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Collagen I Promotes Metastasis in Pancreatic Cancer by Activating c-Jun NH₂-Terminal Kinase 1 and Up-regulating N-Cadherin Expression

Departments of ¹ Oral Biology; ² Biochemistry and Molecular Biology; ³ Genetics, Cell Biology, and Anatomy; and ⁴ Pathology and Microbiology and ⁵ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center; and ⁶ Eppley Cancer Center, Omaha, Nebraska

Requests for reprints: Margaret J. Wheelock, 987696 Nebraska Medical Center, Omaha, NE 68198-7696. Phone: 402-559-3892; Fax: 402-559-3739; E-mail: mwheelock{at}unmc.edu.

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 NH₂-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. (Cancer Res 2006; 66(24): 11745-53)

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