Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression.
We have previously shown that N-cadherin expression is associated with tumor invasion, and that some cancer cells respond to specific extracellular matrix molecules by up-regulating N-cadherin. Pancreatic cancer is characterized by excessive deposition of type I collagen. Here, we show that human pancreatic cancer cells respond to collagen I, but not other matrices, by increasing motility and up-regulating mesenchymal markers, including N-cadherin. Both collagen I-mediated motility and metastasis in a mouse model for pancreatic cancer were inhibited by N-cadherin knockdown. Furthermore, inhibiting c-Jun NH(2)-terminal kinase (JNK) with chemical inhibitors or short hairpin RNA abrogated all collagen I-induced changes. We show that JNK1 is activated in response to collagen I, which increases tumorigenesis by up-regulating N-cadherin expression and by increasing motility.
Shintani
Yasushi
Y
Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Hollingsworth
Michael A
MA
Wheelock
Margaret J
MJ
Johnson
Keith R
KR
D019921:Biotinylation; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement; D024042:Collagen Type I / Q000494:pharmacology*; D017931:DNA Primers; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D015820:Cadherins; D024042:Collagen Type I; D017931:DNA Primers; D011994:Recombinant Proteins; D048031:JNK Mitogen-Activated Protein Kinases