 September 2018
(This article belongs to the Special Issue Targeting Cancer through RNA Biology)
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Abstract

Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin’s anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin’s antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC. View Full-Text
Keywords: melatonin; hepatocellular carcinoma; miRNA let7i-3p; RAF1 melatonin; hepatocellular carcinoma; miRNA let7i-3p; RAF1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Wang, T.-H.; Hsueh, C.; Chen, C.-C.; Li, W.-S.; Yeh, C.-T.; Lian, J.-H.; Chang, J.-L.; Chen, C.-Y. Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction. Int. J. Mol. Sci. 2018, 19, 2687.

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