The expression of genes contributing to pancreatic adenocarcinoma progression is influenced by the respective environment

Abstract

Pancreatic adenocarcinoma is a highly aggressive malignancy with dismal prognosis and limited curative options. We investigated the influence of organ environments on gene expression in RNU rats by orthotopic and intraportal infusion of Suit2-007^luc cells into the pancreas, liver and lung respectively. Tumor tissues from these sites were analyzed by chip array and histopathology. Generated data was analyzed by Chipster and Ingenuity Pathway Analysis (±1.5 expression fold change and p<0.05). Further analysis of functional annotations derived from IPA, was based on selected genes with significant modulation of expression. Comparison of groups was performed by creating ratios from the mean expression values derived from pancreas and respective <i>in vitro</i> values, whereas those from liver and lung were related to pancreas, respectively. Genes of interest from three functional annotations for respective organs were identified by exclusion-overlap analyses. From the resulting six genes, transglutaminase2 (TGM2) was further investigated by various assays. Its knockdown with siRNA induced dose dependent inhibitory and stimulatory effects on cell proliferation and cell migration, respectively. DNA fragmentation indicated apoptotic cell death in response to TGM2 knockdown. Cell cycle analysis by FACS showed that TGM2 knockdown induced G1/S blockade. Therefore, TGM2 and its associated genes may be promising therapeutic targets.