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Abstract: Objective: Mitogen-activated protein kinases (MAPKs) are correlated with a more malignant phenotype in many cancers. This study was designed to evaluate the predictive value of the expression of MAPK phosphatase-1 (MKP-1) and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK_1/2), as the key regulatory mechanism of the MAPKs, in lung squamous cell carcinoma (SCC). Methods: We assessed the expressions of MKP-1 and p-ERK_1/2 in twenty subjects at different differentiation degree of SCC and five normal lungs by immunohistochemistry and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Results: Immunohistochemistry and real-time RT-PCR assay showed that the expression of MKP-1 was gradually decreased as tissue type went from normal lung tissues to increasingly undifferentiated carcinoma, and it was negatively correlated with tumor differentiation (P<0.01). However, the expression of p-ERK_1/2 or ERK_1/2 was gradually increased as tissue type went from normal lung tissues to increasingly undifferentiated carcinoma, and it was positively correlated with tumor differentiation (P<0.01). Conclusions: Our data indicates the relevance of MKP-1 and p-ERK_1/2 in SCC as a potential positive and negative prognostic factor. The imbalanced expression of MKP-1 and p-ERK_1/2 may play a role in the development of SCC and these two molecules may be new targets for the therapy and prognosis of SCC.

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