慢性炎症触发结肠癌"Warburg"效应的发生及机制研究

"Warburg"效应(有氧糖酵解)是恶性肿瘤代谢的特征，既往认为是由缺氧和线粒体功能障碍引起，最近研究表明，在肿瘤形成的初期，缺氧尚未发生时，有氧糖酵解已存在。而慢性炎症是诱导肿瘤发生进展的重要原因，因此，慢性炎症与有氧糖酵解是否有某种内在的联系？我们首先建立慢性炎症诱发的小鼠结肠癌模型，检测慢性炎症在诱发肿瘤的同时对糖酵解途径相关基因表达的影响；其次用IL-6+重组人sIL-6R刺激结肠癌细胞，研究其对肿瘤细胞葡萄糖代谢的影响，并检测其对上述糖酵解基因表达的影响；接着在结肠癌细胞株研究IL-6能否激活下游信号通路，导致STAT3磷酸化，并研究STAT3能否通过与靶基因转录调控元件结合，促进基因转录，从而引发"Warburg"效应；随着肿瘤的进展，缺氧可诱导HIF-1α的表达，HIF-1α和STAT3可能通过形成co-factors或分别结合到靶基因的调控元件，协同促进有氧糖酵解的发生。

Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Previous study disclosed that the Warburg effect was induced by hypoxia and Mitochondrial deficiency. In fact, aerobic glycolysis is established in cancer cells before hypoxia on the early stage of tumorigenesis. Chronic inflammation is a key promoting factor of tumourigenesis. It remains, however,largely unexplored whether and how pro-tumourigenic inflammation regulates glucose metabolism in cancer cells. In this study, we intend to study the relationship of chronic inflammation and the Warburg effect. Firstly, the colitis associated cancer mouse model will be built and the levels of genes related to aerobic glycolysis in tumor also will be detected. Secondly, cancer cells glucose consumption, oxygen consumption and lactate production, as well as the levels of genes expression will be tested after treatment with interleukin-6(IL-6). After that, the levels of phosphorylated STAT3 would be explored if the associated pathway could be activated by IL-6. The phosphorylated STAT3, as a transcription factor, could bind to the cis-element of genes and eventually promote the genes transcription, which contributes to trigger the Warburg effect. Moreover, culture the cancer cells in oxygen limited condition after treatment with IL-6, and that could increase the expression of hypoxia inducible factor-1α(HIF-1α), which would further promote aerobic glycolysis in cancer cells.