幽门螺杆菌cagA介导CDX2调控Claudin-2在肠型胃癌上皮间质转化中作用及温郁金干预机制的研究

The connections among inflammation、epithelial mesenchymal transformation (EMT) and the tumor and the effects of the traditional Chinese medicine have been increasingly studied recently. Helicobacter pylori cagA ,as the important risk factor in the occurrence and development of gastric cancer, is still not completely clear in terms of its tumorigenic mechanism; the bowel transcription factor Cdx2 and the close connexin Claudin-2 play the necessary role in the process from gastritis to intestinalization, even to the intestinal gastric cancer(EMT process). diterpenoid C , which has been isolated from turmeric ether extracts as a kind of new compounds, can inhibit the release of the inflammation factors in gastric cancer cells and the proliferation of gastric cancer cells, and can induce the apoptosis of gastric cancer cells. Whether there are connections among Helicobacter pylori cagA, Cdx2, Claudin-2 and EMT? What are the connections? Whether diterpenoid C has preventive and therapeutic effect? The cells and animals infected by helicobacter pylori and the nude mouses with transplant tumor will be examined as models. The research will be started with the toxic cell factor cagA, which is known at present as the unique factor encoded by Hp that can be injected into cells, to study the connections among helicobacter pylori cagA, Cdx2, Claudin-2 and gastric cancer EMT and the preventive and therapeutic effect of diterpenoid C. The study will lay the theoretical and experimental basis for the expansion of the horizon of the prevention and control of gastric cancer and the further development and use of the medical value in the traditional Chinese medicine turmeric.

炎症、上皮间质转化（EMT）与肿瘤发生发展的关系及中医药的防治是目前关注的热点。幽门螺杆菌cagA作为胃癌发生发展重要的危险因素其致瘤机制仍未完全明确；在胃炎到肠化、肠型胃癌乃至侵袭转移的过程中，肠转录因子Cdx2、紧密连接蛋白Claudin-2起着不容忽视的作用。我们在郁金醚提物中分离得到新的化合物C，前期研究表明其有抑制胃癌细胞炎症因子释放、细胞增殖和诱导胃癌细胞凋亡等作用。幽门螺杆菌cagA、Cdx2、Claudin-2及EMT之间有否联系？怎样的联系？化合物C是否具有防治作用？我们将通过建立幽门螺杆菌慢性感染的细胞和动物模型及裸鼠移植瘤模型，从Hp编码的目前已知的唯一注入细胞的细胞毒性因子CagA入手，研究幽门螺杆菌cag、Cdx2、Claudin-2与胃癌EMT之间的关系及郁金新二萜类化合物C的防治作用，为拓展胃癌防治视野和中药郁金药用价值的进一步开发和利用奠定理论和实验基础。

项目背景：幽门螺杆菌(Helicobacter pylori，Hp)是一种与胃癌发生发展密切相关的外部致病因子，最新的研究表明，Hp持续感染引起慢性胃炎和组织,再生，在组织再生过程中，再生细胞偏离正常的分化方向，形成肠化生，进一步发展成为肠型胃癌，但其致瘤分子机制尚未完全阐明。肠型胃癌的发生与肠特异性转录因子的转录调控失常密切相关，其中CDX2被认为是诱导肠型化生最重要肠特异性转录因子之一[3,6]；CDX2作为Hp感染密切相关的关键基因，参与HP感染后细胞的失接触(scatter)、形态学变化和迁移一系列病理生物学行为；但其在胃癌上皮间质转化中的作用仍不清楚。温郁金在临床常用中药材，我们前期研究发现其提取物可抑制胃癌细胞和瘤体的增，但其对胃癌上皮间质转化中的作用仍也不清楚。主要研究内容：1.温郁金提取物对不同胃癌细胞株的抑制作用差别及机制；2.幽门螺杆菌CagA及VacA介导CDX-2调控Claudin-2促进胃癌AGS细胞侵袭及温郁金的干预作用；3.温郁金对裸鼠移植瘤的作用研究。重要成果：1.①与温郁金二萜类化合物C对各分化程度的胃腺癌细胞均有一定的抑制作用，呈现浓度依赖性，其中对SGC-7901的抑制最为明显；而对人GES-1和HUVEC的抑制作用相对不明显。②温郁金二萜类化合物C能不同程度的抑制各胃腺癌细胞株抗凋亡蛋白Bcl-2的表达，上调促凋亡蛋白Bax的表达；其作用具有浓度依赖性。2.温郁金二萜类化合物C 对SGC-7901 细胞增殖有明显的抑制作用，并能有效地诱导胃癌细胞SGC-7901 凋亡; 温郁金二萜类化合物C 能一定程度地减少胃癌细胞SGC-7901 p65 核转位发生。3.HpCagA+VacA+可促进胃腺癌AGS细胞的侵袭能力，其机制为CagA及VacA介导CDX-2上调Claudin-2的表达、促进细胞梭状变；而温郁金正丁醇提取物可通过下调CDX-2、Claudin-2的表达，抑制AGS细胞侵袭转移。4.温郁金提取物与对照组相比能明显抑制裸鼠胃癌移植瘤的生长。科学意义：研究幽门螺杆菌cag介导Cdx2异常调控claudin-2表达、发挥后者在胃黏膜上皮间质转化过程中的作用及温郁金对其的干预机制。

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