The KLF6 splice variant KLF6-SV1 promotes proliferation and invasion of non-small cell lung cancer by up-regultating PI3K-AKT signaling pathway.

Abstract

Non-small cell lung cancer (NSCLC) is an aggressive type of lung malignancy. Most of the patients have poor prognosis. Increasing evidence has revealed an association between KLF6-SV1, known as an oncogenic splice variant of KLF6, and metastatic potential or poor prognosis in many cancers. We previously demonstrated the increased KLF6-SV1 expression in NSCLC samples. There was a significant association between increased expression of KLF6-SV1 with the pN and pTNM stages and poor survival in NSCLC patients. In the present study, we aimed to further investigate the functional role of KLF6-SV1 in the progression of NSCLC. SK-MES-1 cells were infected with Lenti-virus containing KLF6-SV1 to up-regulate its expression, and the small interfering RNA (siRNA) was designed to knock down KLF6-SV1 transcript level in A549 cells. CCK8, colony formation, wound-healing, and transwell assays were performed to examine cell proliferation, migration, and invasion respectively. Western blot assay was used to detect the expression or phosphorylation of related proteins. We found that in vitro silencing of KLF6-SV1 by siRNA inhibited A549 cell proliferation, migration, and invasion through changes in E-cadherin, N-cadherin, Vimentin, Snail1 and Snail2 expression. Furthermore, KLF6-SV1 isoform knockdown triggered caspase-dependent apoptosis of A549 cells through downregulation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt signaling pathway and apoptosis-related protein expression. Overexpression of KLF6-SV1 transcript induced significant increase in proliferation, migration, invasion and changes in expression of related proteins. Our study support KLF6-SV1 might be an important player in modulating the growth, migration, invasion, and survival of NSCLC cells, and that silencing KLF6-SV1 siRNA has the potential to be a powerful gene therapy strategy for NSCLC.