Methylation Of TMS1Gene In Hepatocellular Carcinoma

Background:The development of hepatocellular carcinoma includes genetic mechanism and epigenetic mechanism, which is a cascade process by polygene and leads to the activation of cancer gene and the inactivation of tumor suppressor. There is not only the change in genetics but also epigenetic alteration that plays an important role in carcinogenesis. The two primary changes of epigenetic mechanism are the DNA methylation and the histone modification. Patterns of DNA methylation are established and maintained by DNA methyltransferases (DNMTs). In humans, DNMT1is thought to be required for maintaining methylation patters and identify the methylated CpG sites of DNA chain. DNMT1is necessary for the establishment of newly methylated promoters. Moreover, DNA methylation are mediated by methyl-CpG binding proteins(MBD). Methylated DNA is recognized by MBD2proteins, which recruits histone deacetylases, resulting in gene silence. The target of methylation-induced silencing (TMSl) is a novel CpG island-associated gene and a tumor-suppressor genes. It promotes cell apoptosis; regulate the NF-γB and the caspase, etc. It has been studied that the TMS1plays an important role in a large amount of malignant tumors.Objective:The objective of the present study was to investigate the promoter methylation status of TMS1gene in HCC, to detect the mechanisms changes of MBD2gene and DNMT1gene in epigenetic, and to evaluate the role of TMS1gene in clinical diagnosis.Methods:48cases of liver tissues of HCC patients were provided by Qilu Hospital, Shandong University from2009^2011and the liver tissues were frozen at-80℃. DNA were isolated from the peripheral blood serum of37cases of HCC patients,26cases of hepatitis B Patients and23cases of normal control group. TMS1, MBD2and DNMT1protein expression were detected by immunohistochemistry, which of48cases of HCC in cancer tissues and adjacent non-cancerous tissues (>3cm)Results:Methylation was detected in70.30%(11/37) HCC patients and50.00%(13/26) the hepatitis B Patients, none was detected in normal control group. Moreover, the positive rate of TMS1in HCC cancer tissue and the paired non-neoplastic liver tissues were26.08%(10/48) and97.92%(47/48); the positive rate of MBD2were18.75%(9/48) and80%(38/48); the positive rate of DNMT1were77.08%(37/48) and32.25%(15/48). It indicates that the aberrant methylation of promoter region CpG islands may be in relation to the down-regulation of TMS1in HCC.Conclusion:Our results suggest that promoter methylation and TMS1modification work together in the TMS1gene silence. It indicates that cooperative effects exist in these epigenetic modifications. It illustrates that the methylation of TMS1happened in HCC except non-cancerous tissues.The aberrant methylation of CpG islands in promoter regions may lead to transcriptional silencing, TMS1down-regulation. It plays an important role in the occurrence of hepatocellular carcinoma. The methylation of TMS1was established in patients of HCC, which provides new insights into the DNA methylation of HCC and may be of prognostic values for HCC.