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DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The majority of HCC cases are associated with liver fibrosis or cirrhosis developing from chronic liver injuries. The immune system of the liver contributes to the severity of tissue damage, the establishment of fibrosis and the disease's progression towards HCC. Herein, we provide a detailed characterization of the DEN-induced HCC rat model during fibrosis progression and HCC development with a special focus on the liver's inflammatory microenvironment. Fischer 344 male rats were treated weekly for 14 weeks with intra-peritoneal injections of 50 mg/kg DEN. The rats were sacrificed before starting DEN-injections at 0 weeks, after 8 weeks, 14 weeks and 20 weeks after the start of DEN-injections. We performed histopathological, immunohistochemical, RT-qPCR, RNA-seq and flow cytometry analysis. Data were compared between tumor and non-tumor samples from the DEN-treated versus untreated rats, as well as versus human HCCs. Chronic DEN injections lead to liver damage, hepatocytes proliferation, liver fibrosis and cirrhosis, disorganized vasculature, and a modulated immune microenvironment that mimics the usual events observed during human HCC development. The RNA-seq results showed that DEN-induced liver tumors in the rat model shared remarkable molecular characteristics with human HCC, especially with HCC associated with high proliferation. In conclusion, our study provides detailed insight into hepatocarcinogenesis in a commonly used model of HCC, facilitating the future use of this model for preclinical testing.

SUBMITTER: Kurma K

PROVIDER: S-EPMC8508319 | biostudies-literature |

REPOSITORIES: biostudies-literature

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DEN-induced rat model reproduces key features of human hepatocellular carcinoma

Project description:Using RNA-seq analysis, we study a DEN-induced HCC rat model during fibrosis progression and HCC development with special focus on liver inflammatory microenvironment. RNA-seq results show that DEN-induced liver tumors in rat model share remarkable molecular characteristics with human HCC, especially with HCC associated with high proliferation. In conclusion, our study provides detailed insight into the hepatocarcinogenesis in a commonly used model of HCC, facilitating the future use of this model for preclinical testing.

2021-10-08 | GSE182860 | GEO

DEN-induced rat model reproduces key features of human hepatocellular carcinoma

Project description:DEN-induced rat model reproduces key features of human hepatocellular carcinoma

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Bile Routing Modification Reproduces Key Features of Gastric Bypass in Rat.

Project description:ObjectiveTo evaluate the role of bile routing modification on the beneficial effects of gastric bypass surgery on glucose and energy metabolism.BackgroundGastric bypass surgery (GBP) promotes early improvements in glucose and energy homeostasis in obese diabetic patients. A suggested mechanism associates a decrease in hepatic glucose production to an enhanced intestinal gluconeogenesis. Moreover, plasma bile acids are elevated after GBP and bile acids are inhibitors of gluconeogenesis.MethodsIn male Sprague-Dawley rats, we performed bile diversions from the bile duct to the midjejunum or the mid-ileum to match the modified bile delivery in the gut occurring in GBP. Body weight, food intake, glucose tolerance, insulin sensitivity, and food preference were analyzed. The expression of gluconeogenesis genes was evaluated in both the liver and the intestine.ResultsBile diversions mimicking GBP promote an increase in plasma bile acids and a marked improvement in glucose control. Bile bioavailability modification is causal because a bile acid sequestrant suppresses the beneficial effects of bile diversions on glucose control. In agreement with the inhibitory role of bile acids on gluconeogenesis, bile diversions promote a blunting in hepatic glucose production, whereas intestinal gluconeogenesis is increased in the gut segments devoid of bile. In rats fed a high-fat-high-sucrose diet, bile diversions improve glucose control and dramatically decrease food intake because of an acquired disinterest in fatty food.ConclusionsThis study shows that bile routing modification is a key mechanistic feature in the beneficial outcomes of GBP.

| S-EPMC5678047 | biostudies-literature

Proteomic analysis of DEN and CCl<sub>4</sub>-induced hepatocellular carcinoma mouse model.

Project description:Hepatocellular carcinoma (HCC) seriously threatens human health, mostly developed from liver fibrosis or cirrhosis. Since diethylnitrosamine (DEN) and carbon tetrachloride (CCl4)-induced HCC mouse model almost recapitulates the characteristic of HCC with fibrosis and inflammation, it is taken as an essential tool to investigate the pathogenesis of HCC. However, a comprehensive understanding of the protein expression profile of this model is little. In this study, we performed proteomic analysis of this model to elucidate its proteomic characteristics. Compared with normal liver tissues, 432 differentially expressed proteins (DEPs) were identified in tumor tissues, among which 365 were up-regulated and 67 were down-regulated. Through Gene Ontology (GO) analysis, Ingenuity Pathway Analysis (IPA), protein-protein interaction networks (PPI) analysis and Gene-set enrichment analysis (GSEA) analysis of DEPs, we identified two distinguishing features of DEN and CCl4-induced HCC mouse model in protein expression, the upregulation of actin cytoskeleton and branched-chain amino acids metabolic reprogramming. In addition, matching DEPs from the mouse model to homologous proteins in the human HCC cohort revealed that the DEN and CCl4-induced HCC mouse model was relatively similar to the subtype of HCC with poor prognosis. Finally, combining clinical information from the HCC cohort, we screened seven proteins with prognostic significance, SMAD2, PTPN1, PCNA, MTHFD1L, MBOAT7, FABP5, and AGRN. Overall, we provided proteomic data of the DEN and CCl4-induced HCC mouse model and highlighted the important proteins and pathways in it, contributing to the rational application of this model in HCC research.

