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Mitogen-Activated Protein Kinase Phosphatase-1 Is Overexpressed in Non-Small Cell Lung Cancer and Is an Independent Predictor of Outcome in Patients

¹ Division of Oncology, Center for Applied Medical Research, Clínica Universitaria/Facultad de Medicina, ² Department of Oncology, Clínica Universitaria, ³ Department of Pathology, Clínica Universitaria, and ⁴ Department of Histology and Pathology, University of Navarra, c/Irunlarrea, Pamplona, Spain, and ⁵ Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands

ABSTRACT

Purpose: An increase in the activity of the mitogen-activated protein kinases (MAPKs) has been correlated with a more malignant phenotype in several tumor models in vitro and in vivo. A key regulatory mechanism of the MAPKs [extracellular signal-regulated kinase (ERK); c-jun NH₂-terminal kinase (JNK); and p38] is the dual specificity phosphatase CL100, also called MAPK phosphatase-1 (MKP-1). This study was designed to examine the involvement of CL100/MKP-1 and stress-related MAPKs in lung cancer.

Experimental Design: We assessed the expression of CL100/MKP-1 and the activation of the MAPKs in a panel of 18 human cell lines [1 primary normal bronchial epithelium, 8 non-small cell lung cancer (NSCLC), 7 small cell lung cancer (SCLC), and 2 carcinoids] and in 108 NSCLC surgical specimens.

Results: In the cell lines, CL100/MKP-1 expression was substantially higher in NSCLC than in SCLC. P-ERK, P-JNK, and P-p38 were activated in SCLC and NSCLC, but the degree of their activation was variable. Immunohistochemistry in NSCLC resection specimens showed high levels of CL100/MKP-1 and activation of the three MAPK compared with normal lung. In univariate analysis, no relationship was found among CL100/MKP-1 expression and P-ERK, P-JNK, or P-p38. Interestingly, high CL100/MKP-1 expression levels independently predicted improved survival in multivariate analysis. JNK activation associated with T_1–2 and early stage, whereas ERK activation correlated with late stages and higher T and N. Neither JNK nor ERK activation were independent prognostic factors when studied for patient survival.

Conclusions: Our data indicate the relevance of MAPKs and CL100/MKP-1 in lung cancer and point at CL100/MKP-1 as a potential positive prognostic factor in NSCLC. Finally, our study supports the search of new molecular targets for lung cancer therapy within the MAPK signaling pathway.

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