IL-6/Periostin/microRNA-155轴影响幽门螺杆菌感染相关性胃癌发生发展机制研究

Helicobacter pylori (Hp) infection is an important risk factor of gastric cancer. Activation of IL-6/STAT3 signaling and modulation of microRNAs (miRNAs) play a critical role in Hp-induced gastric carcinogenesis. Periostin has the capacity to promote malignant phenotypes in gastric cancer cells. Our previous work has shown that Hp infection upregulates periostin in gastric cancer cells and periostin overexpression promotes colony formation, invasion, and miR-155 expression in gastric cancer cells. Moreover, enforced expression of miR-155 facilitates gastric cancer cell proliferation and invasion. These findings suggest that IL-6/Periostin/miR-155 axis is implicated in the development and progression of gastric cancer induced by Hp infection. Therefore, in this project, we aim to determine the molecular mechanism underlying Hp infection-induced upregulation of periostin, to confirm the role of periostin in Hp-induced gastric cancer, to clarify the mediating role of miR-155 in periostin action, and to identify the target genes of miR-155. Completion of this project would be valuable to understand the roles of IL-6/Periostin/miR-155 signaling in Hp-induced gastric cancer and provide new potential therapeutic targets for gastric cancer.

幽门螺杆菌（Hp）感染是胃癌发生的重要危险因素。激活IL-6/STAT3通路和改变microRNAs表达是Hp感染致胃癌的重要机制。Periostin具有促胃癌细胞恶性表型的活性,然而机制仍不清楚。我们预实验结果表明：Hp感染上调Periostin 表达；Periostin可促进胃上皮细胞集落形成和miR-155表达；miR-155可提高胃癌细胞增殖侵袭能力,提示IL-6/Periostin/miR-155轴在Hp感染性胃癌发生发展过程中具有重要功能。本课题拟：（1）揭示 Hp感染诱导Periostin表达上调的机制；（2）阐明Periostin对Hp感染致胃癌的促进作用；（3）确定miR-155对Periostin活性的介导作用；（4）鉴定miR-155靶基因的功能。本研究旨在阐明IL-6/Periostin/miR-155轴在Hp感染致胃癌过程中作用，为新型抗胃癌药物开发提供潜在的靶点

幽门螺杆菌（HP）感染不仅是慢性胃炎、消化性溃疡的重要致病因素，而且与胃癌的发生密切相关。本项目揭示了HP感染通过IL6/STAT3/Twist1通路诱导Periostin表达，并且证实了Periostin在HP诱导胃癌细胞生长和侵袭过程中发挥重要作用。本项目证实Periostin通过诱导miR-214-5p抑制PAX8表达。进一步研究发现，PAX8在胃癌中表达下降，具有抑制胃癌细胞迁移、侵袭、血管生成和上皮-间质转化的功能。PAX8过表达诱导miR-612表达增加，后者靶向抑制FOXM1。过表达FOXM1可以逆转PAX8和miR-612的抑癌活性。在动物模型中，我们进一步证实PAX8通过调控miR-612/FOXM1通路抑制胃癌细胞肺部转移并伴随着肿瘤微血管密度下降。总之，本研究首次揭示Periostin在HP感染相关胃癌进展中发挥重要作用，它通过调控miR-214-5p抑制PAX8表达。并且，我们首次明确PAX8是一个新的胃癌抑制基因。本课题为新型抗胃癌药物的开发提供潜在的靶点。