极性蛋白Hugl-1通过Hippo通路抑制肾癌发生及侵袭转移机制研究

Loss of epithelial cell polarity contributes to tumorigenesis and cancer progression. Hugl, a member of the Scribble polarity protein complex, plays an important role in regulating cell polarity. Accumulating evidence has shown that dysfunction of Hugl-1 is associated with lung, colorectal or breast cancer; however, the precise mechanism remains obscure. Our previous study showed that compared with kidney epithelial cells/tissues adjacent to cancer, renal carcinoma cell lines /cancer tissues had reduced expressions of Hugl-1. Knockdown of Hugl-1 by lentivirus led to downregulation of expressions of some important proteins such as E-cadherin, N-cadherin, Angiomotin, DLG5, phosphorylated YAP, phosphorylated MOB1, and LKB1. Therefore, we postulate that aberrant expression of Hugl-1 causes epithelial cell polarity disorder and ultimately, kidney cancer, which is closely associated with reduced LKB1 and Hippo pathway activity. Based on our preliminary data, we plan to conduct research on the effects of deregulated Hugl-1on malignant progression of human kidney cancer and to clarify a novel mechanism by which Hugl-1 affects the malignant progression. This project is expected to provide a theoretical basis for screening for a novel anti-tumor target.

上皮细胞极性丧失是癌症发生发展的重要特征。Hugl-1是极性密码子Scribble复合物的成员，在维持上皮细胞极性中起着重要作用。已有研究证实肺癌、乳腺癌等患者Hugl-1基因突变或缺失，而目前其作用机制尚不明确。我们的前期研究结果显示，Hugl-1在肾癌细胞/组织中表达明显低于肾上皮细胞/癌旁组织；Hugl-1敲低的肾上皮细胞中极性蛋白LKB1与细胞连接蛋白E-cadherin等表达水平降低，YAP、MOB1磷酸化减少。因此，我们设想：Hugl-1表达减少导致上皮细胞极性紊乱，通过抑制LKB1、Hippo-YAP信号通路活性参与肾癌恶性进程。我们拟以肾癌为研究对象，利用肾癌临床标本及肾癌细胞系，采用细胞分子生物学手段，对Hugl-1表达异常在肾癌发生发展中的作用进行研究。该项目的完成，将阐明Hugl-1异常在肾癌恶性进程中的全新作用机制，并为筛选抗肿瘤药物的新靶点提供理论依据。

Hugl-1是极性密码子Scribble复合物的成员，在维持上皮细胞极性中起着重要作用。已有研究证实肺癌、结肠癌及乳腺癌等患者Hugl-1基因突变或缺失，而其作用机制尚不明确。我们前期研究结果显示，Hugl-1在肾癌细胞/组织中表达明显低于肾上皮细胞/癌旁组织；Hugl-1敲低的肾上皮细胞中E-cadherin、Lkb1、YAP、MOB1磷酸化水平降低。因此，我们设想：Hugl-1表达减少通过抑制Hippo信号通路活性参与肾癌恶性进程。本课题在前期研究的基础上，采用了临床肾透明癌（KIRC）标本分析、公共数据库、细胞实验和免疫组化等研究发现：1) Hugl-1缺失参与肾癌发生发展；2) Hippo通路参与Hugl-1缺失的促癌效应；3) 肾癌中Hugl-1的降低可能是由于Hugl-1基因的甲基化引起的；4）Hugl-2 DNA甲基化可以成为判断KIRC预后的指标。我们的研究结果为KIRC研究和治疗提供了新的思路。受本基金支持，我们以第一作者身份在国际期刊Clinical and Experimental Pharmacology and Physiology发表SCI学术论文1篇。本项目的完成，阐明了Hugl-1异常在肾癌恶性进程中的全新作用机制，并为筛选抗肿瘤药物的新靶点提供理论依据。