膜蛋白CD82抑制肿瘤转移，而CXCR4受体介导骨转移，但两者在功能上是否关联，并不清楚，尤其是关于CD82调控CXCR4内吞的研究鲜有报道。我们已证实CD82促进U2AF2泛素化降解，调控CD44可变剪接，抑制转移（Oncogene,2016）。预实验发现肺癌细胞过表达的CD82与PKCα共沉定，促进泛素连接酶AIP4与CXCR4结合和泛素化，降低膜CXCR4水平，抑制骨转移细胞趋化。推测CD82通过PKCα促进CXCR4内吞，抑制肺癌骨转移。为此，项目拟从分子、细胞、组织及动物等不同层次研究CD82促进CXCR4内吞的生物学功能；探讨CD82怎样加速CXCR4内吞的?阐明CD82如何招募PKCα调节CXCR4内吞?明确CD82通过调节CXCR4内吞抑制骨转移及临床功能。研究工作有望以CXCR4内吞为切入点揭示CD82抑制肺癌骨转移的新机制，为肺癌骨转移治疗提供新的分子靶标与干预策略。

The plasma membrane protein CD82 inhibits tumor metastasis, while CXCR4 receptor plays crucial roles in bone metastasis. However, it is unknown whether there is relevance of functional role between CD82 and CXCR4. In particular, it is still unclear whether CD82 can regulate CXCR4 endocytosis. Our previous study showed that CD82 suppresses CD44 alternative splicing by mediating U2AF2 ubiquitination and degradation to inhibit tumor metastasis, and prevents Rho activation (Oncogene, 2016). In addition, our preliminary data indicated that CD82 can directly bind with PKCα by coimmunoprecipitation (Co-IP), promote the direct binding of E3 ubiquitin ligase AIP4 and CXCR4 to enhance CXCR4 ubiquitination, reduce the levels of CXCR4 at the plasma membrane, and attenuate the chemotactic response to SDF-1 from lung cancer cells with bone metastasis. Therefore, we hypothesize that CD82 regulates CXCR4 receptor endocytosis at the plasma membrane by recruiting PKCα to suppress bone metastasis from lung cancer cells. To prove the hypothesis on basis of the previous study, this project will conduct series of experiments by employing molecular, cell biology technology, mouse model and clinical samples analysis integratively to investigate the biological function of CD82 promoting CXCR4 endocytosis, to discuss how CD82 can accelerate CXCR4 endocytosis, to focus on how CD82 can recruit PKCα to facilitate CXCR4 endocytosis, and to discover biological function and clinical significance that CD82 can suppress bone metastasis from lung cancer cells by regulating CXCR4 endocytosis. This project will uncover the intrinsic molecular mechanism of CD82 regulating bone metastasis on basis of endocytosis of CXCR4 at the plasma membrane from lung cancer. At the same time, the project will provide novel molecular targets and intervention strategies of diagnosis and treatment for patient with lung cancer bone metastasis.