The extent of liver injury determines hepatocyte fate toward senescence or cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA423180 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6395711_1.fastq.gz | Fastqsanger.gz | |||
| SRR6395711_2.fastq.gz | Fastqsanger.gz | |||
| SRR6395712_1.fastq.gz | Fastqsanger.gz | |||
| SRR6395712_2.fastq.gz | Fastqsanger.gz | |||
| SRR6395713_1.fastq.gz | Fastqsanger.gz |
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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:It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear 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, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and 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.
| S-EPMC5951829 | biostudies-literature
Project description:Cellular senescence is associated with aging but also impacts various physiological and pathological processes such as embryonic development and wound healing. Factors secreted by senescent cells can affect their microenvironment, including local spreading of senescence. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood however, the presence of hepatic senescence is associated with poor prognosis and extrahepatic organ failure in acute liver disease. Here, using genetic mouse models of hepatocyte-specific senescence, we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence. In patients with acute indeterminate hepatitis, the extent of hepatocellular senescence predicts the occurrence of extrahepatic dysfunction, need for liver transplantation and mortality. We identify the Transforming Growth Factor β (TGFβ) pathway as a critical mediator of systemic spread of senescence and TGFβ inhibition blocks senescence transmission to other organs preventing renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence which, independent of aging, contributes to multi-organ dysfunction.
2024-08-23 | GSE262705 | GEO
Project description:Cellular senescence is associated with aging but also impacts various physiological and pathological processes such as embryonic development and wound healing. Factors secreted by senescent cells can affect their microenvironment, including local spreading of senescence. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood however, the presence of hepatic senescence is associated with poor prognosis and extrahepatic organ failure in acute liver disease. Here, using genetic mouse models of hepatocyte-specific senescence, we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence. In patients with acute indeterminate hepatitis, the extent of hepatocellular senescence predicts the occurrence of extrahepatic dysfunction, need for liver transplantation and mortality. We identify the Transforming Growth Factor Beta (TGFbeta) pathway as a critical mediator of systemic spread of senescence and TGFbeta inhibition blocks senescence transmission to other organs preventing renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence which, independent of aging, contributes to multi-organ dysfunction.
2024-08-23 | GSE267196 | GEO
Project description:We used microarrays to identify a transcriptional signature of oxidative stress induced senescence in a hepatocyte cell line (HepG2) by globally assessing differential gene expression after treatment with 0.5mM of H2O2 for 60 minutes, compared to nontreated cells as a control. We performed genome-wide comparison of gene expression and identified genes that are differentially expressed in senescent HepG2 cells relative to untreated cells, 4 biological replicates per condition
2015-01-01 | E-GEOD-47739 | biostudies-arrayexpress
Project description:We used microarrays to identify a transcriptional signature of oxidative stress induced senescence in a hepatocyte cell line (HepG2) by globally assessing differential gene expression after treatment with 0.5mM of H2O2 for 60 minutes, compared to nontreated cells as a control.
2015-01-01 | GSE47739 | GEO
Project description:Acute Pten loss initiates prostate tumorigenesis characterized by cellular senescence response. Here we examine the cellular senescence response in epithelial individual cells, by single-cell RNA sequencing (scRNAseq) in Ptenpc-/- and Ptenpc-/-; Timp1-/- GEMMs. ScRNAseq analysis determines a cluster of senescent cells expressing the senescence-related genes. A significant positive correlation is observed between the senescence score and Bcl2 expression. This provides the rational for targeting senescent cells using Bcl2 inhibitor.
2020-10-09 | E-MTAB-9578 | biostudies-arrayexpress
Project description:Therapy-induced senescence of cancer-associated fibroblasts determines survival in rectal cancer
| PRJNA657259 | ENA
Project description:The burden of senescent hepatocytes correlates with MASLD severity but mechanisms driving senescence, and how it exacerbates MASLD are poorly understood. Hepatocytes become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine if the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA seq analysis confirmed that hepatocyte populations of MASLD livers are depleted of Smo(+) cells and enriched with senescent cells. When fed CDA-HFD, Smo(-) mice had lower antioxidant markers and developed worse DNA damage, senescence, MASH and liver fibrosis than Smo(+) mice. Sera and hepatocyte-conditioned medium from Smo(-) mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo(-) hepatocytes with TP reduced senescence and lipotoxicity; inhibiting TP in Smo(+) hepatocytes had the opposite effects and exacerbated hepatocyte senescence, MASH, and fibrosis in CDA-HFD-fed mice.Therefore, we found that inhibiting Hedgehog signaling in hepatocytes promotes MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.
2024-10-01 | GSE273523 | GEO
Project description:Crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, and consequent effects on liver tumourigenesis, are incompletely understood. We show here that hepatocyte specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours, and hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype (SASP). Depleting senescent HSCs by senolytic treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, subsequent SASP development, and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical link between hepatocyte metabolism and HSC senescence that promotes tumour growth.
2020-03-02 | MSV000085045 | MassIVE