Wnt-SCD-LRP5/6 Loop links liver fibrosis with cancer

Wnt-β-catenin pathway is implicated in liver fibrosis and cancer but whether and how this pathway links these two pathologic entities are unknown. Our recent study reveals stearoyl-Co A desaturase (SCD) is inducible by... [ view full abstract ]

Wnt-β-catenin pathway is implicated in liver fibrosis and cancer but whether and how this pathway links these two pathologic entities are unknown. Our recent study reveals stearoyl-Co A desaturase (SCD) is inducible by Wnt-β-catenin pathway and positively feeds forward to amplify Wnt signaling in both hepatic stellate cells (HSCs) and liver tumor-initiating stem cell-like cells (TICs). This loop is mediated by inhibition of Ran1 binding to Transportin-1 by mono-unsaturated fatty acids generated by SCD, resulting in reduced nuclear import of Elav-like protein 1 (ELAVL1), increasing cytosolic levels of ELAVL1 and ELAVL1-mediated stabilization of mRNAs encoding LRP 5 and LRP6. The SCD-mediated loop is essential for activation of HSCs and TICs as such genetic ablation of Scd or pharmacologic inhibition of SCD in each cell type suppresses liver fibrosis and tumorigenesis, respectively. Further, conditional ablation of Scd in activated HSCs (aHSCs) prevents growth of tumors from TICs and attenuates DEN-induced liver tumor development in mice, suggesting Wnt-SCD-mediated tumor promotion by HSCs.  SCD and LRP5/6 are overexpressed in aHSCs and HCC cells in in patients, and SCD expression correlates with the stage of HCC and patient mortality. Collectively, these results suggest a newly identified Wnt-SCD-LRP5/6 loop may serve as a potential therapeutic target for liver fibrosis and cancer.