肿瘤是严重的公共卫生问题，胰腺癌更是恶性程度最高的肿瘤之一。胰腺癌中通常存在Ras基因突变；DNA甲基化紊乱也在胰腺癌中发挥重要作用，但Ras对DNA去甲基化及相关酶的调控及其机制有待进一步阐明。我们前期发现DNA去甲基化相关酶胸腺嘧啶DNA糖基化酶（TDG）的表达受转录调控因子ING4所控制；活化Ras可降低ING4蛋白水平并抑制TDG转录；TDG可上调Fas表达，进而诱导胰腺癌细胞发生凋亡，表明Ras可能通过抑制ING4-TDG-Fas轴来下调细胞对凋亡的敏感性，从而促进胰腺癌发生发展。为证实该假说，我们将在本研究中通过细胞和动物等实验来阐明Ras对ING4以及ING4对TDG的表达调控作用及其机制，明确TDG对Fas表达以及凋亡敏感性的调控作用及其机制。因此，本研究将阐明Ras对DNA去甲基化相关酶的调控机制及其在肿瘤中的作用，从而为胰腺癌等Ras相关肿瘤的有效防治提供新的理论依据。

Cancer remains one of major health problems worldwide. Particularly, pancreatic cancer, with the worst 1 and 5 year survival rates among all cancers, is the fourth common cause of deaths due to cancer and kills more than 338,000 people each year worldwide (http://globocan.iarc.fr). Ras signaling was activated in many especially pancreatic cancers. In addition, epigenetic changes mainly aberrant DNA methylation contributes to human cancer development. Over the years, we have revealed many epigenetic changes leading to the activation of Ras signaling. Meanwhile, activated Ras signaling can also remodel epigenetic regulatory network to promote carcinogenesis. Therefore, it is important to clarify the regulation and function of the interplay between Ras signaling and DNA methylation in human carcinogenesis. In preliminary studies, we found that active Ras significantly reduced the expression of DNA demethylation related enzyme called Thymine DNA Glycosylase (TDG) and transcription regulator ING4 seemed to be involved in this process. Ras downregulated the expression of ING4 which could directly bind to TDG promoter. In addition, ING4 depletion inactivated TDG transcription. Interestingly, ectopic TDG expression inhibited tumor growth and induced Fas expression and cell apoptosis. Therefore, we proposed that activated Ras signaling suppresses Fas expression to promote pancreatic cancer development through repressing TDG transcription. In this proposed study, we will try to prove this hypothesis by clarifying the regulation and function of TDG in Ras-transformed cancer cells and pancreatic cancer cells with Ras gene mutations. By doing so, we believe our study will be helpful to understand the regulation of DNA methylation and its contribution to cancer development and facilitate the development of novel strategies for the prevention and treatment of human cancers with Ras gene mutations.