JPH3调控糖酵解和肿瘤干细胞干性参与结肠癌进展的作用机制研究

Tumor cells mainly rely on glycolysis rather than oxidative phosphorylation in the mitochondria to generate energy even in the presence of oxygen, the energy reprogramming of which is termed as aerobic glycolysis or Warburg effect. Warburg effect could make tumor cells sustain proliferative advantage and served as one of the most emerging tumor hallmarkers. The aerobic glycolysis may modulate tumor stemness and cause chemoradiotherapy resistant, the underlying mechanism of which remain unclear. We previously showed that JPH3 is a potential oncogene, the role of which haven't been reported yet. JPH3 might promote aerobic glycolysis and maintain the stem cell property in colon cancer possibly through the transactivation of Wnt/beta-catenin signalling pathway. Here we proposed that JPH3 might serve as a key modulator of signalling cross talk between aerobic glycolysis and tumor stemness maintainance. In this study, we aim to elucidate the function and underlying mechanism of JPH3 in colon cancer through in vitro and in vivo experiments, which is helpful to identify critical marker and therapeutic target.

肿瘤细胞在有氧条件下以糖酵解而非氧化磷酸化提供能量，这种能量谢途径被称为有氧糖酵解或Warburg效应，能够使肿瘤细胞获得生存优势，是肿瘤最为重要的特征之一。同时，有氧糖酵解可能影响肿瘤细胞干性，是导致肿瘤对放化疗耐受的重要原因，其核心机制尚不明确。我们前期首次发现：（一）JPH3基因是潜在的促癌基因，目前国际上尚无报道；（二）JPH3显著促进结肠癌有氧糖酵解；（三）JPH3维持结肠癌肿瘤干细胞特性，是潜在的肿瘤干性调控基因。（四）JPH3可能调控了Wnt/beta-catenin信号通路，参与了有氧糖酵解和肿瘤干性维持过程。据此我们推测，JPH3可能作为信号串话因子（cross talk）参与了结肠癌能量代谢和干性调控的协调作用，其机制有待明确。本项目拟通过体内外实验，初步揭示JPH3的肿瘤学功能和调控机制，发现和验证关键的肿瘤标志物和干预靶点。

有氧糖酵解是肿瘤能量代谢最为重要的方式，能够使肿瘤细胞快速有效获取能量满足分裂增殖，并在获取能量的过程中调控了线粒体损伤、代谢关键酶、 基因组稳定性、血管生成等，产生的局部酸性环境又促进免疫逃逸、增加侵袭 能力、维持肿瘤细胞干性和放化疗耐受性，深刻的影响了肿瘤多方面的生物学特征。因此，深入探索有氧糖酵解参与肿瘤发生发展的作用机制，揭示关键的信号通路和调控靶点，有助于解决肿瘤能量代谢的关键科学问题，具有重要的临床转化应用价值。本课题初步探讨了JPH3调控结肠癌能量代谢的功能和机制，同时，在本课题的支柱下，项目负责人还完成了FOXC1通过转录调控FBP1的表达促进肿瘤细胞糖代谢影响结肠癌的进展的机制研究；阐明了结肠癌中糖酵解相关的lncRNA MIR17HG通过ceRNA的机制影响miR-138-5P对HK1表达的调控导致结肠癌细胞的糖代谢异常，乳酸堆积激活激活p38/Elk-1信号通路促进CRC细胞中MIR17HG的表达，形成正反馈，导致持续的有氧糖酵解，进而发生肠癌肝转移。本课题揭示了一系列与结肠癌肿瘤细胞异常糖代谢相关的基因，有助于揭示肿瘤发生发展及转移的分子作用机制，有助于阐明关键的信号通路和潜在调控靶点，有助于发现结肠癌进展及预后相关的分子标志物和潜在干预靶点，并可能实现临床转化。