Overexpression of ErbB2 in the exocrine pancreas induces an inflammatory response but not increased proliferation.
Tyrosine kinase receptors such as members of the epidermal growth factor receptor family and their respective ligands are frequently overexpressed in pancreatic cancer as well as in chronic pancreatitis. In this study, the role of ErbB2 in the exocrine pancreas was examined by ectopic overexpression under the control of the proximal rat elastase promoter. Three independent transgenic mouse lines overexpressing ErbB2 were established by pronuclear injection. Pancreatic mRNA and protein levels were analyzed by real time PCR, immunohistochemistry and immunoblot analysis, RAS activity by using a specific immunoprecipitation assay and various kinase activities by phosphospecific antibodies. Overexpression of ErbB2 in the exocrine pancreas resulted in increased RAS activity and downstream activation of ERK1/2, but not in transgenic increased proliferation of acinar and ductal cells. At later timepoints, some mice showed focal areas of acinar cell damage with upregulated mRNA levels for Cyclin D1 and p16(INK4a). Despite the increased mRNA level, cyclin D1 protein levels were downregulated. We observed areas of focal infiltrations with inflammatory cells interspersed in the exocrine pancreas. NF-kappaB activity was induced in transgenic acinar cells compared with controls contributing to high levels of chemokine and cytokine gene expression such as CCR-1 and CCL3. These data suggest that overexpression of ErbB2 in acinar cells leads to increased RAS activity without cell cycle progression and mediates inflammation via NF-kappaB. We conclude that the biological response of ErbB2/RAS signaling depends highly on cellular context.
Algül
Hana
H
II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
Wagner
Martin
M
Lesina
Marina
M
Schmid
Roland M
RM
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020572:Oncogene Proteins v-rel / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000378:metabolism
D019938:Cyclin D1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D020572:Oncogene Proteins v-rel; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins