Fbxo45/STEP介导肺癌细胞ERK信号持续激活的功能及机制研究

Excessive activation of ERK signaling, a key factor in lung cancer development, is considered as an important molecular pathway in clinical treatment of lung cancer patients. At present, it is critical relying on the mutation status of EGFR and Ras family genes for clinical therapy to suppress activation of ERK signaling in lung cancer by using EGF-TKIs, which highly restricts the clinic benefit to lung cancer patients. .It is found in the pre-study of this project that Fbxo45 is able to significantly stabilize the phosphorylation level of ERK in cells, which is not entirely subjected to the sustained activation of its upstream regulator-pMEK, instead, pERK level also has a high associations to the ability of its downstream dephosphorylation protein, tyrosine phosphatase-STEP. Here, we propose a hypothesis: Fbxo45 induces the sustained activation of pERK through affecting the stability of activated STEP protein resulting in reduction or lost of the ability of dephosphorylation from pERK, which thereby makes an important contribution to the occurrence of lung cancer. As well, the potential effects of this proposed mechanism on the drug efficiency in clinical treatment of lung cancer will be also clarified in this project. .This study will provide new strategy and theory for the clinical treatment of lung cancer and for the development of new drug targeting to specific protein, through illustrating a novel mechanism of ERK signaling pathway in lung cancer.

ERK信号过度激活是肺癌发生的关键因素，也是临床上治疗肺癌患者的重要分子途径。目前，临床一线药物抑制ERK信号激活治疗肺癌患者严格依赖于其EGFR、Ras家族基因特异性位点的突变状态，使得肺癌患者临床获益受到极大的限制。.本项目前期研究发现Fbxo45能够显著稳定细胞内ERK的磷酸化水平，并且该信号并不完全依赖于其上游MEK信号的持续激活，而与其下游酪氨酸磷酸酶STEP蛋白的去磷酸化能力存在极大关联。因此，本项目拟以非小细胞肺癌为主要研究对象提出立项假说：Fbxo45通过影响STEP蛋白的稳定性而致其对pERK的去磷酸化能力降低或丧失，进而促进ERK信号的持续激活介导肺癌的发生、发展。同时，该作用机制对目前临床肺癌治疗药物药效的潜在影响也是本项目将要研究阐明的重点。.本研究将通过阐明肺癌细胞中ERK信号通路的作用新机制，为临床治疗肺癌提供新的参考策略，也为后期挖掘新的药物靶点提供理论依据。

在肺癌细胞中，pERK信号的持续过度激活是肺癌发生的重要分子途径，也是临床上治疗肺癌患者的重要靶点。本项目从ERK信号通路的去磷酸化途径着手，研究Fbxo45如何识别并介导STEP蛋白的降解从而影响其磷酸酶活性，探讨Fbxo45-STEP-pERK在肺癌细胞中的作用机理，进一步阐述肺癌发生、发展的分子机制，并针对肺癌细胞突变的异质性考查Fbxo45/STEP在非小细胞肺癌细胞对EGF-TKI敏感性中的影响。本项目研究结果表明Fbxo45在肺腺癌发生、发展过程中具有重要作用，其机理是Fbxo45能够介导STEP46发生K6-Ub连接方式等降解，从而引起ERK信号的持续激活。同时，Fbxo45在肺腺癌细胞中能够导致肿瘤细胞耐药（阿法替尼），抑制Fbxo45可能具有促进临床上阿法替尼对肺腺癌病人的药效，Fbxo45有望成为一个良好的针对肺腺癌的理想药物靶点。