Gene expression profiling of normal mouse hepatocyte, premalignant hepatocytes and fully malignant HCC
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Michael Karin
PROVIDER: E-GEOD-50431 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Gene expression was analyzed and compared of normal mouse hepatocyte, premalignant hepatocytes and fully malignant HCC cells. The results provide valuable information about the gene expression alterations during the chronic process of liver cancer development.
2013-10-11 | GSE50431 | GEO
Project description:Gene expression profiling of normal mouse hepatocyte, premalignant hepatocytes and fully malignant HCC
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Project description:Induction of hepatocyte senescence is known to inhibit hepatocellular carcinoma (HCC). Until now, it has not been clear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury did not result into hepatocyte senescence, but instead led to a significant incidence of HCC. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.
2018-12-20 | GSE108328 | GEO
Project description:Hepatitis B virus (HBV) infection is a major health problem worldwide and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expressions and signaling pathways of infected hepatocytes, and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of transforming growth factor (TGF)-β family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 gene associated with cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase as compared to the predominantly G0/G1 phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA and CEBPB, were up-regulated upon HBV infection and particularly enriched in cells at the G2/M phase. Together, these results support that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predispose infected hepatocytes to subsequent malignant transformation.
2018-08-08 | GSE118295 | GEO
Project description:Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (M?), and sinusoidal endothelial cells (SEC) play functionally important and interdependent roles in adaptive processes such as wound healing, obesity, and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. To address this, we developed a strategy for simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression in response to DEN and found that while there was only a marginal increase in hepatocyte number, M? and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, M? and SEC identified characteristic gene “fingerprints” that define each cell type and their distinct physiological or oncogenic stress signatures. Integration of these cell-specific gene fingerprints with available hepatocellular carcinoma (HCC) patient microarray data demonstrates that the hepatocyte-specific response strongly correlates with the human HCC gene expression profile. Liver-specific M? and SEC gene signatures demonstrate significant alterations in inflammatory and angiogenic gene regulatory pathways, which may impact the hepatocyte response to oncogenic stress. Further validation confirms alterations in components of two key pathways, AP-1 and p53, that have been previously associated with HCC onset and progression. Our data reveal unique gene expression patterns that serve as molecular “fingerprints” for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the development of hepatic cancer. Total RNA isolated from each specific cell type (Hepatocyte (PH), Sinusoidal Endothelial Cell (SEC), and Macrophage (MP)) pooled from 3-4 DEN-treated mice and compared to their untreated counterparts.
2015-09-20 | E-GEOD-67225 | biostudies-arrayexpress
Project description:PR-SET7-mediated histone-4 lysine-20 methylation has been implicated in mitotic condensation, DNA damage response and replication licencing. Here we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis with unusual features of autophagy, termed "endonucleosis". Necrotic death was accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic-regenerative cycles coupled with oncogenic STAT3 activation replaced pre-existing hepatocytes with hepatocellular carcinoma derived entirely from ductal progenitor cells. Hepatocellular carcinoma in these mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. Mice carrying hepatocyte specific inactivation of PR-SET7 were generated in order to investigate the function of PR-SET7 histone methyl transferase in liver organogenesis, hepatocyte proliferation and liver regeneration. P15 WT mice were injected intra-peritoneally (ip) with 25ml per kg DEN (diethyl nitrosamine). Mice were examined for RNA expression at 8 months old.
2014-08-01 | E-GEOD-49555 | biostudies-arrayexpress
Project description:AEG-1 is overexpressed in human hepatocellular carcinoma (HCC) and positively regulates development and progression of HCC A transgenic mouse with hepatocyte-specific expression of human AEG-1 was generated using mouse albumin promoter/enhancer in B6/CBA background. Hepatocytes were isolated from WT and Alb/AEG-1 mice for RNA extraction and Affymetrix microarray hybridization.
2013-07-01 | E-GEOD-46701 | biostudies-arrayexpress
Project description:NF-κB has a crucial tumor-suppression role in chemical hepatocarcinogenesis (HCC) by preventing hepatocyte apoptosis-induced compensatory proliferation. However, NF-κB is typically activated in chemical HCC animal models and in ~40% HCC patients, in which its role in tumor progression is largely not known. Here we report that transcription factor Miz1 limits tumor-promoting function of NF-κB independently of its transcriptional activity in chemical HCC. In a murine model, hepatocyte-specific deletion of Miz1 exacerbates HCC progression. Miz1 loss results in a unique sub-group of hepatocytes with upregulated NF-κB activity and pro-inflammatory cytokine production, skewing infiltrating macrophages toward M1-like pro-inflammatory phenotype. Mechanistically, Miz1 sequestrates and prevents IKK-phosphorylation of Metadherin (MTDH), thereby inhibiting NF-κB nuclear translocation and transcription activity. In HCC patient specimens, Miz1 expression is inversely correlated with phosphorylation of RelA and MTDH, and poor prognosis. Thus, Miz1 preventing hepatocytes from promoting infiltrating macrophage M1-like phenotype and inflammation in chemical HCC progression.
2021-07-13 | GSE142868 | GEO
Project description:Background:
HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1+/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear.
Results:
We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS-/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-kB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-kB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-kB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver.
Conclusions:
HAF is novel transcriptional regulator of the NF-kB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.
| MSV000095959 | MassIVE
Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Hepatocellular carcinoma (HCC) has a high mortality rate and develops based on the chronic inflammatory hepatic disease. Therefore, novel prophylactic or therapeutic strategies are required to improve outcome. In this study, influence of diethylnitrosamine (DEN) and retinoic acid (ATRA) on hepatocarcinogenesis was investigated in mouse. These results suggest that the control of NF-M-NM-:B signaling during the early stage of HCC development is important for the prevention of malignant transformation in hepatocytes. Genes induced by the following treatments in mice liver were investigated at 2 days or 7 days after treatment; DEN: diethylnitrosamine (treatment of DEN (drinking water 80 mg/L)) ATRA: retinoic acid (treatment of ATRA (drinking water 30 mg/L)) G0s2 siRNA : G0s2 knockdown mouse liver (treatment of G0s2 siRNA) Control siRNA: treatment of scramble siRNA (negative control)
2014-06-06 | E-GEOD-57798 | biostudies-arrayexpress