Expression and differential signaling of heregulins in pancreatic cancer cells.
The EGF family of ligands and receptors plays an important role in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and contributes to its aggressiveness. A number of molecular approaches have been developed to block these pathways, and studies have already proven the clinical benefit of this concept in PDAC. In the present study, we sought to determine the potential role of heregulins (HRGs), a family of EGF-like growth factors, in PDAC. Quantitative RT-PCR analysis revealed that HRGs as well as its signaling ErbB receptors were present in 4 of 4 human pancreatic cancer cell lines (PCCL). HRG-beta1 stimulated the growth of 3 of 4 PCCL, whereas HRG-alpha1 inhibited cell growth in 3 of 4 cell lines. Responses towards HRGs could in part be predicted by ErbB2 and ErbB3 expression levels. HRGs induced phosphorylation of different ErbB receptors as well as activation of MAPK, p38MAPK, JNK and PI3K in a cell- and ligand-specific manner. In vivo, HRG was upregulated in pancreatic cancer tissues and localized predominantly in the cancer cells. High HRG-beta levels but not HRG-alpha levels were associated with decreased patient survival. In conclusion, HRG is expressed by pancreatic cancer cells and influences pancreatic cancer cell growth and patient survival.
Kolb
Armin
A
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Kleeff
Jörg
J
Arnold
Nichole
N
Giese
Nathalia A
NA
Giese
Thomas
T
Korc
Murray
M
Friess
Helmut
H
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D020890:Neuregulin-1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D016019:Survival Analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D048051:p38 Mitogen-Activated Protein Kinases; C094131:NRG1 protein, human; C117463:heregulin alpha; C087230:heregulin beta1