Slc26a9基因缺失致使胃粘膜上皮细胞分化及稳态紊乱导致慢性萎缩性胃炎发生发展的分子机制研究

Chronic atrophic gastritis is an important precancerous lesions of gastric cancer, but the melecular mechanism remains poorly understood. We firstly reported that loss of Slc26a9 resulted in the development and progression of gastric cancer （Liu et al., FASEB 2015). Now, we aimed to explore the role of Slc26a9 gene in the pathogenesis of CAG, which was considered as an early event of gastric cancer.Our studies demonstrated that Slc26a9 was down-regulated in the CAG and was progressive decreased in the progression of human gastric cancer. Moreover, expression of relative genes and proteins of P53, Shh, and autophagy signaling pathways were down-regulated in the Slc26a9 deficient mice when compaired with WT control. Therefore, we speculated that absence of Slc26a9 may cause the abnormalities of P53, Shh, and autophagy signaling pathways, which resulted in the disorder of gastric mucosa epithelia cell defferentiation and homeostasis, then leads to the development of CAG and malignant pathological process. In this project, two Slc26a9 deficient mouse models and Slc26a9 gene knock out cell model will be built up, together with human samples collection as well as the performance of gene chip and cell functional analysis to find out the role of Slc26a9 gene in the development and progression of CAG.

慢性萎缩性胃炎（CAG）是一种重要的胃癌癌前病变，其发生的分子机制尚不完全清楚。我们在国内外首次报道了Slc26a9基因的缺失导致了胃癌的发生发展（Liu et al., FASEB 2015) 。我们进一步研究了Slc26a9基因与胃癌发生早期事件-CAG之间的关系：Slc26a9在CAG中表达明显下调，且在CAG发生至胃癌恶性进程中呈渐进性减弱。 Slc26a9基因的缺失导致小鼠发生CAG及恶性病理改变，并伴有P53、Shh、自噬信号通路的相关基因和蛋白质的改变。因此，我们推测：Slc26a9基因缺失或下调可能诱导P53、Shh、自噬等多种信号紊乱，致使胃粘膜上皮细胞的分化与稳态异常，从而导致CAG发生及恶性病理进展。本项目拟通过基因敲除小鼠模型和单细胞敲除模型的建立及人体临床样本收集，结合基因表达谱芯片、分子及细胞功能学实验等探寻Slc26a9在CAG发生发展的作用及主要调控机制。

慢性萎缩性胃炎（CAG）是一种重要的胃癌癌前病变，其发生的分子机制尚不完全清楚。我们在国内外率先报道了Slc26a9基因对于维持胃壁细胞的功能及存活至关重要，Slc26a9的缺失导致了胃癌的发生发展（Liu et al., FASEB 2015) 。但Slc26a9基因与胃癌发生早期事件-CAG之间的关系不清。基于建立Slc26a9整体敲除小鼠及胃壁细胞Slc26a9基因敲除小鼠模型，结合Slc26a9基因敲除细胞株模型的建立和人体临床样本，从动物整体层面、特异性单器官、单细胞水平以及人体活组织层面探寻Slc26a9基因在CAG发生发展中的作用。我们研究发现，两种Slc26a9敲除小鼠模型均证实，Slc26a9的缺失导致正常胃粘膜→慢性炎症→CAG→肠上皮化生→异型增生（上皮内瘤变）→胃癌，证实Slc26a9缺失是启动CAG的关键步骤。此外，Slc26a9基因缺失导致一系列胃功能改变，包括胃酸分泌减少、胃内pH值增高，高胃泌素血症，是CAG发生的直接证据。进一步证实，Slc26a9基因缺失导致在自发性炎性环境下，胃干细胞分子标记物分化紊乱，Lgr5，Lrig1，Mist1表达显著减少，胃肿瘤干细胞分化标记物CD44，从而导致胃黏膜上皮细胞分化紊乱壁细胞缺失及特异性标记物H+-K+-ATPase缺失，主细胞缺失伴特异性标记物Mist1缺失，黏膜上皮受损，特异性标记物MUC5AC下调，胃黏膜细胞转化发生-SPEM及肠化生出现，以及特异性标记物，TFF2, MUC6，MUC2表达显著上调。并通过TGFb信号通路上调导致胃黏膜上皮过度增殖及凋亡的抑制。此外，Slc26a9在CAG人群显著下调，且从正常胃粘膜→慢性炎症→CAG→肠上皮化生→异型增生（上皮内瘤变）→胃癌种渐进性下调。而在细胞水平发现Slc26a9的下调导致TGFb信号及SHH信号通路紊乱。我们的研究显示，Slc26a9基因缺失导致胃干细胞分化和酸/碱稳态紊乱，这是启动CAG发生及恶性病理进程的首要步骤。Slc26a9可能是一种新的控制胃细胞干性的肿瘤抑制基因。