Pro-tumorigenic roles of TGF-β signaling during the early stages of liver tumorigenesis through upregulation of Snail

Many studies have focused on the tumor suppressive role of TGF-β signaling during the early stages of tumorigenesis by activating the target genes involved in cytostasis and apoptosis. We investigated the effects of TGF-β inhibition on early tumorigenesis in the liver, by employing diverse inhibitory methods. Strikingly, TGF-β inhibition consistently suppressed hepatic tumorigenesis that was induced either by activated RAS plus p53 downregulation or by the co-activation of RAS and TAZ signaling; this demonstrates the requirements for canonical TGF-β signaling in tumorigenesis. Moreover, we found that Snail is the target gene of the TGF-β signaling pathway that promotes hepatic carcinogenesis. The knockdown of Snail suppressed the early tumorigenesis in the liver, as did the TGF-β inhibition, while the ectopic expression of Snail restored tumorigenesis that was suppressed by the TGF-β inhibition. Our findings establish the oncogenic TGF-β-Smad- Snail signaling axis during the early tumorigenesis in the liver.