Interferon-alpha2b and transforming growth factor-beta1 treatments on HCC cell lines: Are Wnt/beta-catenin pathway and Smads signaling connected in hepatocellular carcinoma?

摘要

Wnt/beta-catenin pathway is often dysregulated in hepatocellular carcinoma (HCC). Activated beta-catenin accumulates in the cytosol and nucleus and forms a nuclear complex with TCF/LEF factors like TCF4. Interferon-alpha (IFN-alpha) has recently been recognized to harbor therapeutic potential in prevention and treatment of HCC. Transforming Growth Factor-beta1 (TGF-beta1) is a mediator of apoptosis, exerting its effects via Smads proteins. One mode of interaction between Wnt/beta-catenin and TGF-beta1/Smads pathways is the association of Smads with beta-catenin/TCF4. In this study we analyzed the effects of IFN-alpha2b and TGF-beta1 treatments on Wnt/beta-catenin pathway, Smads proteins levels, beta-catenin/TCF4/Smads interaction and proliferation and apoptotic death in HepG2/C3A and Huh7 cell lines. IFN-alpha2b and TGF-beta1 attenuated Wnt/beta-catenin signal by decreasing beta-catenin and Frizzled7 receptor proteins contents and the interaction of beta-catenin with TCF4. Truncated beta-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 beta-catenin protein levels, also generated the increment of Smads proteins contents when comparing with untreated cells. In conclusion, IFN-alpha2b and TGF-beta1 proved to be effective as modulators of Wnt/beta-catenin pathway in HCC cell lines holding both wild-type and truncated beta-catenin. Since the inhibition of beta-catenin/TCF4/Smads complexes formation may have a critical role in slowing down oncogenesis, IFN-alpha2b and TGF-beta1 could be useful as potential treatments in patients with HCC.