c-Myb在KRAS突变结直肠癌恶性表型中的作用及机制研究

KRAS突变结直肠癌(Colorectal cancer, CRC)占临床CRC的30-50%，其中约50%其生存并不依赖于KRAS活性，这些病人是临床干预的难点。前期发现c-Myb在KRAS依赖细胞中显著高表达且促进体外克隆形成，其所调控的许多靶分子均与KRAS突变有协同致死作用，故认为c-Myb在KRAS突变CRC恶性表型形成中起关键作用。围绕该假设，本课题将：1）利用体内外模型，研究c-Myb对KRAS突变CRC细胞迁移、成瘤及转移等恶性表型的作用；2）利用siRNA干扰和转录组芯片等技术筛选c-Myb在KRAS突变CRC中所调节的核心分子网络；3）基于病人样本和随访信息评价核心分子及其组合对KRAS突变CRC的预后预测价值。课题完成后不仅能明确c-Myb在KRAS突变CRC中的作用及分子机制，还能发现一个或多个用于CRC预后预测的多标志群。

It is difficult to treatment the patients with colorectal carcinoma (CRC) when K-ras mutation occurred in cancer cells. We recently found c-Myb is significantly up-regulated and facilitated the clones formation in KRAS dependent CRC than KRAS-independent CRC, and can regulate mitotic signaling and its target molecules, among which has been proved to be synthetic lethality with KRAS mutation. So we hypothesis that c-Myb may play a critical role in the progression of CRC with KRAS mutations. Focusing on this point, we will conduct the following works: 1) to evaluate the role of c-Myb on KRAS-mutation CRC about proliferation, migration, tumor formation and metastases by using the in vivo and in vitro models; 2) to identify the core molecules network regulated by c-Myb in KRAS mutation cells with siRNA interference and expression profile analysis; 3) to test the prognostic value of core network molecules regulated by c-Myb and identify a marker panel for the prediction of CRC prognosis. We can not only elucidate the role and mechanism of c-Myb to CRC with KRAS mutations, and but also build a marker signature containing the optimal numbers of c-Myb targeted genes to predict the prognosis of CRC patients.