Expression of mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) in primary human ovarian carcinoma

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Abstract
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‐1β and tumor necrosis factor‐α 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.