Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells

Quan Liao, Junchao Guo, Jörg Kleeff, Arthur Zimmermann, Markus W. Büchler, Murray Korc, Helmut Friess

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Abstract

Background & Aims: In both pancreatic cancer and chronic pancreatitis, there is enhanced expression of mitogenic growth factors and their tyrosine kinase receptors, which have the capacity to activate mitogen-activated protein kinase (MAPK). In view of the important role of MAPK kinase phosphatase (MKP)-1 in the regulation of MAPK activation, the expression and functional role of MKP-1 was analyzed. Methods: Pancreatic tissues were analyzed by Northern blotting, Western blotting, and immunohistochemistry. Pancreatic cancer cells were transfected with a full-length MKP-1 antisense construct. Growth characteristics and tumorigenicity in vivo and the effects of mitogenic growth factors on cell growth and MAPK activation were determined in transfected and control cells. Results: MKP-1 messenger RNA (mRNA) levels were increased in pancreatic cancer and chronic pancreatitis (CP) tissues. Moderate to strong MKP-1 immunoreactivity was present in the cancer cells, ductal cells of pancreatic intraepithelial neoplasia, and in tubular complexes in CP. Down-regulation of MKP-1 resulted in decreased anchorage-dependent and -independent growth of pancreatic cancer cells, and decreased tumorigenicity in a nude mouse tumor model. MKP-1 down-regulation led to decreased proliferation and sustained MAPK activation in response to mitogens. Conclusions: Suppression of MKP-1 expression reduces the tumorigenicity of pancreatic cancer cells in vivo, suggesting that MKP-1 contributes to enhanced mitogenic signaling in pancreatic cancer cells.

Original languageEnglish (US)
Pages (from-to)1830-1845
Number of pages16
JournalGastroenterology
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Liao, Q., Guo, J., Kleeff, J., Zimmermann, A., Büchler, M. W., Korc, M., & Friess, H. (2003). Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology, 124(7), 1830-1845. https://doi.org/10.1016/S0016-5085(03)00398-6