肿瘤微环境诱导乙酸代谢异常影响结肠癌发生和转移的调控机制研究

Both the morbidity and mortality of cancer is still a big challenge to human beings worldwide although the scientists paid more and more attention and efforts to cancer research，including colon cancer during past decades. Despite a strong association, how tumor microenvironment, tumor metabolism and tumor growth are linked remains unknown. Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. Our preliminary data indicated that tumor metabolism, specially increased acetate secretion, confer a growth advantage to cells exposed to hypoxia, low glucose, or other tumor microenvironmental stresses. To elucidate the role of the Acetate/ACSS2/ HIF-2α signal pathway induced by tumor microenvironment and the related molecular mechanisms on tumor growth and metastasis, the mechanism of ACSS2 translocalization and HIF-2α acetylation are the highlight. At this point, we plan to focus on figuring out the crosslink of the signal pathway induced by hypoxia and glucose deprivation in the colon cancer, with multiple modern research techniques, including microbiome inhibition model and short chain fatty acid (SCFA) metabolism study. Our goal is to find out the early stage biomarker in the colon cancer and provide novel insights on prevent the colon tumor through the diet control.

结肠癌是严重威胁人类健康的重要疾病，也是目前值得关注和亟待解决的公共卫生问题。阐明肿瘤微环境和肿瘤代谢对肿瘤发生发展的影响和调节规律，是当前肿瘤研究的前沿和热点，对于制定科学的肿瘤防治策略，最终实现健康促进和个体化治疗具有非常重要的意义。本项目是在对缺氧和低糖为主要特征的肿瘤微环境诱导乙酸代谢异常的研究基础上，针对乙酸/ACSS2/HIF-2α 乙酰化信号通路调控结肠癌生长和转移的关键环节，以ACSS2参与HIF-2α乙酰化的分子机制为研究主线，通过高通量筛选分析，探讨缺氧和低糖诱导的结肠癌相关信号通路的共性，试图发现结肠癌早期危害的生物标志物。同时以乙酸代谢的机制研究为基础，通过肠道菌群拮抗模型和短链脂肪酸代谢分析，初步探讨膳食摄入对结肠癌防治的影响，为从微环境角度提出防治肿瘤新思路提供依据。

本课题的研究以肿瘤微环境诱导的乙酸异常代谢为研究主线，贯穿ACSS2介导的HIF-2α乙酰化修饰信号通路，结合结肠癌相关的细胞和动物模型，从崭新的视角描述了肿瘤微环境与肿瘤发生发展关系的分子基础；在此基础上进一步采用高通量筛选和多角度分子干预等策略，发现结肠癌早期危害生物标志物，为防治由肿瘤代谢异常和微环境失衡导致的肿瘤生长和转移提供科学依据，同时创新性发现膳食纤维饮食可以降低结肠癌患者肠道中产乙酸菌的丰度，抑制肠道产生乙酸的能力，进而抑制肠癌发生。以上研究结果为结肠癌防治开拓一个新的方向。