Canonical Wnt signaling remodels lipid metabolism in zebrafish hepatocytes following Ras oncogenic insult

Yuxiao Yao, Shaoyang Sun, Jingjing Wang, Fei Fei, Zhaoru Dong, Ai-Wu Ke, Ruoyu He, Lei Wang, Lili Zhang, Min-Biao Ji, Qiang Li, Min Yu (+4 others)
2018 Cancer Research  
There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform in vivo functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human CTNNB1 mt and zebrafish tcf7l2 or murine Myc
more » ... r murine Myc together with kras v12 in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by kras v12 expression alone. UPLC-MS-based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention.
doi:10.1158/0008-5472.can-17-3964 pmid:30065049 fatcat:v2wx2gjzr5amrbz7i2jjngoptu