p42.3基因在从胃炎到胃癌发展过程中的作用及其机制初探

Gastric cancer is one of the generally accepted inflammation related tumors. The NF-kB related signal pathway which could be activated by H.pylori infection/inflammation plays an important role in the tumorigenesis of gastric cancer . p42.3 gene over-expresses in gastric cancer tissues. It can promote both the proliferation and tumorigenicity of gastric cancer cells and also its function is associated with cell cycle control, but the role and mechanism of p42.3 gene in gastric cancer and its multiple sequential precursor lesions are still unclear. We found that p42.3 gene expression increased gradually during the process (chronic non-atrophic gastritis-chronic atrophic gastritis-intestinal metaplasia-dysplasia) and its expression is related to the H.pylori infection. In gastric cancer the expression of p42.3 gene can be regulated by miR-29a whereas miR-29a can be regulated by NF-kB. Therefore the reasonable hypothesis is that H.pylori/inflammation factor may promote gastritis to progress to gastric cancer through the NF-kB-miR-29a-p42.3/ NF-kB-p42.3 pathway which can transfer the inflammation signal outside the cell to the proliferation signal inside. We will use both in vivo and in vitro methods to establish the H.pylori/inflammation factor-NF-kB-miR-29a-p42.3/ NF-kB-p42.3 pathway and explore its role in the progress from gastritis to gastric cancer, and construct the H.pylori induced animal gastric cancer model after interfering the p42.3 gene. This study tries to provide new findings of the mechanism from gastritis to gastric cancer and find the new medicinal target which aims to block this progress.

胃癌是公认的炎症相关肿瘤之一，H.pylori感染/炎症因子导致的NF-kB相关信号通路激活在其中发挥重要作用。p42.3基因在胃癌组织中高表达,它能促进胃癌细胞增殖及其成瘤，并与细胞周期调控有关，但其在胃癌及其多阶段发展过程中的作用和机制目前仍知之甚少。我们的研究显示p42.3基因的表达在慢性非萎缩性胃炎－萎缩性胃炎－肠化－异型增生的发展过程中逐渐升高，并与H.pylori感染有关。 p42.3基因在胃癌中的表达受miR-29a调控，而miR-29a又受NF-kB的调控。为此我们科学假设H.pylori/炎症因子可能通过NF-kB-miR-29a-p42.3或 NF-kB-p42.3直接通路将细胞外炎症信号转化为细胞内增殖信号，从而促进胃炎向胃癌的发展。本研究拟通过体内体外实验确立H.pylori/炎症因子-NF-kB-miR-29a-p42.3/ NF-kB-p42.3信号通路并探究其在胃炎到胃癌发展过程中的作用；建立干扰p42.3基因后H.pylori诱导胃癌发生的动物模型，从而为胃炎到胃癌的发展机制提供新发现，为胃癌的防治提供新的药物治疗靶点。

p42.3基因在胃癌中高表达，但其在胃癌发生发展中的作用及其分子机制目前尚不清楚。我们拟从p42.3基因在胃癌多步骤发展过程中的表达, 其与炎症和幽门螺杆菌的关系, 相关分子通路和下游靶基因着手进行探讨。我们发现：.1.P42.3在从慢性非萎缩性胃炎-萎缩-肠化-异型增生的发展过程中表达逐渐增高（分别为1.3%，45.8%，73.1％和88.7％）。P42.3在肠型胃癌中的表达显著高于弥漫型胃癌（71.1% vs 52.9%）。表达P42.3蛋白的IV期胃癌患者较不表达者有不良的预后趋势，但此差异无统计学意义(P = 0.081)。.2. p42.3与炎症关系密切，其在重度炎症组和幽门螺杆菌阳性组的表达较高。炎症因子TNF-α和幽门螺杆菌可分别促进p42.3基因的表达，且与TNF-α的作用时间有关。.3. TNF-α和幽门螺杆菌亦可激活胃上皮细胞中NF-Kb的表达。 而NF-Kb可直接与p42.3基因启动子区域结合，并参与p42.3基因的表达调节，提示存在TNF-α-NF-Kb-p42.3通路。.4. ERM基因可能是p42.3的下游靶基因之一。其与p42.3的表达模式相似。胃癌组织中，p42.3与ERM表达正相关（rs=0.878,P<0.001)。 并且ERM在mRNA和蛋白水平的表达均受p42.3基因的调节。