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

Abstract

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.

Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses

“…Metallothioneins play a critical role in maintenance of zinc homeostasis and act as scavenger for reactive oxygen species, which explains their role in innate immunity [ 84 ] and carcinogenesis [ 41 ]. Down-regulation of MT1 proteins have been observed in esophageal squamous cell carcinoma [ 85 , 86 ], hepatocellular carcinoma [ 39 , 87 ], papillary thyroid carcinoma [ 88 ], and prostate cancer [ 89 ], suggesting their role as tumor suppressor. It is known that oxidative stress (OS) signals are induced by herpesvirus infection, which favors viral replication [ 90 ].…”

A prognostic prediction system for hepatocellular carcinoma based on gene co‑expression network

“…It has also been demonstrated that increased expression of CDC20 is associated with the development and progression of HCC (39). The expression of MT1G was reported to be negatively associated with aberrant promoter hypermethylation, and the data from TCGA suggested that hypermethylation of MT1G is linked with favorable survival of HCC patients (40). Therefore, the prognostic predictive value of STC2, CDC20 and MT1G in the present study was consistent with the results of previous studies.…”

Research Progress of DNA Methylation in Thyroid Cancer

“…Studies have shown that MT1G gene has abnormal methylation in thyroid cancer, liver cancer, colon cancer, and prostate cancer. It is confirmed that restoring MT1G gene expression could inhibit tumors growth in vivo and in vitro, suggesting that MT1G gene has anticancer effect [27]. It is shown that MT1G gene was abnormally methylated in thyroid cancer (30.3% in malignant tumors and 18.8% in benign tumors).…”