原花青素B2调控DNMT预防胃癌的作用及机制研究

Overexpression of DNA methyltransferase (DNMTs) and hypermethylation of tumor suppressor gene regulatory region is closely linked to gastric carcinogenises. Our previous studies found that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer patients; polymorphisms of DNMTs genes were associated with Helicobacter pylori infection, chronic gastritis and prognosis of gastric cancer. We also found expressions of DNMTs were significant increased in the gastric tumor cell in transgenic mice model. Procyanidins component EGCG could inhibited the gastritis in gerbils, but the mechanism and target gene is unknown. Currently, epigenetic regulation became important strategies against cancers; natural active compound Procyanidin B2 possesses high antioxidant and antitumor activity. The aim of current study is clarify the target spot of procyanidin B2 affect on gastric tumor, through gastric cancer cell lines and K19-Cm2E and Gan transgenic mice models of gastric cancer. That is wether Procyanidin B2 could regulate the expressionof DNMTs, interact with COX-2/PGE2, Wnt/Beta-catenin signaling pathways, and link to related sRNA,miRNA and lncRNA to inhibit or reduce DNA hypermethylation of tumor suppressor genes, further to achieve the objective of prevention and suppression of gastric cancer. Moreover，the study will verify these discoveries in the clinical gastric cancer patients, to explore the molecular mechanisms of chemoprevention of gastric cancer by procyanidin B2.

DNA甲基转移酶(DNMTs)过度表达与抑癌基因区域高甲基化和胃癌密切相关。我们研究发现DNMT3a 的表达水平是胃癌独立预后因子， DNMTs基因多态性与幽门螺杆菌感染，慢性胃炎及胃癌预后密切相关;还发现转基因鼠胃肿瘤细胞DNMTs显著过度表达，原花青素组分EGCG可抑制胃炎，但其作用机制和靶基因尚不明。当前表观治疗成为肿瘤预防的重要策略，天然营养物质原花青素B2具有高效抗氧化和抗肿瘤活性。本研究通过胃癌细胞系和转基因胃癌模型K19-Cm2E和Gan，阐明原花青素B2抑制胃肿瘤的作用靶点,即原花青素B2能否调控DNMTs表达，并通过DNMTs与COX-2/ PGE2, Wnt/β-catenin信号通路相互作用和链接,改变小RNA 和lncRNA途径,抑制或减轻抑癌基因DNA的高甲基化，从而实现预防和抑制胃癌目的。同时结合胃癌病例加以验证,深入探讨原花青素B2化学预防胃癌的分子机制。

DNA甲基转移酶(DNMTs)过度表达与抑癌基因区域高甲基化和胃癌密切相关。我们研究发现DNMT3a 的表达水平是胃癌独立预后因子，DNMTs基因多态性与幽门螺杆菌感染，慢性胃炎及胃癌预后密切相关；还发现转基因鼠胃肿瘤细胞DNMTs显著过度表达，原花青素组分EGCG可抑制胃炎，但其作用机制和靶基因尚不明。当前表观治疗成为肿瘤预防的重要策略，天然营养物质原花青素B2具有高效抗氧化和抗肿瘤活性。本研究通过胃癌细胞系和转基因胃癌模型Gan，阐明原花青素B2抑制胃肿瘤的作用靶点—PTEN，即原花青素B2可以调控DNMTs表达，并通过DNMTs与PTEN/AKT信号通路相互作用和链接，抑制或减轻抑癌基因DNA的高甲基化，从而实现预防和抑制胃癌目的。同时结合胃癌病例加以验证，深入探讨原花青素B2化学预防胃癌的分子机制。