TGFβ1/Smad与PIKKs/Akt信号转导通路交互作用在紫外线诱导日光性角化病向鳞状细胞癌进展的机制研究

紫外线照射致癌前病变日光性角化病(AK)向鳞状细胞癌(cSCC)转变，严重危害人民群众生命健康。国内外研究表明紫外线引起信号通路异常激活是关键致病机制。我们前期研究发现紫外线通过抑制AK中TGFβ1/Smad信号通路，促进AK向cSCC进展；发现紫外线异常激活PIKKs/Akt信号通路，找到DNA-PKcs-mTORC2复合物是紫外线活化Akt的关键因子，Akt异常激活可诱发多种肿瘤。但PIKKs/Akt信号通路在AK、cSCC中的机制不清，是否与TGFβ1/Smad信号通路存在交互作用不明。本项目拟在已建立的高原皮肤癌样本库及前期研究基础上，在病损组织、细胞、小鼠水平，运用转基因技术等分子生物学手段，探讨AK、cSCC中PIKKs/Akt信号通路的分子机制及与TGFβ1/Smad信号通路的交互机制，阐明AK发生及向cSCC进展的机制，为后期筛选云南天然药用植物成分提供靶点。

Ultraviolet radiation induces progression of precancerous lesion-actinic keratosis (AK) to cutaneous squamous cell carcinoman(cSCC), which seriously endangers people's lives and health. Domestic and international research showed that UV-induced abnormal activation of signaling pathway is a key pathogenic mechanism. Our previous researches found that inhibition of TGFβ1/Smad signaling pathway in AK would promote progression to cSCC by ultraviolet radiation; and discovered PIKKs/Akt signaling pathway was abnomal activated by ultraviolet, and found DNA-PKcs-mTORC2 complex was a key factor which mediated UV-induced activation of Akt, whose activation would lead to a variety of tumors. But the machnisms of PIKKs/Akt signaling pathway in AK and cSCC are unclear, and whether it cross-talks with TGFβ1/Smad signaling pathway is unkown. This project based on highlands cutaneous cancer sample library and preliminary studies, to explore molecular mechanisms of PIKKs/Akt in AK and cSCC, and the cross-talk between TGFβ1/Smad and PIKKs/Akt signaling pathways, on the platform of lesion tissues, cells and mice, using a variety of molecular biology techniques, to clarify the pathogenesis of AK and cSCC, and the progression of AK to cSCC. The project is important for providing targets to screen medicinal ingredients of Yunnan natural plants.