Nonstructural 5A protein activates β-catenin signaling cascades: Implication of hepatitis C virus-induced liver pathogenesis

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

“…Our data suggest that the interaction of NS5A with b-catenin predominantly involves the N-terminal 144 residues of NS5A, with only limited contribution from residues 144-448. This is in agreement with a study published during the preparation of this manuscript (Park et al, 2009), in which the N-terminal 147 residues of NS5A were shown to be necessary and sufficient to interact with FLAG-tagged bcatenin.…”

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…This caused augmented transcription of β-catenin-dependent genes and was supposed to facilitate neoplastic transformation of HCV-infected hepatocytes. Involvement of NS5A protein in activation of the Wnt/β-catenin signaling pathway was confirmed in subsequent studies [7], documenting direct activation of endogenous, unphosphorylated wild-type β-catenin by NS5A protein and co-localization of the two proteins in cytoplasm of HepG2 cells. The mechanism of β-catenin accumulation at the protein level, also through inactivation of GSK-3β, was confirmed.…”

“…The mechanism of β-catenin accumulation at the protein level, also through inactivation of GSK-3β, was confirmed. In addition, the investigators proved that NS5A protein may directly interact with β-catenin through its N-terminus and the ARM 1-6 region of β-catenin [7]. The authors also succeeded in demonstrating that the N terminus of NS5A affects TCF-4-dependent transcriptional activity.…”

“…Already at the beginning of this century more numerous mutations of β-catenin were found to develop in HCV-associated HCC than with HBV-related HCC [5]. Recent years have brought the results of studies on direct interactions between oncogenic HCV proteins and components of the Wnt/β-catenin signaling pathway [6][7][8][9][10].…”

Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts

“…These alterations may include (i) loss of tumor suppressor proteins, (ii) activation of oncoproteins, such as c-Myc, (iii) activation and secretion of cytokines, such as transforming growth factor ␤ (TGF-␤), and (iv) alterations in the Wnt/␤-catenin signaling, leading to nuclear accumulation of ␤-catenin, which are found in 33 to 67% of HCC cases (6,38). Activation of ␤-catenin is essential for liver development; deletion of the protein in mice results in fetal death due to impaired liver cell proliferation and increased apoptosis (50).…”