胃癌糖代谢酶FBP2基因启动子异常高甲基化的分子机制研究

The significant difference between cancer and normal cells lies in glucose metabolism, which plays an important role in cancer development. In the previous study, we found that fructose-1,6-bisphosphatase-2 (FBP2), the key enzyme in glucose metabolism, expressed lower compared with adjacent normal tissues; also we found that FBP2 overexpression in GC cell lines inhibited aerobic glycolysis, induced apoptosis, and suppressed cell proliferation; the decrease in FBP2 in GC was associated with promoter hypermethylation. Altered expression of DNA methyltransferase (DNMT) and DNA demethylation enzyme ten-eleven translocation (TET) family proteins has been found in gastric cancer. On the basis, we proposed that altered expression of DNMT and TET may lead to hypermethylation of FBP2 promoter and decreased expression of FBP2 in gastric cancer. To confirm this hypothesis, we plan to study: 1) the correlation between the expression of DNMT/TET and FBP2, and the effect on clinical outcome in GC specimens; 2) whether and how the change of DNMT expression has an effect on the methylation level in gastric cancer cell lines; 3) whether and how the change of TET expression has an effect on the methylation level in gastric cancer cell lines. Our study will make an effect on further revealing molecular mechanism of GC, drug design and prognosis for GC, improving GC therapy in China.

胃癌异常糖代谢模式与胃癌的发生发展密切相关。我们发现果糖-1,6-双磷酸酶-2（FBP2）在胃癌组织中表达显著低于癌旁组织，在胃癌细胞株中过表达FBP2能够抑制细胞糖酵解，进而激活细胞凋亡途径，显著抑制胃癌细胞增殖。进一步研究发现胃癌细胞中FBP2启动子高甲基化导致其低表达。有报道DNA甲基转移酶（DNMT）和去甲基化酶（TET）在胃癌中表达异常。我们推测：DNMT或TET在胃癌中表达异常导致FBP2启动子高甲基化和FBP2低表达。为了验证这一假说，我们拟研究：1）胃癌样本中DNMT或TET家族蛋白表达水平与FBP2启动子甲基化水平及临床预后的关系；2）胃癌细胞中改变DNMT表达量是否和如何改变FBP2启动子甲基化水平；3）胃癌细胞中改变TET表达量是否和如何改变FBP2启动子甲基化水平。该研究对进一步揭示胃癌发病的分子机制、设计合理的治疗药物及判断预后，提高我国胃癌的治疗水平具有重要意义

胃癌异常糖代谢模式与胃癌的发生发展密切相关。我们发现果糖-1,6-双磷酸酶-2（FBP2）在胃癌组织中表达显著低于癌旁组织，在胃癌细胞株中过表达FBP2能够抑制细胞糖酵解，进而激活细胞凋亡途径，显著抑制胃癌细胞增殖。进一步研究发现胃癌组织和细胞中FBP2启动子区高甲基化与FBP2低表达相关。FBP2启动子区甲基化受到甲基转移酶DNMT3A的调控作用。此外，我们结合TCGA数据库，开展对FBP2与其他糖代谢酶PKM2关系的研究。该研究对进一步揭示胃癌发病的分子机制、设计合理的治疗药物及判断预后，提高我国胃癌的治疗水平具有重要意义。