Overexpression of P21-activated kinase 4 is associated with poor prognosis in non-small cell lung cancer and promotes migration and invasion.

Songwang Cai,Yimin Weng,Hongbo Wei,Sen Lao,Xiaohong Wang,Yuhang Pan,Lian Li,Zhiqiang Ye

doi:10.1186/s13046-015-0165-2

Abstract

BackgroundP21-activated kinase 4 (PAK4), an effector of the Rho family protein Cdc42, is an important oncogene whose expression is increased in many human cancers and is generally positively correlated with advanced disease and decreased survival. However, little is known about the expression and biological function of PAK4 in human non-small cell lung cancer (NSCLC).MethodsPAK4 expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry, real-time PCR, and western blotting. Prognostic value of PAK4 expression was evaluated by Kaplan-Meier analysis and Cox regression. siRNA-mediated gene silencing and protein kinase assay was applied to demonstrate the role and the mechanism of PAK4 in lung cancer cell migration, invasion.ResultsThe results showed that PAK4 was overexpressed in NSCLC cell lines and human NSCLC tissues. PAK4 expression was detected both in the membranes and cytoplasm of NSCLC cancer cells in vivo. Moreover, increased expression of PAK4 was associated with metastasis, shorter overall survival, advanced stage of NSCLC. Furthermore, PAK4 expression was positively correlated with phosphorylation of LIMK1 expression levels. Knockdown of PAK4 in NSCLC cell lines led to reduce the phosphorylation of LIMK1, which resulted in decrease of the cell migration and invasion. In addition, PAK4 bound to LIMK1 directly and activated it via phosphorylation.ConclusionsThese data demonstrate that PAK4 mediated LIMK1 phosphorylation regulates the migration and invasion in NSCLC. Therefore, PAK4 might be a significant prognostic marker and potential therapeutic molecular target in NSCLC.

Highlights

P21-activated kinase 4 (PAK4), an effector of the Rho family protein Cdc42, is an important oncogene whose expression is increased in many human cancers and is generally positively correlated with advanced disease and decreased survival
To explore PAK4 protein expression in non-small cell lung cancer (NSCLC), we examined its expression in a human bronchial epithelial cell line (HBE) and several NSCLC cell lines using western blotting
To determine whether PAK4 was overexpressed at the transcriptional level, we examined PAK4 mRNA levels in the human bronchial epithelial cells (HBE) and NSCLC cell lines using real-time PCR

Summary

Introduction

P21-activated kinase 4 (PAK4), an effector of the Rho family protein Cdc, is an important oncogene whose expression is increased in many human cancers and is generally positively correlated with advanced disease and decreased survival. Overexpression or mutational activation of PAK isoforms frequently occurs in various human tumors; given their involvement in cancer cell motility, survival, apoptosis, and metastasis, PAK isoforms are important regulators of cancer cell signaling networks [9].

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