Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.
Wnt/beta-catenin signaling contributes to diverse cellular functions, such as Drosophila wing development and colon carcinogenesis. Recently, stabilizing mutations of beta-catenin, a hallmark of Wnt signaling, were documented in significant numbers of primary hepatocellular carcinomas (HCC). However, whether the beta-catenin mutation leads to the activation of Wnt/beta-catenin signaling in hepatoma cells has not been established. We found that Wnt/beta-catenin signaling could be activated by ectopic expression of Wnt-1 in some hepatoma cells, such as Hep3B and PLC/PRF/5 cells, but not in others, such as Huh7 and Chang cells. Importantly, we noted that the former were derived from hepatitis B virus (HBV)-infected livers, whereas the latter were derived from HBV-negative livers. It was then speculated that HBx, a viral regulatory protein of HBV, is involved in activating Wnt/beta-catenin signaling in hepatoma cells. In agreement with this notion, ectopic expression of HBx along with Wnt-1 activated Wnt/beta-catenin signaling in Huh7 cells by stabilizing cytoplasmic beta-catenin. Further, we showed that such stabilization of beta-catenin by HBx was achieved by suppressing glycogen synthase kinase 3 activity via the activation of Src kinase. In conclusion, the data suggest that Wnt-1 is necessary but insufficient to activate Wnt/beta-catenin signaling in hepatoma cells and the enhanced stabilization of beta-catenin by HBx, in addition to Wnt-1, is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.
Cha
Man-Young
MY
Department of Biochemistry, Yonsei University, Seoul, Korea.
Kim
Chang-Myeong
CM
Park
Young-Min
YM
Ryu
Wang-Shick
WS
D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D054334:Viral Regulatory and Accessory Proteins; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin; C057628:hepatitis B virus X protein