Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis
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PROVIDER: PRJNA691910 | ENA |
REPOSITORIES: ENA
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Project description:Patients with hepatocellular carcinoma (HCC) associated to non-alcoholic steatohepatitis (NASH) are increasing globally, but their molecular traits are not well characterized. Our molecular characterization revealed higher rates of ACVR2A mutations (10%) – a potential tumour suppressor, presence of a novel mutational signature (MutSig-NASH-HCC), a more relevant role of Wnt/TGF-β proliferation subclass in tumours (42%) and immunosuppressive traits in the adjacent non-tumoral tissue.
| EGAS00001005222 | EGA
Project description:Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterizing NASH-HCC compared to other HCC aetiologies. We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n=53 NASH-HCC; n=74 NASH) and whole exome sequencing (n=50 NASH-HCC) data were compared to HCCs of other aetiologies (n=184). Three NASH-HCC mouse models were analysed with RNAseq/expression-array (n=20). ACVR2A was silenced in HCC cells and proliferation assessed by MTT and colony formation assays. Mutational profiling of NASH-HCC tumours revealed TERT-promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most-frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% versus 3%, p<0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs 2% in viral/alcohol-HCC, p=0.03). Tumour mutational burden (TMB) was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 versus 0.94 mutations/Mb; p<0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% versus 26%, p=0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of immunosuppressive cancer field. In three murine models of NASH-HCC key features of human NASH-HCC were preserved. NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature.
2021-06-29 | GSE164760 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.
2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress
Project description:NCOA5 haploinsufficiency in myeloid cells sufficiently causes non-alcoholic steatohepatitis and hepatocellular carcinoma
| PRJNA791927 | ENA
Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.
2013-04-02 | E-GEOD-37031 | biostudies-arrayexpress
Project description:Molecular and cellular mechanisms causing the onset and progression of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and HCC remain poorly understood. Here we show that myeloid-cell-specific heterozygous deletion of Ncoa5 (Ncoa5ΔM/+) sufficiently causes the development of NAFLD/NASH and HCC in male mice. The platelet factor 4 (PF4) overexpressed by Ncoa5ΔM/+ intrahepatic macrophages is identified as a potent mediator to trigger lipid accumulation in hepatocytes by inducing expression of genes promoting lipogenesis. Enrichment score of the gene expression signature derived from Ncoa5ΔM/+ hepatic macrophages correlated with unfavorable clinical parameters of NAFLD patients. Moreover, in HCC patients, the high PF4 expression correlated with poor overall survival and increased infiltrations of M2 macrophages, exhausted CD8 T cells, and MDSCs in HCCs. Our results reveal a novel macrophage-underlying mechanism for the onset of NAFLD and NASH-related HCC and suggest that NCOA5-PF4 axis is a potential target for therapeutic inhibition of NAFLD/NASH progression.
2023-09-12 | GSE192554 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) results from accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well-characterized clinical and histological pathology for NASH-driven HCC in humans, its etiology remains unclear and there is a deficiency in pre-clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC-related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH-driven HCC that can be utilized for future molecular mechanistic studies of this disease.
2022-06-14 | GSE197884 | GEO
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress
Project description:High-calorie diets lead hepatic steatosis and to the development of non-alcoholic fatty liver disease (NAFLD), which can evolve over many years into the inflammatory form non-alcoholic steatohepatits (NASH) posing a risk for the development of hepatocellular carcinoma (HCC). Due to the diet and the liver alteration, the axis between liver and gut is disturbed, resulting in gut microbiome alterations. Consequently, detecting these gut microbiome alterations repre-sents a promising strategy for early NASH and HCC detection. We analyzed medical parame-ters and the fecal metaproteome of 19 healthy controls, 32 NASH, and 29 HCC patients target-ing the discovery of diagnostic biomarkers. Here, NASH and HCC resulted in increased in-flammation status and shifts within the composition of the gut microbiome. Increased abun-dance of kielin/chordin, E3 ubiquitin ligase, and nucleophosmin 1 represented valuable fecal biomarkers indicating disease-related changes in the liver. Whereas a single biomarker failed to separate NASH and HCC, machine learning-based classification algorithms provided 0.86% accuracy in distinguishing between controls, NASH, and HCC. Conclusion: Fecal metaproteomics enables early detection of NASH and HCC by providing single biomarkers and ma-chine learning-based metaprotein panels.
2022-10-13 | PXD034175 | Pride
Project description:A NEW PRECLINICAL MODEL OF WESTERN DIET-INDUCED PROGRESSION OF NON-ALCOHOLIC STEATOHEPATITIS TO HEPATOCELLULAR CARCINOMA
| PRJNA812592 | ENA