Rac1/PAK2/AKT/Tiam1正反馈调控环路促进套细胞淋巴瘤进展的机制研究

套细胞淋巴瘤（MCL）是目前临床不可治愈的一类B细胞淋巴瘤。前期我们发现Rac1在MCL中高表达活化，并证实其为MCL的促癌候选基因，但具体调控机制尚未阐明。预实验中我们揭示Tiam1和PAK2分别为Rac1的上下游相互作用蛋白。其中，PAK2是肿瘤信号网络的关键调节因子之一，而Tiam1则与肿瘤转移侵袭密切相关。同时，我们在MCL中建立了一条新的信号通路：PAK2/AKT/Tiam1。我们推测，Rac1通过激活PAK2/AKT/Tiam1通路而发挥促癌作用，而激活的Tiam1反馈性促进Rac1上调活化，形成正反馈环路。本项目拟从分子、细胞和整体水平，以免疫共沉淀联合质谱分析、基因编辑、人源肿瘤异种移植模型等方法，确定Rac1/PAK2/AKT/Tiam1正反馈环在MCL的正调节作用。本项目的开展将揭示MCL中一个全新的促癌调控通路，并为靶向Rac1在MCL个体化治疗中的应用提供理论依据。

Mantle Cell Lymphoma is currently an incurably B cell lymphoma. Previously, applicant has screened that Rac1 is significantly overexpressed and highly activated in MCL. Moreover, our study has proved that Rac1 could facilitate the progression of MCL and its overexpression was correlated with poor outcome. However, the mechanism has not been identified yet. Preliminary data showed that Tiam1 and PAK2 are the upstream and downstream regulators of Rac1 respectively. PAK2 has been identified as a core protein in tumor signaling pathway network and Tiam1 is correlated with tumor metastasis and invasion. Moreover, we identified a new signaling pathway in MCL: PAK2/AKT/Tiam1. Based on these data, we hypothesized that the oncogenic role of Rac1 in MCL was through activating PAK2/AKT/Tiam1 signaling pathway. Simultaneously, activated Tiam1 could facilitate the Rac1-GTP transformation in feedback way and form the positive loop. This proposal is planning using multiple methods, including Co-IP with MS, gene overexpression or knock down techniques and patient-derived xenograft mice model at different angles to confirm the positive regulatory role of Tiam1/Rac1/PAK2/AKT loop in MCL. The launching of this project will unravel a completely new oncogenic pathway in MCL and provide the theoretical foundation for the application of individualized treatment in MCL.