甲基供体代谢关键酶MAT2B促肝癌细胞增殖作用机制研究

Aberrant DNA methylation is closely related to the carcinogenesis of liver cancer. Developing new drugs against this abnormality has been arising as a hot spot in cancer treatment. S-adenosylmethionine (SAMe) is the sole methyl donor in vivo, synthesized by methionine adenosyltransferase (MAT). MAT2B is a rate-limiting isoenzyme of MAT1A which decreases SAMe and global methylation level. Our primary study has revealed MAT2B is specifically overexpressed in liver cancer, and its down-regulation inhibits both growth and metastasis of liver cancer cells. In microarray analysis of liver cancer tissues, CYP2E1, an important cytochrome P450 family member and the major producer of reactive oxygen species in vivo, was found to be hypo-methylated. As ROS has been reported to promote tumor cell proliferation and metastasis through p38/MAPK pathway, we speculate the overexpression of MAT2B could increase the expression of CYP2E1 by suppressing DNA methylation, thereby activate p38/MAPK axis via ROS generation and result in the augmented malignancy of liver cancer. To confirm this proposal, we plan to seek for evidences at cellular level and in clinical specimens. Tandem mass spectrometry and various analyzing technologies would be applied to verify the expression of different proteins in this pathway and their clinical significance. Our study will provide theoretic basis for the development of novel drugs for liver cancer targeting at the abnormal methylation.

表观遗传修饰与肝癌发生密切相关，逆转异常甲基化成为抗肝癌药物研发新热点。S-腺苷蛋氨酸 (SAMe) 是体内唯一甲基供体，蛋氨酸腺苷转移酶2B (MAT2B) 是其合成关键限速酶，上调其表达将致SAMe降低并伴有体内低甲基化。申请人发现MAT2B在肝癌组织高表达，下调其表达可抑制肝癌生长；进一步通过全基因组DNA甲基化分析发现，细胞色素P450 (CYP450)家族重要成员CYP2E1呈显著低甲基化状态。结合CYP2E1是体内活性氧(ROS)的主要来源，且ROS可通过p38/MAPK通路促进肿瘤增殖，故推测过表达MAT2B可通过调控DNA去甲基化而上调CYP2E1表达，进而经由ROS激活p38/MAPK通路促肝癌增殖作用。下一步拟在细胞及临床标本中证实该通路，并用串联质谱等技术分析该通路诸分子的表达及其临床意义。本研究将为寻找新的针对肝癌异常甲基化药物研发提供理论依据。