Copy number variation of metallothionein 1 (MT1) associates with MT1X isoform expression and the overall survival of hepatocellular carcinoma patients in Guangxi

Abstract

Metallothionein 1 (MT1) is a group of protein isoforms associated with tumorigenesis, progression and prognosis in various tumors. The effect of copy number variation at the MT1 locus (MT1-CNV) on the expression of all MT1 isoforms and its impacts on hepatocellular carcinoma (HCC) have not been fully understood. In this study, the CNV consistency of all MT1 genes was first found in 45 %(18/40) of cancer tissues by aCGH analysis and FISH detection, including 37.5 % genes loss and 7.5 % genes gain. MT1-CNV in cancer tissues was significantly correlated with overall survival (OS) in patients (HR = 3.655, p < 0.01, by Kaplan-Meier method analysis), and MT1-Loss can be used as an independent predictor of OS (HR = 3.218, p < 0.05, by multivariate Cox regression analysis). MT1-CN is a sensitive and specific indicator for HCC diagnosis (AUC = 0.825, p < 0.0001, by ROC curve drawing). Compared with adjacent tissues, the results of RT-qPCR and immunohistochemistry showed that MT1 isoforms in cancer tissues are significantly down-regulated at both transcriptional and translational levels (p < 0.05 and p < 0.01–0.0001 respectively), and MT1 protein is basically proportional to MT1-CN (p < 0.001, r = 0.6563). Furthermore, MT1-Loss further down-regulates the expression of MT1 isoforms, especially MT1X, in cancer tissues and may leads to worse OS in patients (p = 0.0045). In summary, the uniform loss of MT1 genes leads to simultaneous down-regulation of most MT1 isoforms, thereby weakening the tumor suppressive effect of each MT1 isoform, especially MT1X, and ultimately reducing the OS in HCC patients. Finally, MT1-Loss in cancer tissues reduces OS in HCC patients and can be used as a candidate for HCC diagnosis.