FLNA promotes chemoresistance of colorectal cancer through inducing epithelial-mesenchymal transition and smad2 signaling pathway

Chemoresistance is a leading cause of tumor relapse and treatment failure in colorectal cancer (CRC) patients and is correlated with epithelial-mesenchymal transition (EMT). This study was aimed to explore the mechanism of EMT in chemoresistant CRC. Bioinformatic method was used to screen differentially expressed genes between 5-FU sensitive and resistant CRC cells. Immunohistochemistry staining was utilized to analyze the expression of FLNA in CRC tissues. The roles of FLNA in chemoresistance were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic CRC animal model. The regulation of c-Met signaling by FLNA was explored via Co-Immunoprecipitation and luciferase reporter assays. Our results suggested FLNA directly regulated the metastasis and EMT of chemoresistant CRC cells. Moreover, c-Met- AKT mediated ser2152 phosphorylation of FLNA was demonstrated to be correlated with EMT. In turn, FLNA enhanced c-Met promoter activity by its interaction with smad2. Clinically, the expression of FLNA was significantly associated with c-Met protein levels in CRC tissues. These data established that FLNA could be a novel and reliable CRC marker and a potential therapeutic target against CRC.