癌蛋白Gankyrin通过YAP对结肠癌干细胞特性的调控作用及机制研究

If patients with advanced colon cancer develop drug-resistance during treatment, the recurrence and metastasis of the tumor will occur.Therefore, elucidating the mechanism of drug-resistance in colon cancer is very important for diagnosis and treatment of colon cancer and improving patients’ prognosis. Although a large number of studies have shown that cancer stem cells (CSCs) are closely related to the drug resistance of colon cancer, its molecular mechanism has not been elucidated. To this end, our group has screened the key gene Gankyrin regulating colon CSCs by transcriptome sequencing. We alos found its downstream target gene YAP. Therefore, this project is on the basis of previous studies, to further discuss whether Gankyrin promotes colon CSCs is dependent on the regulation mechanism of YAP, and expound the combination of Gankyrin and CSCs marker is available for indicating the resistance, prognosis and targeted therapy of patients with colon cancer. We propose the following hypothesis: 1) Gankyrin facilitates the stem-like characteristics of colon CSCs in a YAP-dependent manner; 2) Gankyrin indirectly or directly promote the stability of cytoplasmic YAP, resulting in YAP nuclear transcription which triggers the transcription of stem cell factors; 3) Inhibiting Gankyrin/YAP combined with conventional chemotherapy can reverse the drug-resistance of colon cancer.

中晚期结肠癌患者在治疗过程中一旦出现耐药，会进而发生肿瘤的复发、转移，因此阐明结肠癌的耐药相关机制，对于结肠癌的诊治及改善患者的预后至关重要。大量研究表明肿瘤干细胞与结肠癌的耐药密切相关，但其分子机制尚未阐明。为此，本课题组前期通过转录组测序筛选出调控结肠癌干细胞特性的关键基因Gankyrin，并找到了其下游的靶基因YAP。因此本项目拟在前期研究的基础上，进一步探讨Gankyrin促进结肠癌干细胞的调控机制是否依赖于YAP，并阐明Gankyrin结合肿瘤干细胞标志物是否可作为结肠癌患者耐药、预后评估及靶向治疗的重要指标。我们提出如下科学假说：1）Gankyrin通过YAP依赖的机制促进结肠癌干细胞的特性；2）Gankyrin间接或直接促进YAP的胞浆稳定性，从而导致YAP入核启动干细胞转录因子的转录；3）阐明通过抑制Gankyrin/YAP并联合传统化疗方案可逆转结肠癌的化疗耐药。

结肠癌的发病率和致死率较高，目前对于结肠癌的治疗方式为综合治疗，以手术切除为主，术后辅助化疗或放疗防止肿瘤复发、转移。但是许多患者在治疗过程中会发生肿瘤的复发、转移，最终影响患者的生存。因此，阐明结肠癌的耐药、复发和转移相关机制，并找到预测、监测上述肿瘤生物学行为指标及治疗的关键靶点，对于结肠癌的诊治及改善患者的预后至关重要。已有大量研究致力于结肠癌耐药、复发和转移相关的分子机制，而肿瘤干细胞被认为在其中发挥着重要的作用。为了进一步阐明结肠癌干细胞相关分子机制，找到结肠癌新的治疗靶点，我们通过转录组测序筛选出调控结肠癌干细胞特性的关键蛋白Gankyrin，并发现Gankyrin通过YAP依赖的机制促进CD133阳性结肠癌干细胞的自我更新、成瘤性及耐药性；另外，在结肠癌组织中，Gankyrin和肿瘤干细胞标志物CD133的表达呈正相关。本项目为结肠癌干细胞的调控机制提供了新依据，还为结肠癌患者提供了新的预后评估标志物。