C20orf24通过调控MAPK/ERK通路促进结直肠癌增殖的分子机制研究

人类暗蛋白质组中潜存着与肿瘤相关的新蛋白，具有极高的挖掘价值。前期我们构建了人类20号染色体新蛋白的shRNA文库，经细胞增殖等实验筛选发现：敲低C20orf24能够抑制结直肠癌（CRC）细胞增殖。目前该蛋白在肿瘤中的功能仍未知。预实验结果表明：C20orf24在CRC中异常高表达，且与患者TNM分期晚、预后差相关；C20orf24能够激活MAPK/ERK通路并促进CRC细胞增殖；该蛋白能够与小GTP酶Rab5结合并提高其活性。我们提出假说：C20orf24通过结合并激活Rab5，从而促进MAPK/ERK通路介导的恶性增殖。本项目拟深入研究C20orf24对MAPK/ERK通路的调控机制，阐明C20orf24与Rab5结合模式及其对Rab5的激活机理，探究C20orf24/Rab5/MAPK信号轴在CRC增殖中的调控作用与机制，为诠释CRC增殖的分子机制和寻找诊疗的新靶点提供依据。

The human dark proteome contains rich source of potentially novel tumor-associated proteins for tumor biomarker mining. We established shRNA library against the 35 dark proteins on human Chromosome 20 listed by HUPO organization, and found that knockdown of chromosome 20 open reading frame 24 (C20orf24) inhibited cell proliferation of colorectal cancer (CRC). In addition, C20orf24 was up-regulated in CRC tissues, and was associated with advanced tumor node metastasis (TNM) stage and unfavorable prognosis. In vivo and in vitro experiments demonstrated that C20orf24 could promote CRC growth via activating MAPK/ERK signaling pathway. Immunoprecipitation-mass spectrometry experiment and Western blotting assays revealed that C20orf24 binds to Rab5 for activating MAPK/ERK signaling, promoting CRC progression. In this study, we proposed to explore in detail the underlying mechanism of how C20orf24 binds and activates Rab5 in the promotion of CRC proliferation. Our study may reveal for the first time the functionality of C20orf24 in CRC, illustrating the molecular mechanism for the C20orf24 involvement in the malignant process of CRC and providing a potential prognostic biomarker and a promising therapeutic target in CRC.