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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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
Externally publishedYes

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Dual-Specificity Phosphatases
Dual Specificity Phosphatase 1
Pancreatic Neoplasms
Down-Regulation
Mitogen-Activated Protein Kinases
Chronic Pancreatitis
Intercellular Signaling Peptides and Proteins
Growth
MAP Kinase Kinase 1
Neoplasms
Receptor Protein-Tyrosine Kinases
Mitogens
Phosphoric Monoester Hydrolases
Nude Mice
Northern Blotting
Western Blotting
Immunohistochemistry
Messenger RNA

ASJC Scopus subject areas

  • Gastroenterology

Cite this

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

Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. / Liao, Quan; Guo, Junchao; Kleeff, Jörg; Zimmermann, Arthur; Büchler, Markus W.; Korc, Murray; Friess, Helmut.

In: Gastroenterology, Vol. 124, No. 7, 01.07.2003, p. 1830-1845.

Research output: Contribution to journalArticle

Liao, Q, Guo, J, Kleeff, J, Zimmermann, A, Büchler, MW, Korc, M & Friess, H 2003, 'Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells', Gastroenterology, vol. 124, no. 7, pp. 1830-1845. https://doi.org/10.1016/S0016-5085(03)00398-6
Liao, Quan ; Guo, Junchao ; Kleeff, Jörg ; Zimmermann, Arthur ; Büchler, Markus W. ; Korc, Murray ; Friess, Helmut. / Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. In: Gastroenterology. 2003 ; Vol. 124, No. 7. pp. 1830-1845.
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