title: Interferon-α2b and transforming growth factor-β1 treatments on HCC cell lines: Are Wnt/β-catenin pathway and Smads signaling connected in hepatocellular carcinoma?
abstract: Wnt/β-catenin pathway is often dysregulated in hepatocellular carcinoma (HCC). Activated β-catenin accumulates in the cytosol and nucleus and forms a nuclear complex with TCF/LEF factors like TCF4. Interferon-α (IFN-α) has recently been recognized to harbor therapeutic potential in prevention and treatment of HCC. Transforming Growth Factor-β1 (TGF-β1) is a mediator of apoptosis, exerting its effects via Smads proteins. One mode of interaction between Wnt/β-catenin and TGF-β1/Smads pathways is the association of Smads with β-catenin/TCF4. In this study we analyzed the effects of IFN-α2b and TGF-β1 treatments on Wnt/β-catenin pathway, Smads proteins levels, β-catenin/TCF4/Smads interaction and proliferation and apoptotic death in HepG2/C3A and Huh7 cell lines. IFN-α2b and TGF-β1 attenuated Wnt/β-catenin signal by decreasing β-catenin and Frizzled7 receptor proteins contents and the interaction of β-catenin with TCF4. Truncated β-catenin form present in C3A cell line also diminished after treatments. Both cytokines declined Smads proteins and their interaction with TCF4. The overall cellular response to cytokines was the decrease in proliferation and increase in apoptotic death. Treatment with Wnt3a, which elevates β-catenin protein levels, also generated the increment of Smads proteins contents when comparing with untreated cells. In conclusion, IFN-α2b and TGF-β1 proved to be effective as modulators of Wnt/β-catenin pathway in HCC cell lines holding both wild-type and truncated β-catenin. Since the inhibition of β-catenin/TCF4/Smads complexes formation may have a critical role in slowing down oncogenesis, IFN-α2b and TGF-β1 could be useful as potential treatments in patients with HCC.
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina. ceballos@ifise-conicet.gov.ar
authors.forename: María Paula
authors.initials: MP
authors.lastname: Ceballos
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Parody
authors.forename: María de Luján
authors.initials: Mde L
authors.lastname: Alvarez
authors.forename: Paola Inés
authors.initials: PI
authors.lastname: Ingaramo
authors.forename: Cristina Ester
authors.initials: CE
authors.lastname: Carnovale
authors.forename: María Cristina
authors.initials: MC
authors.lastname: Carrillo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051153:Wnt Proteins / Q000502:physiology*; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D051785:Smad Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060509:Wnt3A Protein; D051176:beta Catenin