Abstract: Objective To detect the protein expression of Rap1GAP1 in human pancreatic ductal adenocarcinomas(PDACs) and rap1GAP1 mutational status in three pancreatic cancer cell lines,and to explore its roles in the pathogenesis of PDAC. Methods (1)The protein expression of Rap1GAP1 was detected by immunohistochemistry in 73 specimens of PDAC cases and normal pancreatic tissues adjacent to PDACs.The relation of Rap1GAP1 with the clinicopathological characteristics of HDACs was analyzed.(2)rap1GAP1 mutational status was detected by RT-PCR and then DNA sequencing. Results (1)The positive rates of Rap1GAP1 expression in normal pancreatic tissues adjacent to PDACs,pancreatic intraepithelial neoplasia (PanIN 1a,1b,2,3) and invasive PDACs were 100%,93.8%,92.3%,70.0%,57.9% and 13.7%,respectively.Rap1GAP1 expression was significantly decreased in invasive PDACs(P<0.01),compared with those in the normal pancreatic tissues adjacent to PDACs and PanIN 1-3.The positive rate of Rap1GAP1 expressions in histologically well,moderate and poor differentiated PDACs were 26.9%,7.1% and %,respectively.Rap1GAP1 expression was significantly decreased in poor differentiated PDACs(P<0.05).However,Rap1GAP1 expression was not related to age,gender,status of metastasis of lymph nodes and clinical stage.(2) Panc-1 and MiaPaCa-2 cells had large fragment lost of rap1GAP1,while Aspc-1 cells had full catalytic domain of rap1GAP1. Conclusion Rap1GAP1 expression was significantly decreased in invasive PDACs and related to tumor cell differentiation,suggesting that loss of Rap1GAP1 happens at a later stage of PDAC progression.Mutational status in three pancreatic cancer cell lines suggested that loss of Rap1GAP1 might be due to large fragment lost of rap1GAP1.