Analysis of beta-Catenin/Sox2/p63 Signal Pathway in Lung Epithelial Differentiation and Tumorigenesis

我们明确了Wnt/ β -catenin信号通路及其相关因子在肺癌中的表达，以及β -catenin与Sox2表达之间的调控机制。Sox2在小细胞癌和鳞状细胞癌中高表达，Sox9在鳞状细胞癌中高表达，但也在腺细胞癌和大细胞癌中表达，p63在鳞状细胞癌中表达，Notch1在腺癌中表达尤为明显。这些数据表明它们在每种肺癌亚型的肿瘤发生或肿瘤进展中具有各自的功能。建立了人支气管基底细胞（VA10）的三维培养体系。通过该系统，我们证实了BIO （GSK3抑制剂）有助于形成细胞极性，Wnt3a和EGF的共同刺激诱导细胞从球体集落中明显延伸，表明其具有加速细胞循环或细胞分裂的功能。ChIP分析显示β -catenin可能不是直接结合Sox2启动子区，而是通过其他间接方式下调Sox2的表达。

We clarified the expression of Wnt/beta-catenin signaling and related factors in lung cancers and the regulatory mechanisms between beta-catenin and Sox2 expression. Sox2 was highly expressed in small and squamous cell carcinomas, Sox9 in squamous but also in adeno and large cell carcinomas, p63 in squamous cell carcinomas, and Notch1 especially in adenocarcinomas. These data suggests their own functions in tumorigenesis or tumor progression in each lung cancer subtype. Next we established the 3D culture system of human bronchial basal cells (VA10). Using this system we clarified that BIO (GSK3 inhibitor) contributed to form cell polarity and co-stimulation of Wnt3a and EGF induced distinct extension of cells from the sphere colonies suggesting the function to accelerate cell cycling or cell division. ChIP analysis revealed that beta-catenin might not directly bind the Sox2 promoter region and downregulate Sox2 expression in other indirect way.