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CCAAT/enhancer-binding protein homologous (CHOP) protein promotes carcinogenesis in the DEN-induced hepatocellular carcinoma model.

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Experimental Zika Virus Inoculation in a New World Monkey Model Reproduces Key Features of the Human Infection.

Project description:A monkey model of Zika virus (ZIKV) infection is urgently needed to better understand transmission and pathogenesis, given its proven association with fetal brain defects in pregnant women and acute neurological illness. Here we experimentally infected 4 male marmosets with ZIKV (prototype 1947 African strain) and monitored them clinically with sampling of various body fluids and tissues for nearly 3 months. We show that the course of acute infection with ZIKV in these New World monkeys resembles the human illness in many respects, including (1) lack of apparent clinical symptoms in most cases, (2) persistence of the virus in body fluids such as semen and saliva for longer periods of time than in serum, and (3) generation of neutralizing antibodies as well as an antiviral immunological host response. Importantly, ZIKV-infected saliva samples (in addition to serum) were found to be infectious, suggesting potential capacity for viral transmission by the oral route. Re-challenge of a previously infected marmoset with a contemporary outbreak strain SPH2015 from Brazil resulted in continued protection against infection, no viral shedding, and boosting of the immune response. Given the key similarities to human infection, a marmoset model of ZIKV infection may be useful for testing of new drugs and vaccines.

| S-EPMC5719425 | biostudies-literature

Recombinant soluble gp130 protein reduces DEN-induced primary hepatocellular carcinoma in mice.

Project description:IL-6 (interleukin 6) plays an important role in the development and growth of hepatocellular carcinoma (HCC) via both classic signaling and trans-signaling pathways. Soluble gp130 (sgp130) is known to be a natural inhibitor of the trans-signaling pathway. In the present study, our goal was to investigate whether recombinant sgp130 could suppress the initiation and progression of HCC in mouse models. Our results demonstrate that sgp130 induced an apoptosis of HepG2 cells and inhibited the clonogenicity of HepG2 in vitro. Moreover, the IL-6 trans-signaling pathway is significantly suppressed by sgp130 as reflected by the decrease in the level of STAT3 phosphorylation and other inflammatory factors both in vitro and in vivo. In the DEN-induced HCC mouse model, intravenous injection of sgp130 attenuated hepatic fibrosis at 16 weeks and reduced the initiation and progression of primary HCC at 36 weeks. Furthermore, our results also demonstrate that intravenous administration of sgp130 significantly suppressed the growth and metastasis of xenograft human HCC in NOD/SCID mice.

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Thymoquinone Suppresses Angiogenesis in DEN-Induced Hepatocellular Carcinoma by Targeting miR-1-3p.

Project description:Hepatocellular carcinoma (HCC) is characterized by its high vascularity and metastasis. Thymoquinone (TQ), the main bio-active constituent of Nigella sativa, has shown anticancer and hepatoprotective effects. TQ's anticancer effect is mediated through miRNA regulation. miR-1-3p plays a significant role in various cancers but its role in HCC invasiveness remains poorly understood. Bio-informatics analysis predicted that the 3'-UTR of TIMP3 is a target for miR-1-3p; Rats were equally divided into four groups: Group 1, the negative control; Group 2 received TQ; Group 3 received DEN; and Group 4 received DEN after pretreatment with TQ. The expression of TIMP3, MMP2, MMP9, and VEGF in rats' liver was determined immunohistochemically. RT-qPCR was used to measure the miR-1-3p level in rats' liver, and TIMP3, MMP2, MMP9, and VEGF in the HepG2 cells after being transfected with miR-1-3p mimic or inhibitor; In rats pretreated with TQ, a decreased expression of MMP2, MMP9 and VEGF, and increased expression levels of TIMP3 and miR-1-3p were detected. Treating the HepG2 cells with miR-1-3p mimic led to the upregulation of TIMP3 and downregulation of MMP2, MMP9, and VEGF, and showed a significant delay in wound healing; These results suggested that the anti-angiogenic effect of TQ in HCC may be mediated through the regulation of miR-1-3p.

| S-EPMC9781440 | biostudies-literature

Gene expression data from DEN-induced hepatocellular carcinoma mice

Project description:We used microarrays to detail the molecular mechanism underlying the HLF (hepatic leukemia factor)-triggered HCC (hepatocellular carcinoma) initiation We conducted transcriptome microarray analysis of DEN (diethylnitrosamine)-induced HCCs from HLF-deficient mice or WT (wild type) mice.

2019-02-01 | GSE125934 | GEO

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Project description:To better characterize the pathogenesis of hepatocarcinogenesis, we established mouse HCC model by diethylnitrosamine (DEN) exposures and performed whole genome expression profiling.

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