Galectin-1通过Hedgehog信号通路调控幽门螺杆菌相关解痉多肽表达型化生（SPEM）发生的机制研究

Helicobacter pylori is a known Carcinogen for type Ⅰ gastric cancer. Spasmolytic polypeptide-expressing metaplasia （SPEM） happens at Helicobacter pylori infected gastric mucosa of mice and human. It is known as a kind of precancerosis in which the pseudopyloric gland metaplasia happens. However, how Helicobacter pylori infection is related to SPEM is still unclear. Studies suggested that after infected by Helicobacter pylori, the gastric epithelial cell is damaged and it can recruit mesenchymal stem cells to migrate to the mucosa and then transformed into cancer-associated fibroblasts (CAFs) under the influence of Helicobacter pylori. What’s more, Helicobacter pylori infection can also recruit myeloid cells to the stomach and within this reaction, aberrantly activation of Hedgehog (HH) pathway is necessary. SPEM is triggered when myeloid cell is migrating to the stomach. Our previous work revealed the high expression of Galectin-1 after Helicobacter pylori infection. MSCs can transform into CAFs if the expression of Galectin-1 is up-regulated. If transformed, high expression of Galectin-1 in CAFs can aberrantly activate HH pathway. Therefore, we propose our hypothesis as after Helicobacter pylori infection, the gastric epithelial cell can recruit MSCs to the gastric mucosa and stimulate MSCs to overexpress Galectin-1. Following this, the MSCs can transform into CAFs which can secrete Galectin-1 into microenvironment and aberrantly activates HH pathway. The myeloid cell is recruited to the stomach thus triggered SPEM. To verify our hypothesis. We plan to use clinicopathological observation, gene transfection, gene silencing, in vitro co-culture and knockout mice to conduct our experiments. We will explore the mechanism of Galectin-1 regulating Helicobacter pylori-related SPEM through HH pathway. If successfully conducted, our study can not only illustrate the functional molecular regulation mechanism of Helicobacter pylori caused precancerosis, but also it can provide new evidence for gastric carcinogenesis and management.

幽门螺杆菌是Ⅰ型胃癌致癌物质，解痉多肽表达型化生（SPEM）是感染幽门螺杆菌形成的假幽门腺化生，属癌前病变，然而幽门螺杆菌如何诱导SPEM目前仍是个“谜”。文献报道幽门螺杆菌感染招募间质干细胞（MSCs）迁移至胃，促进MSCs转化为肿瘤相关成纤维（CAFs）；幽门螺杆菌感染激活Hedgehog(HH)通路导致髓样细胞也募集至胃；髓样细胞向胃募集导致SPEM发生。我们前期发现幽门螺杆菌感染MSCs后Galectin-1高表达，MSCs向CAFs转化。为此，我们提出假说：幽门螺杆菌感染募集MSCs至胃并刺激其高表达Galectin-1后转化为CAFs，CAFs分泌Galectin-1激活HH通路募集髓样细胞迁移至胃，导致SPEM发生。为验证这一假说，我们拟通过临床病理学观察、体外共培养和敲基因鼠实验，探讨Galectin-1通过HH通路调控幽门螺杆菌相关SPEM发生机制，丰富胃癌的防治策略。

胃癌的发生被广泛认为同与幽门螺杆菌的感染密切相关，当幽门螺杆菌感染胃出现炎症及损伤时候能迁移到相应部位发挥修复损伤的作用，同时也成为肿瘤发生的根源。解痉多肽表达型化生（SPEM）是感染幽门螺杆菌形成的假幽门腺化生，属癌前病变。间质干细胞（MSCs）是炎症和肿瘤发生微环境中的重要成员之一，其具体作用方式和机制尚不清楚。文献报道幽门螺杆菌感染招募MSCs迁移至胃，促进MSCs转化为肿瘤相关成纤维（CAFs），但是具体的分子机制并不清楚。幽门螺杆菌刺激Galectin-1表达上调能促进胃癌的发展。于是我们提出假说：幽门螺杆菌感染募集MSCs至胃并刺激其高表达Galectin-1后转化为CAFs，CAFs分泌Galectin-1激活HH通路募集髓样细胞迁移至胃，导致SPEM发生。我们得出幽门螺杆菌感染胃上皮细胞直接招募MSCs至胃黏膜，并诱导Galectin-1介导的MSCs转化为CAFs的发生，CAFs分泌Galectin-1募集髓样细胞并异常激活HH信号通路诱导SPEM发生。我们研究发现Galectin-1蛋白能预测幽门螺杆菌感染的SPEM的严重程度，却不能预测是否存在SPEM。幽门螺杆菌的根除可以有效减轻SPEM的程度。幽门螺杆菌的存在刺激MSCs高表达Galectin-1，通过Hedgehog信号通路促进NCI-N87粘液细胞的生物学行为。本研究阐明干扰癌前病变中的Galectin-1表达和/或HH信号通路，将有望成为胃癌早期防控的靶点分子，进一步丰富胃癌的综合治疗策略。