Rap1GAP通过负调控CDK4的稳定性抑制胃癌细胞增殖的分子机制研究

The expression disorders of tumor suppressor protein Rap1GAP and cell cycle kinase CDK4 play important roles in the proliferation of malignant tumors, but there have not any reports about the function of Rap1GAP in gastric cancer development and the relationship of both proteins. In previous work, we found that Rap1GAP expression was significantly down-regulated in gastric cancer. Rap1GAP inhibits the proliferation of tumor cells, and knocking-down Rap1GAP expression accelerates cell cycle progression. Rap1GAP specifically interacts and decreases the stability of CDK4 protein by increasing the ubiquitination of CDK4. So we speculate that in the process of development of gastric cancer, down-regulated Rap1GAP leads to abnormal increased CDK4 protein levels, which accelerates the conversion from G1 to S phase and promotes malignant proliferation of gastric cancer cells. This project will further study the correlation between Rap1GAP expression and clinical indicators in gastric cancer, verify the function of Rap1GAP on gastric cancer cell proliferation, and ascertain the molecular mechanisms of Rap1GAP in regulating the stability of CDK4. This study is expected to illuminate the functions and molecular mechanisms of Rap1GAP in gastric cancer development, and to provide new ideas on exploring the molecular targets in prevention and treatment of gastric cancer.

抑癌蛋白Rap1GAP及细胞周期激酶CDK4的表达失调在肿瘤的恶性增殖中扮演重要角色，但 Rap1GAP在胃癌发生中的作用及其与CDK4的关系未见报道。我们的前期研究发现：Rap1GAP在胃癌组织中的表达显著下调；Rap1GAP可抑制肿瘤细胞的增殖，削减后细胞周期进程加快；在分子水平，Rap1GAP可以特异性地和CDK4相互作用，增加CDK4的多聚泛素化水平，降低其蛋白稳定性。据此，我们推测在胃癌发生发展的过程中，Rap1GAP表达下调导致CDK4的蛋白水平异常增加，加速了细胞周期进程，促进了胃癌细胞的恶性增殖。本项目将通过临床标本分析及细胞生物学实验进一步研究Rap1GAP的表达与胃癌病例临床特征的关系、Rap1GAP对胃癌细胞增殖的作用及其对CDK4稳定性调控的分子机制，进而阐明Rap1GAP在胃癌发生发展过程中的作用和机制，为探寻胃癌防治的分子靶点提供理论依据和思路。

抑癌蛋白Rap1GAP及细胞周期激酶CDK4的表达失调在肿瘤的恶性增殖中扮演重要角色，但Rap1GAP在胃癌发生中的作用及其与CDK4的关系未见报道。本项目通过分析Rap1GAP与CDK4在胃癌病例中的表达特征，证实Rap1GAP促进胃癌增殖的功能以及揭示Rap1GAP调控CDK4蛋白稳定性的分子机制，研究发现：1) Rap1GAP在胃癌组织中的表达显著下调，相反，CDK4的蛋白水平却显著升高；2) Rap1GAP通过与HSP90β-CDC37复合物竞争性地结合CDK4，促进CDK4的泛素化降解，进而抑制肿瘤细胞的增殖；3) CDK4抑制剂Palbociclib可逆转Rap1GAP表达下调而引起的胃癌细胞增殖及移殖瘤生长。该研究结果有望为胃癌的精准靶向治疗提供新的实验依据和思路。