Abstract

<div>Abstract<p>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 <i>in vivo</i> functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human <i>CTNNB1<sup>mt</sup></i> and zebrafish <i>tcf7l2</i> or murine <i>Myc</i> together with <i>kras<sup>v12</sup></i> in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by <i>kras<sup>v12</sup></i> 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.</p><p><b>Significance:</b> These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma.</p><p><b>Graphical Abstract:</b> <a href="http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg" target="_blank">http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg</a>. <i>Cancer Res; 78(19); 5548–60. ©2018 AACR</i>.</p></div>

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