The Role And Mechanism Of PAK2 Regulating Proliferation,Migration And Invasion In Nonsmall Cell Lung Cancer

Background: p21-activated kinase 2(PAK2)is a member of the serine/threonine kinases family located downstream of small Cdc42(Cell Division Control Protein 42Homolog)and Rac1(Rac Family Small GTPase 1)that have been shown to play an important role in a variety of cellular processes.Previous studies have shown that PAK2 is upregulated or overactivated in various tumors and strongly associated with tumor migration,invasion and poor prognosis.However,the role of PAK2 in NSCLC progression has not been comprehensively analyzed,and the underlying molecular mechanisms are unclear.Methods: We detected the m RNA level,DNA copy number and protein level of PAK2 in human NSCLC tissues and adjacent non-tumor tissues via quantitative realtime PCR and immunohistochemical staining,respectively.We used colony formation assays,cell counting Kit-8 assays,invasion assays,wound healing assays and xenograft model in nude mice to investigate the function of PAK2 in NSCLC.Moreover,we examined the expression levels of LIMK1,p-LIMK1,cofilin,p-cofilin and actin in sh PAK2 and sh CTL cell lines.We also performed microscopic analysis of sh PAK2 and sh CTL cells to analyze the effect of PAK2 on cellular morphology.We transfected p CDNA-LIMK1 plasmid to overexpress LIMK1 in sh PAK2 cells to verify that PAK2 involved in NSCLC progression through LIMK1/cofilin signaling pathway.Results: The results of quantitative real-time PCR and immunohistochemical staining experiment showed that the expression level of PAK2 in NSCLC tissues increased significantly compared with adjacent non tumor tissues.The overexpression of PAK2 was associated with the poor prognosis of patients with NSCLC.Based on the above analysis,we systematically studied and analyzed the biological functions of PAK2 in NSCLC.We used the technology of sh RNA interference and overexpression to downregulate and upregulate PAK2 in H226 cells,found that knockdown of PAK2 significantly inhibited the process of proliferation,migration,invasion and EMT in NSCLC cells.However,overexpression of PAK2 promoted proliferation,migration and invasion in NSCLC cells.The experiment of xenograft tumor models was constructed and the results of the experiment were in agreement with the results of cell experiments in vitro.Further mechanism study showed that PAK2 regulated tumor cells movement by promoting LIMK1/cofilin mediated actin depolymerization to promote the metastasis of NSCLC.Our results suggest that the PAK2/LIMK1/cofilin signaling pathway is expected to become the new target for NSCLC.Conclusion: This study provided the comprehensive insight into the potential role of PAK2 in the progression of NSCLC and its associated mechanisms.PAK2 regulated the proliferation,migration and invasive ability of NSCLC cells through the PAK2/LIMK1/cofilin signaling pathway.Disrupted of actin dynamics and inhibited the LIMK1/cofilin signaling pathway may become potential targets for NSCLC therapeutic strategies and provide clues for the molecular level treatment of NSCLC.