Interferon-α2b and transforming growth factor-β1 treatments on HCC cell lines: Are Wnt/β-catenin pathway and Smads signaling connected in hepatocellular carcinoma?

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.

Ceballos MP ，Parody JP ，Alvarez Mde L ，Ingaramo PI ，Carnovale CE ，Carrillo MC ... -  《-》

FoxO3a nuclear localization and its association with β-catenin and Smads in IFN-α-treated hepatocellular carcinoma cell lines.

Ceballos MP ，Parody JP ，Quiroga AD ，Casella ML ，Francés DE ，Larocca MC ，Carnovale CE ，Alvarez Mde L ，Carrillo MC ... -  《-》

Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo.

Wei W ，Chua MS ，Grepper S ，So S ... -  《-》

Attenuation of the Wnt/beta-catenin/TCF pathway by in vivo interferon-alpha2b (IFN-alpha2b) treatment in preneoplastic rat livers.

Parody JP ，Alvarez ML ，Quiroga AD ，Ceballos MP ，Frances DE ，Pisani GB ，Pellegrino JM ，Carnovale CE ，Carrillo MC ... -  《-》

The murine gastrin promoter is synergistically activated by transforming growth factor-beta/Smad and Wnt signaling pathways.

Lei S ，Dubeykovskiy A ，Chakladar A ，Wojtukiewicz L ，Wang TC ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》