Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): Co-expression in metastatic serous ovarian carcinoma

Ben Davidson, Vered Givant-Horwitz, Philip Lazarovici, Bjorn Risberg, Jahn M. Nesland, Claes G. Tropé, Erik Schaefer, Reuven Reich

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Abstract

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P = 0.048), protein expression (P = 0.046) and gelatinolytic activity (P = 0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P = 0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P = 0.046), but enzyme activity showed inverse relationship with both p-ERK (P = 0.05) and p-p38 (P = 0.033) expression. EMMPRIN expression correlated with MMP-1 (P < 0.001), MMP-2 (P = 0.042) and MMP-9 (P = 0.029) expression, as well as with ERK activity (P = 0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy.

Original languageEnglish (US)
Pages (from-to)621-631
Number of pages11
JournalClinical and Experimental Metastasis
Volume20
Issue number7
DOIs
StatePublished - Dec 8 2003

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CD147 Antigens
Matrix Metalloproteinase 2
Mitogen-Activated Protein Kinases
Matrix Metalloproteinases
Matrix Metalloproteinase 9
Carcinoma
Phosphotransferases
MAP Kinase Kinase 4
Matrix Metalloproteinase 1
Glycerol Kinase
Phosphorylation
Messenger RNA
JNK Mitogen-Activated Protein Kinases
Immunoblotting
Osmolar Concentration
In Situ Hybridization
Proteins
Theoretical Models
Immunohistochemistry
Enzymes

Keywords

  • EMMPRIN
  • Effusions
  • Matrix metalloproteinases
  • Mitogen-activated protein kinases
  • Ovarian carcinoma

ASJC Scopus subject areas

  • Cancer Research

Cite this

Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK) : Co-expression in metastatic serous ovarian carcinoma. / Davidson, Ben; Givant-Horwitz, Vered; Lazarovici, Philip; Risberg, Bjorn; Nesland, Jahn M.; Tropé, Claes G.; Schaefer, Erik; Reich, Reuven.

In: Clinical and Experimental Metastasis, Vol. 20, No. 7, 08.12.2003, p. 621-631.

Research output: Contribution to journalArticle

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AU - Lazarovici, Philip

AU - Risberg, Bjorn

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AU - Tropé, Claes G.

AU - Schaefer, Erik

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