Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma.
The mitogen-activated protein kinase phosphatase-1, MKP-1 (CL100) is involved in inactivation of MAP-kinase pathways, regulation of stress-responses and suppression of apoptosis. We investigated expression of MKP-1 in 90 cases of primary ovarian tumors, 11 normal ovaries as well as 4 ovarian carcinoma cell lines. Immunohistochemical expression of MKP-1 protein was reduced in tissue from LMP tumors and invasive ovarian carcinomas compared to normal ovaries and cystadenomas. A moderate to strong expression of MKP-1 was detected in 57.6% of invasive ovarian carcinomas. In a descriptive univariate survival analysis, MKP-1 expression was a prognostic marker for shorter progression-free survival of patients with invasive ovarian carcinomas. Patients with carcinomas positive for MKP-1 had a median progression-free survival of only 18.3 months compared to 40.6 months for patients with carcinomas negative for MKP-1 (log-rank test, p = 0.019). Other prognostic parameters for progression-free survival were FIGO stage, grade and pT stage. In an exploratory multivariate analysis, we found that MKP-1 expression as well as FIGO stage and grade were independent prognostic factors for progression-free survival. In contrast to progression-free survival, we did not find any influence of MKP-1 expression on patient overall survival. We investigated expression and regulation of MKP-1 mRNA by Northern Blot in vitro using 4 ovarian carcinoma cell lines (SKOV-3, OVCAR-3, CAOV-3, OAW-42). MKP-1 mRNA was inducible by interleukin-1beta and tumor necrosis factor-alpha in SKOV-3 and OVCAR-3 cells, whereas CAOV-3 and OAW-42 expressed MKP-1 mRNA constitutively. In OVCAR-3 cells MKP-1 mRNA levels were strongly inducible upon treatment of cells with cisplatin. Our data indicate that MKP-1 is expressed in a subset of ovarian carcinomas and regulated by inflammatory mediators. Expression of MKP-1 may be associated with shorter progression-free survival times. Further studies are needed to determine whether MKP-1 expression is a clinically useful marker to estimate patient prognosis as well as the response to chemotherapy.
Denkert
Carsten
C
Institute of Pathology, Charité Hospital, Berlin, Germany.
Schmitt
Wolfgang D
WD
Berger
Stefan
S
Reles
Angela
A
Pest
Sören
S
Siegert
Antje
A
Lichtenegger
Werner
W
Dietel
Manfred
M
Hauptmann
Steffen
S
D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000494:pharmacology; D003537:Cystadenoma / Q000201:enzymology; D054638:Dual Specificity Phosphatase 1; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D010053:Ovary / Q000201:enzymology; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012189:Retrospective Studies; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D002945:Cisplatin