KIAA0247结合E3连接酶WWP1调控Notch信号通路机制及对肺癌生物学行为的影响

The migration and invasion of lung cancer are closely related to lung cancer-related death. Previous studies found that KIAA0247 was positively correlated with differentiation and survival rate of lung cancer, negatively correlated with lymph node metastasis and stage of lung cancer; KIAA0247 inhibit Notch signaling pathway, inhibit proliferation through down-regulation of p21-Cyclin D1-CDK4 axis, inhibit migration and invasion through down-regulation of RhoA, RhoC, MMP9, up-regulation of RhoB. Immunoco-precipitation showed that KIAA0247 could bind with WWP1, and co-localization was found by immunofluorescence. Preliminary results suggest that KIAA0247 may reduce Notch signaling pathway activity and inhibit malignant phenotype of lung cancer by binding to WWP1 and ubiquitinating Notch 1. This project aims to study the interaction and mode of action between KIAA0247 and WWP1, ubiquitinate Notch1 to inhibit Notch pathway activity, and finally study the effect of KIAA0247 in vivo . This project can clarify the new mechanism of KIAA0247 inhibiting proliferation, migration and invasion of non-small cell lung cancer, and provide a new way for the treatment of lung cancer.

肺癌的迁移和侵袭与肺癌相关性死亡密切相关。前期研究发现，KIAA0247与肺癌的分化程度、生存期呈正相关，与淋巴结转移、肺癌分期呈负相关；KIAA0247可以通过抑制Notch信号通路，下调p21-Cyclin D1-CDK4轴、抑制增殖能力，下调RhoA，RhoC，MMP9，上调RhoB，抑制迁移和侵袭能力。免疫共沉淀发现该蛋白与WWP1能够结合，细胞免疫荧光发现该二者存在共定位。通过系列前期结果推测，KIAA0247可能通过与WWP1结合，泛素化降解Notch1从而降低Notch信号通路活性，抑制肺癌恶性表型。本项目拟研究KIAA0247与WWP1存在相互作用及作用方式，泛素化Notch1，从而抑制Notch通路活性；最后研究KIAA0247在或体内作用情况。本项目能明确KIAA0247抑制非小细胞肺癌增殖，迁移和侵袭的新机制，为肺癌的治疗提供新途径。

肺癌的发病率及死亡率，仍位列各种恶性肿瘤之首，约80%的死因为侵袭和转移的发生。因此解释肺癌侵袭与转移的分子机制，寻找肺癌发生发展中的关键标志物，对肺癌的预后评估大有益处，且也能为靶向药物的开发提供实验基础。实验组首次发现KIAA0247通过Notch信号通路抑制非小细胞肺癌的生物学行为，本课题中，课题组首次证实E3泛素连接酶WWP1可泛素化降解Notch1，并且首次证实KIAA0247是通过E3泛素连接酶WWP1泛素化降解Notch1，降低Notch1蛋白表达水平，进而实现对非小细胞肺癌生物学行为的负向调控。针对为何抑癌蛋白KIAA0247出现了肿瘤中的表达降低也进行了一系列的研究，不仅从下游功能发挥，也从上游蛋白的表达改变，提出了新的理论猜想及实验研究，为肺癌发生及发展的多步骤多阶段，进行了进一步的基础研究，为肺癌的预防及治疗提供了新的理论依据。

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