大肠癌发生发展中肠菌影响糖代谢重编程的组蛋白修饰与信号通路网络机制

Colorectal cancer (CRC) is one of higher morbidity cancers worldwide. Its progression involves in gut flora dysbiosis, activation of proliferation pathways, abnormal chromatin modification and reprogrammed cell glucose metabolism. In our previous studies, we found disturbances of gut bacterial communities suppressed the production of butyrate, decreased histone acetylation and activated ERK-MAPK and STAT pathways. The histone demethylmethylase JMJD2B, which was induced by HIF-1α, promoted cell proliferation through STAT3 pathway. In low glucose environment, JMJD2B expression was significantly elevated and it exhibited colocalization with phosphorylated ERK1/2, leading to ERK-MAPK pathway activation. Conversely, inhibition of ERK-MAPK pathway decreased JMJD2B expression and impaired glucose uptake in CRC cells. Meanwhile, tumor anti-angiogenesis therapy resulted in inhibition of mitochondria respiratory function and enhanced activity of glycolysis. However, it remains to be clarified the mechanism of how gut flora impact on histone modifications and pathways activations in intestinal mucosal cells. In another aspect, whether and how do gut bacterial communities influence reprogramming of cell glucose metabolism? Herein lies the problem of how these regulatory networks function in CRC development and progression. In the present study, we will identify these regulatory networks both in vivo and ex vivo, by the approaches of ChIP-sequence in combination with GO annotation, pathway analysis, quantitative mass spectrometry, gene knockdown or knockup and so on. We will also establish whether and how manipulation of gut microbial dysbiosis may be used as a potential therapeutic approach in the treatment of human CRC.

大肠癌（CRC）发病率高，肠道菌群紊乱、染色质修饰异常、细胞糖代谢重编程和增殖相关信号通路活化参与其发生中。我们曾发现肠菌异常致黏膜丁酸盐减少、组蛋白乙酰化降低和ERK-MAPK与STAT通路活化；HIF-1α诱导的组蛋白去甲基化酶JMJD2B通过STAT3通路而促进增殖，低糖时JMJD2B增高、与p-ERK1/2在胞内共定位且通路活化；CRC细胞中抑制ERK通路则降低JMJD2B而减少细胞摄取葡萄糖；抑制肿瘤血管形成则CRC细胞线粒体受抑而糖酵解增强。以下问题亟待解决①肠菌影响肠黏膜细胞组蛋白修饰和信号通路变化的详细机制是何？②肠菌怎样影响细胞糖代谢重编程？③其间的网络调控如何参与大肠癌的发生发展？我们将在临床标本分析和体内外实验中，通过ChIP- seq结合GO注释和pathway分析、定量质谱、基因敲除与导入等研究，阐释上述网络关系，探讨通过调节肠菌而预防CRC的可行性及其机制。

本项目在以下方面取得重大进展：①发现具核梭杆菌（Fusobacterium nucleatum）的丰度与CRC患者的糖代谢水平呈正相关；具核梭杆菌或可通过提高CRC细胞的糖代谢水平促进肿瘤发生（Gut, 2020）。②阐释了大肠癌发生发展中糖代谢异常的机制，首次发现GLCC1 lncRNA能够响应糖饥饿的诱导表达上调后进一步促进糖酵解和肿瘤细胞生长恶变，最终促进大肠癌的发生发展（Nat Commun, 2019）。③证实了具核梭杆菌通过诱导大肠癌细胞自噬而促进大肠癌化疗耐药: 大肠癌患者肠黏膜组织中具核梭杆菌丰度升高为最常用的化疗药物5-FU和奥沙利铂耐药化疗失败及复发的预警标志，该诱导耐药与激活肿瘤细胞自噬有关（Cell, 2017）。得到三页的Cell同期述评。论文发表3年内即被正面引用超过400次，包括3篇Science期刊论文。该研究为将来肠菌标志物预测大肠癌术后化疗效果和复发倾向，及根除该菌逆转化疗耐药而改善预后等，提供了坚实的临床和基础研究证据。.项目实施过程中，我们申请的国家发明专利《粪便中共生梭菌预警大肠癌》已经转让给深圳亚能公司，正处于扩大验证和开发试剂盒阶段；培养了2名博士生，课题组成员获上海市科技启明星；获2018年国家科技进步二等奖；新承担科技部2020年重点研发专项（“蛋白质机器与生命过程调控”）（资助2220万元）和3项NSFC重点项目资助。仁济消化科在全国消化内科排名中处于1-2位。