title: Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Oncology, Center for Applied Medical Research, Clínica Universitaria/Facultad de Medicina, University of Navarra, Pamplona, Spain.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Vicent
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garayoa
authors.forename: José M
authors.initials: JM
authors.lastname: López-Picazo
authors.forename: María D
authors.initials: MD
authors.lastname: Lozano
authors.forename: Gemma
authors.initials: G
authors.lastname: Toledo
authors.forename: Frederik B J M
authors.initials: FB
authors.lastname: Thunnissen
authors.forename: Ramón G
authors.initials: RG
authors.lastname: Manzano
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000628:therapy; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000628:therapy; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis*; D011379:Prognosis; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D012313:RNA; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases