Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes.
Lab Invest. 2015 Aug 24. Epub 2015 Aug 24. PMID: 26302188
Epithelial-mesenchymal transition (EMT) occurs during adult tissue remodeling responses including carcinogenesis and fibrosis. Existing evidence reveals that hepatocytes can undergo EMT in adult liver, which is critically involved in chronic liver injury. We herein established a hypoxia-induced EMT model in human LO2 hepatocytes treated with cobalt chloride (CoCl2) in vitro, and evaluated the effects of curcumin, a natural antifibrotic compound, on hepatocyte EMT and explored the underlying molecular mechanisms. We found that CoCl2 at non-toxic doses induced a mesenchymal cell phenotype in hepatocytes and upregulated several mesenchymal markers includingα-smooth muscle actin, vimentin, N-cadherin, fibronectin and Snail (an EMT-related transcription factor), but downregulated the epithelial marker E-cadherin in hepatocytes. However, curcumin reversed the morphological changes, abrogated the increased expression of mesenchymal markers, and rescued E-cadherin expression in CoCl2-treated hepatocytes, suggesting the inhibition of hepatocyte EMT in vitro. We further found that curcumin interfered with the transforming growth factor-β (TGF-β) signaling by reducing the expression of TGF-β receptor I and inhibiting the expression and phosphorylation of Smad2 and Smad3. Use of SB431542, a specific inhibitor of TGF-β receptor I, demonstrated that interference with the TGF-β/Smad pathway was associated with curcumin suppression of hepatocyte EMT. Our in vivo data showed that curcumin affected hepatic EMT in rat fibrotic liver caused by carbontetrachloride, which was associated with the inhibition of TGF-β/Smad signaling. These findings characterized a novel mechanism by which curcumin modulated hepatocyte EMT implicated in treatment of liver fibrosis.Laboratory Investigation advance online publication, 24 August 2015; doi:10.1038/labinvest.2015.107.