4EBP1“去磷酸化”对口腔鳞癌增殖转移相关蛋白翻译起始的抑制作用及其意义

蛋白的“去磷酸化/磷酸化”转换是细胞的生物开关，其异常可导致细胞的异常增殖和转移。4EBP1是调控蛋白翻译起始的核心蛋白，其磷酸化可加速癌相关蛋白的翻译，促进肿瘤的发生，推测其去磷酸化则具有抑制作用（Nature 2015），但鲜有研究证实，其在肿瘤增殖与转移中的作用也急待阐明。申请人前期研究（JNCI 2014）发现4EBP1上游信号分子mTOR去磷酸化，可下调4EBP1下游的癌相关蛋白的表达，提示级联反应导致了其去磷酸化并抑制了蛋白翻译，但精细机制也有待诠释。本课题拟以我国高发的口腔鳞癌为模型，建立特异性表达去磷酸化4EBP1突变的细胞系，解析其对翻译起始复合物的抑制作用；观察其抑制鳞癌增殖转移的生物学功能，剖析其具体调控的分子与通路；探索以4EBP1去磷酸化为靶标、研发新分子药物的可能。结果将揭示4EBP1介导的过度翻译在恶性肿瘤中的精细机制，并对口腔鳞癌的临床防治具有指导意义。

Recently it has been reported that protein "dephosphorylation/phosphorylation" state transition regulates multiple cellular events, and its dysregulation may cause cancer. Overexpression of cancer-associated protein is one of the major features in malignant tumors. 4EBP1 is the key effector of translation initiation control. Its phosphorylation induces oncogenic protein expression; presumably 4EBP1 dephosphorylation inhibit translation（Nature 2015）, but it is still lack of direct evidence, and its effect on tumor proliferation and metastasis regulation have not been clarified. The applicant confirmed (JNCI 2014) that mTOR dephosphorylation downregulates oncogenic protein expression, cyclinD1, for example, suggesting that dephosphorylation cascade leading to 4EBP1 and inhibits protein translation, but further research need to be performed. In this proposal, we intend to use oral squamous cell carcinoma, a high incidence of disease in China as the model to study the following: to establish mutant format of 4EBP1, specifically expressing a dephosphorylated 4EBP1, studying its function on translation initiation complex; to find out if 4EBP1 dephosphorylation inhibits proliferation and metastasis, and clear the molecules regulated in this progress; to find out the possibility of using 4EBP1 as a target. The results will reveal the molecular mechanism of "4EBP1 mediated translation initiation control" in cancer, and guide the clinical strategy in the treatment of oral squamous cell carcinoma.