幽门螺旋杆菌通过激活HIF-1α/PKM2有氧糖酵解信号通路参与胃癌发病的机制研究

Pyruvate kinase type M2 (PKM2) is a co-activator of hypoxia-inducible factor(HIF)-1α transcription. The positive feedback loop between HIF-1α and PKM2 plays an important role in aerobic glycolysis and tumour growth. At present, the crosstalk between HIF-1α and PKM2 in Helicobacter pylori(Hp)-associated gastric carcinogenesis has yet not been identified. In our preliminary study, the HIF-1α and PKM2 expression showed a significant relationship with Hp-associated gastric tumorigenesis, suggesting that the positive feedback loop may be the key molecular target in the development of gastric cancer. Based on the findings, we plan to clarify the characteristic expression profile of HIF-1α and PKM2 in the different pathological tissue of Hp-infected gastric mucosa. Additionally, to explore the feedback loop-regulation effects and biological behaviors of gastric epithelial and gastric cancer cell lines infected with different virulent Hp strains, we are trying to establish cell models of overexpression or reduced expression of HIF-1α and PKM2. Moreover, two different animal models will be applied to further study the influence of the positive feedback loop between HIF-1α and PKM2 that may contribute to Hp-associated gastric carcinogenesis, as well as the role of Hp eradication in gastric disease prevention. This study may be beneficial to illustrate the function and potential molecular mechanism of abnormal cellular energy metabolism in Hp-associated gastric carcinogenesis, and find novel biomarkers for human gastric cancer targeted therapy.

低氧诱导因子(HIF)-1α可与M2型丙酮酸激酶(PKM2)构成正反馈信号通路，造成细胞能量代谢方式转换。目前，幽门螺旋杆菌(Hp)感染是否参与激活该通路并促进胃癌发生尚不明确。项目组前期研究发现HIF-1α和PKM2的表达与胃癌病理进展相关，并与Hp感染和菌株毒力关联紧密，这提示该通路极有可能是Hp介导胃癌发生的重要分子靶区。我们拟进一步收集胃组织恶性转化不同阶段标本，分析该通路在胃粘膜病理改变过程中的特征性Hp相关表达谱。另外，通过构建过表达或抑制表达的HIF-1α或PKM2细胞模型，在与Hp悬液共培养条件下，研究不同毒力Hp感染对该信号通路的调控和对细胞生物学行为的影响。通过构建动物模型，明确HIF-1α和PKM2表达在胃粘膜恶性转化中的变化规律，及其与Hp干预显效的相关性。研究结果将有助于解释能量代谢方式转换在Hp介导胃癌发生中的作用及调控机制，将为胃癌靶向治疗提供全新视角。

近年来，肿瘤能量代谢机制领域的探索已成为研究热点。M2型丙酮酸激酶(PKM2)系肿瘤糖酵解途径中的关键因子，能够与低氧诱导因子(HIF)-1α形成正反馈环路，进而重新编排肿瘤细胞糖代谢程序。该正反馈环路在胃癌发生发展中的作用及其与幽门螺旋杆菌(Hp)感染的关系研究尚属空白领域。本项目以此为切入点，通过收集胃组织恶性转化不同阶段的标本，分析该通路在胃粘膜病理改变过程中的特征性Hp相关表达谱。另外，通过构建稳定沉默的HIF-1α或PKM2细胞模型，在与Hp悬液共培养条件下，研究不同毒力Hp感染对该信号通路的调控和对细胞生物学行为的影响。通过构建动物模型，明确HIF-1α和PKM2表达在胃粘膜恶性转化中的变化规律，及其与Hp干预显效的相关性。本研究揭示了能量代谢方式转换在Hp介导胃癌发生中的作用及调控机制，从能量代谢角度对Hp致胃癌发生发展的分子机制进行全新认识，并为胃癌的靶向治疗提供了全新视角。