The expression of genes contributing to pancreatic adenocarcinoma progression is influenced by the respective environment
Micah N. Sagini1, Michael Zepp1, Frank Bergmann2, Matthias Bozza3, Richard Harbottle3 and Martin R. Berger1
1 Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 University Clinic of Heidelberg, Institute of Pathology, Heidelberg, Germany
3 DNA Vectors, German Cancer Research Center (DKFZ), Heidelberg, Germany
Correspondence:
Martin R. Berger, email:
Keywords: PDAC, gene expression profiles, tumor model, tumor micro-environment, TGM2
Received: April 19, 2018 Accepted: June 16, 2018 Published: June 23, 2018
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 Suit2-007luc 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 in vitro 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.
