Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Biochem Pharmacol. 2011 Dec 1;82(11):1682-91. doi: 10.1016/j.bcp.2011.08.001. Epub 2011 Aug 6.
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.
Wnt/β-catenin 通路在肝细胞癌（HCC）中经常失调。激活的β-catenin 在细胞质和核内积累，并与 TCF/LEF 因子（如 TCF4）形成核复合物。干扰素-α（IFN-α）最近被认为具有预防和治疗 HCC 的治疗潜力。转化生长因子-β1（TGF-β1）是凋亡的介质，通过 Smads 蛋白发挥作用。Wnt/β-catenin 和 TGF-β1/Smads 通路之间的一种相互作用模式是 Smads 与β-catenin/TCF4 的关联。在这项研究中，我们分析了 IFN-α2b 和 TGF-β1 处理对 HepG2/C3A 和 Huh7 细胞系中 Wnt/β-catenin 通路、Smads 蛋白水平、β-catenin/TCF4/Smads 相互作用以及增殖和凋亡的影响。IFN-α2b 和 TGF-β1 通过降低β-catenin 和 Frizzled7 受体蛋白含量以及β-catenin 与 TCF4 的相互作用来减弱 Wnt/β-catenin 信号。在处理后，C3A 细胞系中也出现了截短的β-catenin 形式。两种细胞因子均降低了 Smads 蛋白及其与 TCF4 的相互作用。细胞对细胞因子的总体反应是增殖减少和凋亡增加。与未处理的细胞相比，用 Wnt3a 处理（可升高β-catenin 蛋白水平）也会增加 Smads 蛋白的含量。总之，IFN-α2b 和 TGF-β1 被证明是 HCC 细胞系中 Wnt/β-catenin 通路的有效调节剂，这些细胞系既有野生型β-catenin 又有截短型β-catenin。由于抑制β-catenin/TCF4/Smads 复合物的形成可能在减缓肿瘤发生中起关键作用，因此 IFN-α2b 和 TGF-β1 可用作 HCC 患者的潜在治疗方法。
