Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in mice to retard tumour growth, increase intrahepatic caspase-1 activation, and alter metabolic markers.

Abstract

e16303 Background: Dipeptidyl peptidase 9 (DPP9) is one of four enzymes targeted by a novel compound class that includes talabostat and BXCL701, which have reached clinical oncology trials. DPP9 supresses NLRP1 inflammasome activation and BRCA2 activity. Global DPP9 gene inactivation is lethal in mice and humans. Therefore, to study primary hepatocellular carcinoma, we examined mice in which DPP9 expression is depleted only from hepatocytes. Methods: A hepatocyte-specific DPP9 knockout mouse (Alb-DPP9-KO) was achieved by floxing exons 5 to 7 of full-length DPP9 and crossing this DPP9fl/fl mouse strain with a mouse strain that expresses Cre recombinase under an albumin promoter. Primary liver cancer was induced by treating with diethylnitrosamine (DEN; once), then thioacetamide (TAA) and a high fat diet (HFD) from 4-28 weeks of age. Measurements included tumour burden and total liver qPCR of immunological and autophagy markers. Results: Alb-DPP9-KO mice were healthy. Compared to littermate controls, Alb-DPP9-KO mice had reduced liver mass and subcutaneous adipose tissue mass and had lower fasting plasma glucose. Alb-DPP9-KO mice had fewer small macroscopic liver nodules (< 3 mm diameter) compared to littermate controls. There were no differences in the total number of macroscopic liver nodules, tumour burden, inflammation, fibrosis and steatosis. However, Alb-DPP9-KO livers had increased levels of active caspase-1 protein, indicative of increased inflammasome activity, and increased levels of Nfkbib, Cxcl10 and Ccl5. The Alb-DPP9-KO livers contained increased protein levels of the tumour suppressor p53, and of autophagy markers LC3B, p62 and beclin1. Conclusions: Lifelong intrahepatic DPP9 depletion reduced tumour sizes at 28 weeks of age in this DEN/TAA/HFD experimental model. Mechanisms might include increased caspase-1 activation following NLRP1 activation, increased autophagy and p53 and improved energy metabolism in epithelial cells. DPP9 inhibition may contribute to efficacy in therapies that target DPP4 protease family.