ABSTRACT
Hypoxia-induced epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) was investigated. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) is a positive regulator of the Wnt/ß-catenin signaling pathway and is overexpressed in many human tumors. However, the expression and role of FRAT1 in HCC has not been elucidated. In this study, we investigated the effect of FRAT1 on EMT process in HCC cells induced by hypoxia. Our results showed that FRAT1 is highly expressed in HCC tissues and cell lines. Hypoxia significantly induced FRAT1 expression in HCC cells. FRAT1 knockdown inhibited hypoxia-induced cell migration/invasion, downregulation of epithelial markers and upregulation of mesenchymal markers. Moreover, FRAT1 knockdown suppressed the expression levels of ß-catenin, cyclin D1 and c-myc in HCC cells under the same hypoxic condition. Our results revealed that FRAT1 is a hypoxia factor that is critical for the induction of EMT in HCC cells. These data suggest a potential role for targeting FRAT1 in the prevention of hypoxia-induced HCC cancer progression and metastasis mediated by EMT.
Subject(s)
Carcinoma, Hepatocellular/genetics , Intracellular Signaling Peptides and Proteins/genetics , Liver Neoplasms/genetics , Proto-Oncogene Proteins/genetics , Adaptor Proteins, Signal Transducing , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/pathology , Tumor Hypoxia/genetics , Wnt Signaling Pathway/genetics , beta Catenin/biosynthesis , beta Catenin/geneticsABSTRACT
Non-structural protein 5A (NS5A) appears to interact with a variety of cellular proteins and play an important role in mediating cell growth, cellular signaling pathways and pathogenesis of hepatitis C virus (HCV). NS5ATP9 was identified as a NS5A trans-activated protein in suppression subtractive hybridization (SSH), and the regulation was confirmed by luciferase reporter assay and quantitative real time PCR (qRT-PCR). A minimal promoter region contained within the 211bp (nucleotides -161 to +50bp) immediately upstream of the transcription initiation site. NS5ATP9 is a NS5A up-regulation gene which may play a role in the pathogenesis of HCV-associated hepatocellular carcinoma.