Research Papers:

Association of melatonin membrane receptor 1A/1B gene polymorphisms with the occurrence and metastasis of hepatocellular carcinoma

Shih-Chi Su, Yung-Chuan Ho, Yu-Fan Liu, Russel J. Reiter, Chia-Hsuan Chou, Chia-Ming Yeh, Hsiang-Lin Lee, Wen-Hung Chung, Ming-Ju Hsieh and Shun-Fa Yang _

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Oncotarget. 2017; 8:85655-85669. https://doi.org/10.18632/oncotarget.21107

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Shih-Chi Su1,2, Yung-Chuan Ho3, Yu-Fan Liu4, Russel J. Reiter5, Chia-Hsuan Chou6, Chia-Ming Yeh6, Hsiang-Lin Lee6,7, Wen-Hung Chung1,2,8, Ming-Ju Hsieh6,9,10 and Shun-Fa Yang6,11

1Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan

2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung, Taiwan

3School of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan

4Department of Biomedical Sciences, College of Medicine Sciences and Technology, Chung Shan Medical University, Taichung, Taiwan

5Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA

6Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

7Deptartment of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan

8College of Medicine, Chang Gung University, Taoyuan, Taiwan

9Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan

10Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

11Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

Correspondence to:

Shun-Fa Yang, email: [email protected]

Ming-Ju Hsieh, email: [email protected]

Keywords: melatonin receptor, polymorphism, hepatocellular carcinoma, metastasis

Received: August 12, 2017     Accepted: September 04, 2017     Published: September 20, 2017


Hepatocellular carcinoma (HCC) is a prevalent primary neoplasm of the liver, whose heterogeneous global incidence suggests the likely impact of genetic variations among individuals on the susceptibility to this disease. Increasing evidence indicates that melatonin exhibits oncostatic properties in many cancer types at least in part mediated by its membrane-bound receptors, melatonin receptor 1A (encoded by MTNR1A) and 1B (MTNR1B). In this study, the effect of melatonin receptor gene polymorphisms on the risk and progression of hepatic tumors was evaluated between 335 HCC patients and 1196 cancer-free subjects. We detected a significant association of MTNR1A single nucleotide polymorphism (SNP), rs6553010, with the elevated risk of HCC (AOR, 1.587; 95% CI, 1.053–2.389; p = 0.027) after being adjusted for two potential confounders, age and alcohol use. In addition, patients who carry at least one polymorphic allele (heterozygote or homozygote) of MTNR1A rs2119882 or rs2375801 were more prone to develop distant metastasis (OR, 5.202; 95% CI, 1.163–23.270; p = 0.031, and OR, 7.782; 95% CI, 1.015–59.663; p = 0.048, for rs2119882 and rs2375801, respectively). Further analyses revealed that rs2119882 is located on the consensus binding site of GATA2 transcription factor within the promoter region of MTNR1A gene, and that a correlation between the levels of GATA2 and melatonin receptor 1A was observed in the TCGA (The Cancer Genome Atlas) dataset. Moreover, individuals bearing a specific haplotype of four MTNR1B SNPs were more prone to develop HCC. In conclusion, our data suggest an association of melatonin receptor gene polymorphisms with the risk of HCC and hepatic cancer metastasis.

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