Objective: Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide which is not eligible for therapy due to resistant to traditional cytotoxic treatment and metastasis.Kruppel-like factor 5 (KLF5) is a basic transcriptional factor that involves in many biological and pathological processes.Herein,we try to elucidate the roles of KLF5 in the migration and invasion of HCC.Methods: SMMC-7721/HepG2 cell lines with stably over-expressed KLF5 and SMMC-7721/HCCLM3 cells with stably knock-downed KLF5 were established;CCK8 and subcutaneous xenograft were used to measure cell proliferation and tumor growth in vitro and in vivo respectively;wound healing,transwell and xCELLigence system assays and bioluminescence images were applied to determine the migration and invasion of cells in vitro and in vivo;co-Immunoprecipitation (co-IP) and Immunofluorescence analysis (IF) were identify employed to the interaction of proteins.Results: Our results showed that many cell lines of HCC expressed KLF5,and inhibition of KLF5 enhanced the migration and invasion of HCC cells in vitro and promoted pulmonary metastasis in vivo when intravenous HCC cells into tail vein;while the HCC cell proliferation in vitro and subcutaneous xenograft tumor growth in vivo had no significant difference.Whats more,over-expression of KLF5 could inhibit the migration and invasion of HCC cells.Furthermore,re-expressing of KLF5 could partly rescue the migration and invasion of HCC cells induced by knock-down KLF5.To explore the mechanism of knock-down KLF5-induced metastasis,PCR array was used and FOXC2 showed to be a potential KLF5-target that mediates KLFS-knockdown induced migration and invasion of HCCs,and bio-informatic analysis showed several KLF5-binding sites in the promoter of FOXC2 gene.Besides,KLF5 and Slug could co-localize and interact with each other.Conclusion: Knockdown of KLF5 promotes migration and invasion of HCC in vitro and in vivo;and Slug and FOXC2 might involve in the migration and invasion induced by KLF5-knockdown.