Canonical Wnt Signaling Remodels Lipid Metabolism in Zebrafish Hepatocytes following Ras Oncogenic Insult

Abstract

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 functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human and zebrafish or murine together with in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by 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. 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. http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg .

Combinatorial genetic replenishments in myocardial and outflow tract tissues restore heart function in tnnt2 mutant zebrafish

“…Myl7 promoter has also been extensively employed to drive gene expression in atrial and ventricular myocardium in zebrafish hearts at all stages (Thisse et al, 2004; Hsiao et al, 2003). We generated myl7 promotor-driven and dosage-induced (Tet-On system) transgenic cassettes (Yao et al, 2018) for delicate regulations of tnnt2a expression (Fig. 2A,B).…”

Wnt Signaling in Cancer Metabolism and Immunity

“…Furthermore, linoleic acid was shown to induce breast cancer cell migration through plasminogen activator inhibitor-1 (PAI-1) and SMAD4 [63]. In a recent study, Yao et al found that canonical Wnt signaling through MYC promotes the conversion of triacylglycerol to phospholipid and increases unsaturated fatty acyl groups in phospholipids [64]. This lipid metabolism remodeling is extensively used by cancer cells as unsaturated fatty acids are crucial for the cell membrane maintenance, energy storage and signaling [65].…”

NUDT7 Loss Promotes KrasG12D CRC Development

“…Wnt signaling is involved in the stability of Ras through regulation of glycogen synthase kinas 3β-mediated Ras phosphorylation [56]. In hepatocellular carcinoma, Wnt signaling modulates lipid homeostasis in a Ras-dependent manner [57]. In this study, we found that Ras activity modulates the expression level of NUDT7 in an opposite manner, and decreased levels of NUDT7 deregulate lipid homeostasis by the upregulation of Wnt signaling.…”