J Cancer 2018; 9(16):2807-2816. doi:10.7150/jca.25680

Research Paper

MT1G is Silenced by DNA Methylation and Contributes to the Pathogenesis of Hepatocellular Carcinoma

Ju-deng Zeng1*, Ning Zhang2*, Gui-jun Zhao3*, Li-xia Xu2, Yang Yang1, Xiao-yi Xu1, Meng-ke Chen1, Hui-yun Wang1✉, Steven Xiao-feng Zheng1,4✉, Xiao-xing Li1✉

1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
2. Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
3. Department of Gastroenterology and Hepatology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, China
4. Rutgers Cancer Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
* These authors have equally contributed to this work.

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Zeng Jd, Zhang N, Zhao Gj, Xu Lx, Yang Y, Xu Xy, Chen Mk, Wang Hy, Zheng SXf, Li Xx. MT1G is Silenced by DNA Methylation and Contributes to the Pathogenesis of Hepatocellular Carcinoma. J Cancer 2018; 9(16):2807-2816. doi:10.7150/jca.25680. Available from http://www.jcancer.org/v09p2807.htm

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Using genome-wide screening and TCGA-based data analysis, we identified a DNA methylation-related gene named metallothionein-1G (MT1G), which may play an important role in hepatocellular carcinoma (HCC). In this study, we found that MT1G expression was silenced in 4/6 HCC cell lines and negatively related to aberrant promoter hypermethylation. Its mRNA level was restored with demethylation treatment. Moreover, MT1G downregulation at both the transcriptional and protein level was also detected in 8 pairs of clinical HCC samples compared with its expression in adjacent normal tissues. Ectopic expression of MT1G in silenced HCC cell lines inhibited colony formation, suppressed cell migration and invasion, and repressed xenograft tumor growth in nude mice. In contrast, knockdown of MT1G by short hairpin RNA showed the opposite effect on cell proliferation and the malignant phenotype. Moreover, our data showed that MT1G suppressed tumor invasion and metastasis mainly through regulating the expression of proteins in the matrix metalloproteinase family (MMP) and modulating the epithelial-mesenchymal transition (EMT) process. To our surprise, the data from TCGA showed that hypermethylation of MT1G is associated with good survival of HCC patients. In conclusion, our study demonstrated that MT1G acts as a tumor suppressor gene in HCC development, but its clinical potential in HCC requires further evaluation.

Keywords: MT1G, Hepatocellular Carcinoma, Tumor Suppressor Gene, Promoter Hypermethylation