HOXC6介导自噬促进上皮间质转化调控肠癌肝转移的机制研究

Liver metastasis is the most primary factor of survival in colorectal cancer patients, and it is of great significance to find the target for early prediction of colorectal cancer liver metastasis and to elucidate the molecular mechanism. Further excavation of the results in our previous study, we found the high expression of transcript factor HOXC6 in colorectal cancer tissue with liver metastasis at early stage. Besides, HOXC6 promotes metastasis in colorectal cancer cells. Further research on mechanism show that HOXC6 mediates autophagy by transcriptional regulation the pivotal protein Beclin1, and then promotes epithelial mesenchymal transition (EMT) which is widely recognized as an early event of metastasis. Based on these results, we would like to conduct in vivo and in vitro experiments to explore the exactly molecular mechanisms of HOXC6 in regulating autophagy and facilitating cancer cell metastasis, to identify molecular target of HOXC6 regulating autophagy signaling pathway, to describe downstream molecular pathways of HOXC6, and then to validate molecular regulation through human tissue and its clinical significance. At currently, the study of HOXC6 in colorectal cancer is still limited, especially the mechanism on colorectal liver metastasis. We expect to achieve a high quality results in the study of HOXC6 and find a potential new target for targeted therapy of colorectal liver metastasis.

肝转移是影响结直肠癌患者预后的最主要因素，寻找肠癌肝转移早期预测靶标，阐明其中的分子机制具有重要的临床意义。申请人通过进一步挖掘前期研究结果发现，转录因子HOXC6在早期即发生肝转移的肠癌组织中高表达；细胞实验证实HOXC6具有促进肠癌细胞转移的表型。进一步探讨其作用机制显示，HOXC6可通过转录调控自噬关键蛋白Beclin1介导了细胞的自噬，自噬效应的启动促进了上皮间质转化（EMT）这一转移早期事件，致使肠癌细胞的转移能力增强。本项目拟通过体内和体外实验深入探讨HOXC6介导自噬进而促进肠癌细胞转移的分子机制，明确HOXC6调控自噬通路的分子靶点，描绘出HOXC6下游调控的分子途径，并在组织水平验证分子间调控作用和分析其临床意义。目前国内外对HOXC6在结直肠癌中的研究尚处于初级阶段，我们在大量前期工作基础上深入探讨其介导自噬调节EMT过程影响转移的分子机制，为临床提供潜在的靶点。

肝转移是影响结直肠癌患者预后的最主要因素，寻找肠癌肝转移早期预测靶标，阐明其中的分子机制具有重要的临床意义。本项目通过进一步挖掘前期研究结果发现，转录因子HOXC6在肝转移的肠癌组织中高表达；细胞水平实验、动物水平实验分别证实HOXC6具有促进肠癌细胞转移的表型。进一步探讨其作用机制显示，HOXC6可调控上皮间质转化（EMT）进而促进肿瘤的转移。报告基因实验和染色体免疫共沉淀实验发现自噬关键分子Atg5、EMT关键调控分子Snail1分别是HOXC6的靶分子。RNA-seq测序结果显示，敲低HOXC6后，cell adhesion通路变化最为显著，是HOXC6促进肿瘤转移过程中的可能通路。本研究初步明确HOXC6通过转录调控自噬关键蛋白Atg5、转录调控Snail1促进上皮间质转化最终发挥促进肿瘤转移的作用。.