KLF2 Protein Inhibits Hepatocellular Carcinoma Cell Motility Through Regulation Of TGF-β/Smad Signaling

Hepatocellular carcinoma(HCC)is the major form of primary liver cancer and one of the leading causes of cancer-related death,threatening human health seriously.Transforming growth factor beta(TGF-β)mainly initiates the Smad signaling pathway that controls many physiological responses and plays a complex role in HCC progression.Feedback regulation plays a pivotal role in determining the intensity and duration of TGF-β signaling,thereby affecting the pathophysiological roles of TGF-β including those in liver malignancy.KLF2,a member of the Krüppel-like factor(KLF)family transcription factors,has been implicated in impeding hepatocellular carcinoma development.However,the underlying molecular mechanisms are not fully understood.In the present study,we found that TGF-β stimulates the expression of KLF2 gene in several HCC cell lines.KLF2 protein is able to inhibit TGF-β/Smad signaling in HCC cells as assessed by luciferase reporter assay.Further studies indicated that KLF2 inhibits the transcriptional activity of Smad2/3 and Smad4 and ameliorates TGF-β-induced target gene expression,therefore creating a novel negative feedback loop in TGF-β signaling.Functionally,stably expression of KLF2 attenuated TGF-β-induced cancer cell motility in wound-healing and transwell assays by interfering with TGF-β-mediated expression of EMT-related genes.Together,our results revealed that KLF2 protein has a tumor-suppressive function in HCC through a negative feedback loop over TGF-β signaling.