临床研究显示，II型糖尿病能够促进胰腺癌发生，但具体机制尚不明确，胰岛素/IGF-1轴可能参与其中。我们的预实验提示：胰岛素能够促进KRAS突变而非KRAS野生型的胰腺导管上皮细胞发生恶性转化，同时COX-2正反馈激活Ras机制在其中发挥重要作用。因此，我们提出假说：胰岛素/IGF-1轴通过促进依赖于COX-2的Ras蛋白激活参与II型糖尿病促胰腺癌发生。为验证这一假说，我们将在一项病例-对照研究的基础上开展临床观察研究。通过在体外运用siRNA、质粒转染等技术，同时构建多个转基因小鼠，并结合选择性COX-2抑制剂的使用，研究控制胰岛素/IGF-1轴和KRAS突变两个因素对于胰腺内Ras激活水平和癌症发生的影响，并探讨COX-2对于Ras活化的正反馈调节机制。本项目旨在明确II型糖尿病促进胰腺癌发生的分子机制，并为临床防治胰腺癌提供新的策略的治疗靶点。

Clinical researches suggest that type II diabetes mellitus (T2DM) can lead to incidence of pancreatic cancer, however, its detail mechanism is still unknown; insulin/IGF-1 axis may play a role in it. Results from our preliminary studies showed that insulin could promote carcinogenesis in human pancreatic ductal epithelial cells with KRAS mutation, but not in cells with wild-type KRAS, and a positive feedback from COX-2 is critical for the activation of Ras. Based on these important findings, we proposed our hypothesis: The insulin/IGF-1 axis is involved in pancreatic carcinogenesis on the basis of T2DM via its ability to initiate COX-2-dependent Ras activation. We will conduct clinical observational studies on the basis of a case-control cohort. With using in vitro siRNA and transfection techniques, series of transgenic mice in animal experiments, and selective COX-2 inhibitor, we will investigate effects insulin/IGF-1 axis and/or KRAS mutation on Ras activation and cancer formation, and the positive feedback mechanism of COX-2 on Ras activation. The aims of our project are to clarify the molecular mechanisms underlining pancreatic carcinogenesis on the basis of T2DM and to provide novel prevention strategy and therapeutic target for pancreatic cancer.