CAP70经调节PTEN磷酸化影响肾癌恶性表型的研究

Dysregulation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays an important role in the development of renal cell carcinoma. In preliminary work we found that PTEN phosphorylation level was aberrantly high so that PTEN was inactivated in renal cell carcinoma. Currently it is unclear that how PTEN phosphorylation level was regulated. Our preliminary study result also showed that CAP70 can interact with PTEN, further inhibit PTEN phosphorylation. Simultaneously we found that CAP70 was aberrantly downregulated in renal cell carcinoma tissue. Based on this, we hypothesized that CAP70 aberrantly downregulated in renal cell carcinoma tissue led to the rising of PTEN phosphorylation level and abnormal activation of PI3K/AKT/mTOR pathway, further promoted the development of renal cell carcinoma. In this study, we intend to identify the molecular mechanism of the interaction between CAP70 and PTEN in renal tissue, confirm the inhibiting effect of CAP70 on PTEN phosphorylation level through interaction by experiments in cell lines, nude mice and clinical samples, further to influence PTEN-mediated renal cancer malignant phenotype. This study will characterize a novel protein-protein interaction between CAP70 and PTEN and explore a novel molecular mechanism regulating PTEN function by interacting with CAP70. This will help to understand pathogenesis and metastatic mechanism of renal cell carcinoma and provide new target for drug research and clinical treatment of renal cell carcinoma.

PTEN-PI3K/AKT/mTOR通路异常在肾癌发生发展中起着重要作用，我们前期工作发现肾癌组织中PTEN磷酸化水平异常升高，使PTEN处于失活状态，而目前调节PTEN磷酸化的分子机制尚未阐明。前期工作还发现CAP70与PTEN有相互作用，并可抑制PTEN的磷酸化，同时发现在肾癌中CAP70异常下调。据此我们认为：在肾癌中CAP70异常下调使PTEN磷酸化水平增高，引起PI3K/AKT/mTOR通路异常活化，导致了肾癌的发生发展。本课题拟进一步研究CAP70与PTEN在肾组织中的相互作用及分子机制；并从细胞、动物和临床水平阐明CAP70通过与PTEN相互作用来抑制肾组织中PTEN的磷酸化，进而影响肾癌细胞的增殖侵袭能力。本研究拟明确CAP70与PTEN的新的相互作用，揭示CAP70调节PTEN功能的新机制，有助于进一步阐明肾癌发生和转移的分子机制，为肾癌的药物研发和临床治疗提供新靶标。

PTEN-PI3K/AKT/mTOR通路异常在肾癌发生发展中起着重要作用，而调节此通路的分子机制尚未阐明。本项目结果表明，肾癌组织中PTEN因磷酸化而失活，PTEN失活后可通过激活肾癌中mTOR及其下游分子来促进肾癌的恶性表型。本项目结果还表明，CAP70可与PTEN相互作用。CAP70通过与PTEN相互作用，抑制了PTEN的磷酸化水平及下游信号分子的激活。而肾癌中CAP70表达水平异常下调，使其调节的PTEN-PI3K/AKT/mTOR信号通路功能异常，进而导致肾癌恶性表型的发生。且CAP70的过表达可增强肾癌细胞对mTOR抑制剂雷帕霉素的敏感性。本研究发现了肾癌中PTEN失活的机制，CAP70与PTEN的新的相互作用，揭示了CAP70调节PTEN功能的新机制，有助于进一步阐明肾癌发生和转移的分子机制，为肾癌的药物研发和临床治疗提供了新靶标。据此在SCI收录期刊发表基金资助论文11篇，总IF = 29.255。还发表中文核心期刊论文2篇及待发表SCI论文1篇。