Sanguinarine inhibits epithelial-mesenchymal transition via targeting HIF-1α/TGF-β feed-forward loop in hepatocellular carcinoma

Epithelial-mesenchymal transition (EMT) plays a crucial role in hepatocellular carcinoma (HCC) progression. Hypoxia and excessive transforming growth factor-beta (TGF-beta) have been identified as inducers and target for EMT in HCC. Here, we show hypoxia inducible factor-1 alpha (HIF-1 alpha) and TGF-beta form a feed-forward loop to induce EMT in HCC cells. Further mechanistic study indicates under both hypoxia and TGF-beta stimulation, Smad and PI3K-AKT pathways are activated. We show sanguinarine, a natural benzophenanthridine alkaloid, impairs the proliferation of nine kinds of HCC cell lines and the colony formation of HCC cells. In hypoxic and TGF-beta cell models, sanguinarine inhibits HIF-1 alpha signaling and the expression of EMT markers, translocation of Snail and activation of both Smad and PI3K-AKT pathways. Sanguinarine could also inhibit TGF-beta-induced cell migration in HCC cells. In vivo studies reveal that the administration of sanguinarine inhibits tumor growth and HIF-1 alpha signaling, inhibits the expression changes of EMT markers as well as Smad and PI3K-AKT pathway proteins. Our findings suggest that sanguinarine is a promising candidate targeting HIF-1 alpha/TGF-beta signaling to improve the treatment for HCC patients.