原钙粘素7在肺癌发生发展中的作用和机制研究

Lung cancer is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatments, there is a great need to identify new driver genes that promote lung tumorigenesis and novel therapeutic targets. We employed a transposon mutagenesis strategy to identify functional relevant driver genes in a human lung cancer cell model. This led to identification of PCDH7, a poorly characterized molecule that is likely to function as a novel oncogene in human lung cancer. PCDH7 is frequently overexpressed in lung tumor and high expression correlates with poor survival of lung adenocarcinoma patients. Moreover, PCDH7 expression strongly potentiates KRAS mutation mediated transformation of human bronchial epithelial cells through sustained activation of ERK signaling pathway. We also identified interactions between PCDH7 and SET, which is an inhibitor of protein phosphatase 2 ( PP2A). Conditional transgenic mice have been established to determine the consequence of PCDH7 overexpression and the mechanisms through which PCDH7 promotes lung cancer development. Importantly, the growth of lung cancer cells in vivo is significantly inhibited by knocking down PCDH7 expression, suggesting that it might be a drug target for the treatment of lung cancer. This therapeutic potential will be evaluated with multiple strategies including a rapid PCDH7 gene knock-out mouse model and the results may lead to a new way to prevent and treat lung cancer.

肺癌是我国发病率和死亡率最高的恶性肿瘤，亟待加强基础研究，鉴定关键致病基因并寻找有效的治疗靶点。前期研究提示原钙粘素7（PCDH7）可能是一个新的肺癌致病基因。该分子在肺癌中表达增高并显著影响疾病预后。PCDH7高表达能诱导支气管上皮细胞恶性转化，并且激活ERK信号、显著增强肺癌细胞在体内外的生长，其机制可能与结合SET蛋白有关。本课题首先将采用PCDH7转基因小鼠，通过动物模型验证其高表达是否促进肺癌形成；进而分析PCDH7与SET蛋白相互作用，明确PCDH7促进细胞恶性转化的机制。最后，建立PCDH7基因敲除细胞系和动物模型，探讨能否通过阻断PCDH7的功能来抑制肿瘤生长。研究结果将加深我们对肺癌发生和发展机制的理解，并为临床治疗提供新的思路和方法。

肺癌是我国发病率和死亡率最高的恶性肿瘤，亟待加强基础研究，鉴定关键致病基因并寻找有效的治疗靶点。前期提示原钙粘素7（PCDH7）可能是一个新的肺癌致病基因，本课题在此基础上开展深入研究，旨在阐明PCDH7在肺癌中的作用和机制，评估其作为药物靶点的价值。本课题的研究内容主要有以下三个方面：①PCDH7在肺腺癌中的表达水平以及临床相关性。②PCDH7在胰腺癌细胞中和肺癌动物模型中的作用。③ 验证PCDH7是通过与SET/PP2A相互作用促进肺腺癌的进展。我们发现，PCDH7在肺癌细胞膜表面高表达，和预后差密切相关，高表达PCDH7的肺癌细胞株恶性度显著增强。在肺癌动物模型中，高表达PCDH7导致肿瘤进展加快，而敲除PCDH7基因后肿瘤生长受到显著的抑制，提示PCDH7在肺癌中起关键作用。另外，PCDH7作用机制和PCDH7/SET/PP2A通路有关。PP2A（Protein phosphatase 2, PP2A）通过去磷酸化的作用抑制ERK信号，对MAPK等信号通路起重要负反馈调节；而SET是抑制PP2A活性的重要因子，PCDH7可以和SET结合，进而抑制PP2A的活性，导致ERK通路过度活化，促进肿瘤进展，相关研究结果最近发表在Cancer Res和Mol Cancer Res等杂志上。. 在本课题的资助下，我们也开展了一些探索性研究：PCDH7的高表达在胰腺癌中也常见，并和预后差相关。高表达PCDH7使KRAS突变的胰腺癌细胞的恶性度显著增加，并促进对靶向治疗的耐药，提示PCDH7可能具有广泛的促癌作用。更重要的是，我们首次发现PCDH7的配体可能是细胞外基质中层粘连蛋白Laminin-332，推论在KRAS突变的胰腺癌中，Laminin-332通过结合肿瘤细胞表面的PCDH7，激活PCDH7/SET/PP2A通路，促进肿瘤的生长和转移。下一步，我们将对此假说进行充分验证，并评估阻断Laminin-332和 PCDH7的结合对胰腺癌是否具有抑制作用。我们目前已经获得了PCDH7条件性基因敲除小鼠，拟建立肺癌和胰腺癌动物模型，开展体内研究。我们也制备了PCDH7单抗，目的是筛选阻断性抗体并开展转化性研究，验证其在肺癌和胰腺癌中的治疗价值。