Rab11在FGFR4诱导结直肠癌细胞上皮间质化中的分子机制研究

Metastasis is one of the main factors that negatively influence the proper prognosis of colorectal cancer (CRC), and fibroblast growth factor receptor4 (FGFR4) plays a critical role in the metastasis of CRC. In our previous studies, FGFR4 was found to be highly expressed in CRC tissues compared with noncancerous adjacent tissues. The interstitial characteristics and invasion ability of cancer cells changed significantly when FGFR4 expression was altered, indicating that FGFR4 may involve in the metastasis of CRC by promoting epithelial mesenchymal transition (EMT). Using bioinformatics analysis, we identified Rab11 as a potential upstream regulator of FGFR4, and further biological experiments validated that Rab11 can regulate the expression of FGFR4. Thereby, Rab11 may promote FGFR4 recycling, thereby up-regulating FGFR expression, and ultimately lead to EMT by activating WNT/β-catenin pathway in CRC. In this proposal we will try to elucidate the correlation between Rab11 and FGFR4, the mechanism of how Rab11 regulates FGFR4 expression and promotes EMT, as well as their relation to the tumorigenesis and prognosis of CRC. This study will lead to a better understanding of the regulatory role of Rab11 in FGFR4-mediated CRC metastasis, which can help evaluate the effectiveness and feasibility of using related intervention measures to reduce cancer metastasis.

成纤维细胞生长因子受体4（FGFR4）与肿瘤转移密切相关。前期研究中我们发现FGFR4在结直肠癌中显著高表达，增加或抑制FGFR4的表达可明显改变肿瘤细胞的间质化特征，提示FGFR4有可能通过促进上皮细胞间质化（EMT）参与结直肠癌的转移。我们基于蛋白质相互作用网络分析筛选出Rab11是FGFR4上游的潜在调控因子，并且通过实验证实了Rab11可以调控FGFR4的表达，提示Rab11可能通过促进FGFR4的循环利用，从而上调FGFR4的表达，最终通过激活WNT/β-catenin信号通路促进结直肠癌EMT的发生。本项目拟在前期基础上，明确Rab11和FGFR4与结直肠癌发生以及两者的表达相关性；阐明Rab11通过调控FGFR4的表达诱导结直肠癌EMT的分子机制。本课题的实施有助于深入解析Rab11和FGFR4诱发结直肠癌转移过程的分子机制，并评价干预措施对降低肿瘤转移风险的有效性和可行性。

成纤维细胞生长因子受体4（FGFR4）与肿瘤转移密切相关。前期研究中我们发现FGFR4在结直肠癌中显著高表达，增加或抑制FGFR4的表达可明显改变肿瘤细胞的间质化特征，提示FGFR4有可能通过促进上皮细胞间质化（EMT）参与结直肠癌的转移。我们基于蛋白质相互作用网络分析筛选出Rab11是FGFR4上游的潜在调控因子，并且通过实验证实了Rab11可以调控FGFR4的表达，提示Rab11可能通过促进FGFR4的循环利用，从而上调FGFR4的表达，最终通过激活WNT/β-catenin信号通路促进结直肠癌EMT的发生。本项目在前期基础上，进一步建立临床样本库，明确Rab11和FGFR4在结直肠癌转移中的异常表达及其临床意义；建立多种细胞转移模型与实验动物荷瘤模型，明确Rab11和FGFR4协同调控结直肠癌转移的生物学功能；综合运用多种细胞分子生物学方法，阐明Rab11和FGFR4协同诱导结直肠癌转移的信号调控网络。本课题的实施有助于深入解析Rab11和FGFR4诱发结直肠癌转移过程的分子机制，并评价干预措施对降低肿瘤转移风险的有效性和可行性。