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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
Authors: Vicent, S. (Silvestre)
Garayoa, M. (Mercedes)
Lopez-Picazo, J.M. (José M.)
Lozano, M.D. (María Dolores)
Toledo, G. (Gemma)
Thunnissen, F.B. (Frederick B.)
Manzano, R.G. (Ramón G.)
Montuenga, L.M. (Luis M.)
Keywords: Lung Neoplasms/therapy
Protein Phosphatase 1
Issue Date: 2004
Publisher: American Association for Cancer Research
Publisher version: http://clincancerres.aacrjournals.org/content/10/11/3639
ISSN: 1557-3265
Citation: Vicent S, Garayoa M, Lopez-Picazo JM, Lozano MD, Toledo G, Thunnissen FB, et al. Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin Cancer Res 2004 Jun 1;10(11):3639-3649.
Abstract
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 NH(2)-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.
Permanent link: http://hdl.handle.net/10171/18811
Appears in Collections:DA - Ciencias - HAP - Artículos de revista
DA - CIMA - Oncología - Biomarcadores - Artículos de Revista

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