Slc26a9基因缺失或下调导致胃癌发生发展的分子机制研究

Gastric cancer is a common malignant tumor in the gastrointestinal tract and the molecular mechanism of it is still need to be further studied .Chloride channel- Slc26a9 is highly expressed in the stomach of murine and humans, it is essential for parietal cell function and survival as well as normal gastric morphogenesis. Previous study reported that Slc26a9 deficiency causes a series of precancerous changes in murine stomach at 5 weeks of age (Xu et al., PNAS 2008), suggesting that Slc26a9 may be involved in gastric malignancy with increasing of age. Our preliminary experiments demonstrated that loss of Slc26a9 expression leads to spontaneous broad premalignant and malignant lesions in the gastric epithelia of mice at 15 month of age. Furthermore, expression of Slc26a9 is downregulated in the tissue and cell lines of gastric cancer when compared with health control. Based on these findings,we speculate that deletion or downregulation of Slc26a9 may cause gastric cancer. Slc26a9 may be a candidate tumor suppressor gene in the development and progression of human gastric cancer. In this study, we seek to investigate the relationship between slc26a9 and gastric cancer, and the role of Slc26a9 in the promotion and progression of gastric cancer, which aims to provide new theory basis for the cellular and molecular pathogenesis of gastric cancer. It is likely that this study will reveal a new oncosuppressor gene in gastric cancer.

胃癌是消化系统常见的恶性肿瘤，其发生的分子机制仍需深入研究。氯离子通道Slc26a9在小鼠和人的胃中呈高表达，对于维持壁细胞的功能和存活,保持胃的正常形态是必不可缺的。以往的研究发现Slc26a9基因缺失5周便导致小鼠胃粘膜出现一系列与胃癌发生相关的病理变化（Xu et al., PNAS 2008)。提示随着时间推移，Slc26a9基因的缺失会导致小鼠胃癌的发生。而在本课题的前期研究中发现15个月的Slc26a9基因敲除小鼠自发性表现出广泛的一系列癌前病变以及早期胃癌的发生，同时在人胃癌组织及胃癌细胞株中，相比正常对照组，Slc26a9的表达均下调。基于以上事实，我们推测Slc26a9的缺失或下调可能导致胃癌的发生，其在胃癌的发生发展中可能是一种抑癌基因。本课题拟研究Slc26a9基因与胃癌发生发展的关系，有可能揭示一种新的胃癌的抑癌基因，为胃癌发生的细胞分子机制提供新的理论依据。

以往研究发现Slc26a9缺失导致壁细胞功能和存活异常。本项目研究Slc26a9缺失是否会导致小鼠自发成瘤，以及SLC26A9在人胃癌发生发展中的作用。基于Slc26a9基因敲除小鼠模型，人体临床标本及胃癌细胞株等结合免疫组化，原为杂交，基因芯片及分子生物学实验探寻Slc26a9敲除小鼠的胃组织学形态及分子机制，SLC26A9对人胃癌发生的影响及肿瘤生物学行为探寻。本项目发现，Slc26a9缺失导致小鼠胃粘膜自发出现一系列癌前病变和胃癌的发生，并导致自发炎症环境下胃干细胞分化异常，上皮间质转化发生，黏膜屏障功能障碍。临床病理分析显示，Slc26a9在人胃癌及胃癌癌前病变中显著下调，并与短生存期密切相关。在胃癌细胞AGS中过表达SLC26A9能促进胃癌细胞凋亡，抑制胃癌细胞增殖，侵袭和迁移。并通过削弱WNT信号通路抑制上皮间质转化发生。综上所述，Slc26a9缺失导致小鼠自发出现一系列癌前病变和胃癌发生，并与人胃癌的发生发展密切相关。本项目为研究胃癌发病机制提供了新的方向，并可能提供新的预后标志物。

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