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 .
Background Hepatoblastoma (HB) is the most common hepatic malignancy in children, accounting for approximately 80% of all childhood liver tumors. Previous genome-wide association studies (GWASs) have found that the LINC00673 rs11655237 C>T polymorphism is associated with the risk of several different adult cancers. However, the association between this polymorphism and HB susceptibility remains unclear. Methods We analyzed the association between the LINC00673 rs11655237 C>T polymorphism and HB susceptibility in a hospital-based study of Chinese children. We enrolled 213 HB patients and 958 healthy controls with genotypes determined by TaqMan, and the strength of the association of interest was determined by calculating odds ratios (ORs) and 95% confidence intervals (CIs). Findings We found a significant association between the LINC00673 rs11655237 C>T polymorphism and HB risk (CT/TT compared with CC: adjusted OR = 1.40, 95% CI = 1.04–1.88, p = 0.029). Furthermore, stratified analysis indicated that rs11655237 T allele carriers in the following subgroups were more likely to develop HB: children older than 17 months, males, and those with tumors of clinical stages III + IV. Interpretation In conclusion, we confirmed that the LINC00673 rs11655237 C>T polymorphism may be associated with HB susceptibility. Prospective studies with larger sample sizes and patients of different ethnicities are needed to validate our findings.
Background Hepatoblastoma is the most common hepatic malignancy in children, accounting for approximately 80% of all childhood liver tumors. KRAS and NRAS , members of the RAS gene family, are closely linked to tumorigenesis, and are frequently mutated in a variety of malignancies. They may thus play critical roles in tumorigenesis. However, there are few studies on the association between the RAS gene polymorphisms and risk of hepatoblastoma. Methods We investigated whether the polymorphisms at these genes are associated with hepatoblastoma susceptibility in a hospital-based study of 213 affected Chinese children and 958 cancer-free controls. Genotypes were determined by TaqMan assay, and association with hepatoblastoma risk was assessed based on odds ratios and 95% confidence intervals. Results No significant differences were observed between patients and controls in terms of age and gender frequency. All NRAS and KRAS genotypes are in Hardy–Weinberg equilibrium in the entire study population. We did not observe any significant association between hepatoblastoma risk and polymorphisms at NRAS and KRAS . The association between selected polymorphisms and hepatoblastoma risk was assessed after stratification by age, gender, and clinical stage. However, no significant association was observed even after stratification by age, gender, and clinical stage. Conclusions The data suggest that NRAS and KRAS polymorphisms are irrelevant to hepatoblastoma susceptibility among Chinese population. Electronic supplementary material The online version of this article (10.1186/s40164-019-0135-z) contains supplementary material, which is available to authorized users.
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