| Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Given the fact that HCC is so malignant, in spite of the advances of classical therapies, the current therapeutic targets and treatment is limited, thus, especially for those patients with advanced stage of HCC, it’s an emergency for us to identify new targets for HCC treatment in order to reduce mortality and improve patient outcomes.Hepatocarcinogenesis is a chronic multistep process in which chronic hepatic injury is often happened and accomplished with many metabolic abnormalities, including S-adenosyl methionine (SAM). SAM is an important metabolic product and the principal biological methyl donor, its synthesis and metabolic processes are mainly found in the liver. Recently, researches on tumor cell metabolism and epigenetics are hot and how to reverse the abnormal tumor cell metabolism and methylation status has becoming a new therapeutic target. SAM homeostasis is critical for the for the maintenance of normal liver cell growth, and chronic liver damage or HCC often cause SAM levels decreased, which will promote the carcinogenesis process or facilitate the growth of cancer cells in return.Methionine adenosyltransferase(MAT) is the key enzyme for the synthesis of SAM. Loss of SAM homeostasis is mainly due to the type conversion and decreased activity of MAT. MAT2B gene belongs to a member of the MAT family, which encodes β regulatory subunit and regulates the MAT Ⅱ activity by reducing Ki values for the SAM and Km values for methionine, thus affecting the SAM level. In normal liver, the MAT2B gene expression is very low, but when the chronic liver injury or HCC happen, the expression of this gene will unregulated, which affects the SAM homeostasis and participates in the regulation of cancer cell growth and apoptosis and some other vital processes.Notably, our previous study has found that the transposon insertion of MAT2B gene in mice could cause the upregulation of protein expression, which ultimately lead to the generation of HCC.We conduct current study with the aim of further exploring and clarifying the role of MAT2B in HCC progression both in vitro and in vivo, including its role in cell proliferation and migration at the cellular level, as well as in animal model and the clinical prognosis value in patients with hepatocellular carcinoma. The main results are as follows:1. MAT2B protein expression in HCC tumor tissues was significantly increased when compared with adjacent tissues, and was positively correlated with the tumor size and patients poor prognosis.2. CCK-8, crystal violet staining demonstrated that interfere MAT2B could inhibit HepG2, HCCLM6 cell proliferation, flow cytometry detection cycle found that interfere group apparent S-phase accumulation, subcutaneous tumor formation experiments also confirmed downregulation of MAT2B significantly inhibited tumor growth in vivo, Western-Blot revealed that inhibit effects may cause by downregulation of p-AKT, p-p38MAPK and accumulation of p21, p27.3. Wound healing assay and transwell assay discovered that interfere MAT2B significantly inhibited HepG2, HCCLM6 cell migration, Western-Blot found that inhibit effect may due to downregulation of MMP2, MMP9, SAMD3, Vimentin and translocation of HuR from plasma to nuclear.In conclusion, we found that MAT2B was upregulated in tumor tissues and correlated with the poor prognosis of HCC patients, while interference MAT2B can effectively inhibit liver cancer cell proliferation and migration both in vitro and in vivo. Therefore, MAT2B is expected to become a new effective target for the management of HCC. |
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