Showing papers by "Zhiyuan Gong published in 2018"
TL;DR: Together, these 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.
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 in vivo functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human CTNNB1mt and zebrafish tcf7l2 or murine Myc together with krasv12 in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by krasv12 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.Significance: 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.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg Cancer Res; 78(19); 5548-60. ©2018 AACR.
42 citations
TL;DR: It is revealed that representatives of major categories of environmental pollutants could cause an acute inflammatory response in zebrafish larvae as shown by alterations in the neutrophils, which may imply a common immunotoxicity mechanism for most environmental pollutants.
33 citations
TL;DR: The findings suggest that micafungin has considerable potential as a novel inhibitor against the viral replication, and intracellular and extracellular transmission of CHIKV, and has a little effect on virus stability, and could have curative effects on other alphavirus infections.
25 citations
TL;DR: A rapid change of microenvironment after krasV12-induction in zebrafish liver with progressively increased stromal cell number and enlarged liver size is found and the underlying mechanism may provide potential therapeutic targets for liver diseases.
Abstract: Activation of hepatic stellate cells (HSC) plays a crucial role in the liver disease progression from liver fibrosis/cirrhosis to cancer. Here, we found a rapid change of microenvironment after kras V12 -induction in zebrafish liver with progressively increased stromal cell number and enlarged liver size. Neutrophils and macrophages exhibited a faster response than HSCs. By manipulating the numbers of neutrophils and macrophages through morpholino knockdown, we found that macrophages contributed to both HSC survival and activation while neutrophils appear to be only required for HSC activation. Serotonin, which is essential for HSC survival and activation, was found up-regulated in hepatocytes and macrophages, but not in neutrophils after kras V12 induction. Serotonin receptor was highly expressed in HSCs; increase of the receptor activity by an agonist stimulated HSCs and oncogenic growth of the liver while an opposite effect was observed with an antagonist. Activated HSCs promoted the pro-tumorigenesis functions of neutrophils and macrophages through secretion of Tgfb1. Overall, these observations elucidated a cellular interaction in microenvironment where that upregulated serotonin in hepatocytes and macrophages activated HSCs. Since the microenvironment crosstalk plays a vital role in manipulation of liver carcinogenesis, the underlying mechanism may provide potential therapeutic targets for liver diseases.
22 citations
TL;DR: A novel interaction between oncogenic hepatocytes and HSCs is concluded through the fibrinogen related pathway in both the zebrafish HCC model and human liver disease samples.
20 citations
TL;DR: It is demonstrated how information can be obtained using adverse outcome pathway framework to derive biological effect-based monitoring tools and can supplement analytical chemistry to provide more comprehensive monitoring of discharged effluents and their receiving waters.
18 citations
TL;DR: The results demonstrate that krasV12 overexpression induces intestinal tumorigenesis in zebrafish, which mimics intestinal tumor formation in humans, and may provide a valuable in vivo platform that can be used to investigate tumor initiation and anticancer drugs for gastrointestinal cancers.
12 citations
TL;DR: Zebrafish was proved to be more sensitive than medaka to PCB 126 and to PeCDF in this study, suggesting species-specific sensitivity to DLCs in fish and will facilitate choosing a sensitive and reliable fish model or tool to evaluate the risk of dioxins and DLCs exposure.
9 citations
TL;DR: Investigating the expression of jumonji domain-containing 4 in colon adenocarcinoma (CA) revealed that JMJD4 expression could be a prognostic indicator for patients with CA and may provide a new target for the development of novel therapies for the treatment of CA.
8 citations
TL;DR: This chapter described a protocol for both label-free and label-based proteomic methods to analyse proteomic changes in both embryos and adult livers of zebrafish exposed to the teratogen TCDD (tetrachlorodibenzo-p-dioxin) as an example.
Abstract: Traditional toxicological screens based on the zebrafish model use observable phenotypic endpoints during their development to determine the toxicity of teratogens. Yet toxicity does not always translate to obvious phenotypic changes and the criteria used to score the toxicity of a teratogen are frequently subjected to human perception. The advancement in omics-based technologies has allowed us to quantitatively and objectively determine the toxicity of a teratogen based on biomolecular changes. The field of proteomics has been gaining popularity as a valuable tool in toxicology. Hence, in this chapter, we described a protocol for both label-free and label-based proteomic methods to analyse proteomic changes in both embryos and adult livers of zebrafish exposed to the teratogen TCDD (tetrachlorodibenzo-p-dioxin) as an example.
1 citations