BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors d...BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.AIM To develop a signature of senescence-associated genes(SAGs) that predicts patients' overall survival(OS) to improve prognosis prediction of HCC.METHODS SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort(GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO(GSE14520) and the Cancer Genome Atlas datasets, respectively.Time-dependent receiver operating characteristic(ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein(AFP).RESULTS A total of 42 SAGs were screened and seven of them, including KIF18 B, CEP55,CIT, MCM7, CDC45, EZH2, and MCM5, were used to construct a prognostic formula. All seven genes were significantly downregulated in senescent cells andupregulated in HCC tissues. Survival analysis indicated that our seven-SAG signature was strongly associated with OS, especially in Asian populations, both in discovery and validation cohorts. Moreover, time-dependent ROC curve analysis suggested the seven-gene signature had a better predictive accuracy than serum AFP in predicting HCC patients' 1-, 3-, and 5-year OS.CONCLUSION We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.展开更多
Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently ...Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently but remains metabolically active.Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers,such as,morphological changes,expression of cell cycle inhibitors,senescence associatedβ-galactosidase activity,and changes in nuclear membrane.When cells in an organ become senescent,the entire organism can be affected.This may occur through the senescence-associated secretory phenotype(SASP).SASP may exert beneficial or harmful effects on the microenvironment of tissues.Research on senescence has become a very exciting field in cell biology since the link between age-related diseases,including cancer,and senescence has been established.The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence.The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes.Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration.This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.展开更多
An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43...An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43（GAP-43） is closely associated with neurite outgrowth and axon regeneration during neural development. We speculate that an enriched environment can reduce damage to dopaminergic neurons by affecting the expression of GAP-43. This study is designed to test this hypothesis. Three-month-old female senescence-accelerated mouse prone 8（SAMP8） mice were housed for 3 months in an enriched environment or a standard environment. These mice were then subcutaneously injected in the abdomen with 14 mg/kg MPTP four times at 2-hour intervals. Morris water maze testing demonstrated that learning and memory abilities were better in the enriched environment group than in the standard environment group. Reverse-transcription polymerase chain reaction, immunohistochemistry and western blot assays showed that m RNA and protein levels of GAP-43 in the substantia nigra were higher after MPTP application in the enriched environment group compared with the standard environment group. These findings indicate that an enriched environment can increase GAP-43 expression in SAMP8 mice. The upregulation of GAP-43 may be a mechanism by which an enriched environment protects against MPTP-induced neuronal damage.展开更多
In order to unravel the biochemical pathways and understand the molecular mechanisms involved in leaf senescence, suppression subtractive hybridization (SSH) was used to generate a cDNA library enriched for transcript...In order to unravel the biochemical pathways and understand the molecular mechanisms involved in leaf senescence, suppression subtractive hybridization (SSH) was used to generate a cDNA library enriched for transcripts differentially expressed in developmental senescence cotyledons of upland cotton. After differential screening by membrane- based hybridization and subsequent confirmation by reverse Northern blot analysis, selected 678 clones were sequenced and analyzed. Sequencing of these cDNA fragments reveals that 216 of expressed se- quence tags (ESTs) represented unique genes. Of these 216 cDNAs, 151 clones (69.9%) show signifi- cant homologies to previously known genes, while the remaining 65 do not match any known sequences. 151 unique ESTs are assigned to twelve different categories based on their putative functions gener- ated by BLAST analysis. These SAG-encoded pro- teins are likely to participate in macromolecule deg- radation, nutrient recycling, detoxification of oxidative metabolites, and signaling and regulatory events. The expression pattern of selection of genes was confirmed using northern hybridization. Northern hybridization confirmed several distinct patterns, from expression at a very early stage to the terminal phase of the senescence syndrome. Clones encod- ing proteases and proteins involved in macromole- cule degradation and gluconeogenesis, as well as stress-related genes, are up regulated in senescence cotyledons.展开更多
基金Supported by the National Natural Science Foundation of China,No.81773128 and No.81871998the Natural Science Basic Research Plan in Shaanxi Province of China,No.2018JM7013 and No.2017JM8039+1 种基金the Research Fund for Young Star of Science and Technology in Shaanxi Province,No.2018KJXX-022China Postdoctoral Science Foundation,No.2018M641000
文摘BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.AIM To develop a signature of senescence-associated genes(SAGs) that predicts patients' overall survival(OS) to improve prognosis prediction of HCC.METHODS SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort(GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO(GSE14520) and the Cancer Genome Atlas datasets, respectively.Time-dependent receiver operating characteristic(ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein(AFP).RESULTS A total of 42 SAGs were screened and seven of them, including KIF18 B, CEP55,CIT, MCM7, CDC45, EZH2, and MCM5, were used to construct a prognostic formula. All seven genes were significantly downregulated in senescent cells andupregulated in HCC tissues. Survival analysis indicated that our seven-SAG signature was strongly associated with OS, especially in Asian populations, both in discovery and validation cohorts. Moreover, time-dependent ROC curve analysis suggested the seven-gene signature had a better predictive accuracy than serum AFP in predicting HCC patients' 1-, 3-, and 5-year OS.CONCLUSION We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.
文摘Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently but remains metabolically active.Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers,such as,morphological changes,expression of cell cycle inhibitors,senescence associatedβ-galactosidase activity,and changes in nuclear membrane.When cells in an organ become senescent,the entire organism can be affected.This may occur through the senescence-associated secretory phenotype(SASP).SASP may exert beneficial or harmful effects on the microenvironment of tissues.Research on senescence has become a very exciting field in cell biology since the link between age-related diseases,including cancer,and senescence has been established.The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence.The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes.Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration.This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.
基金supported by a grant from the Health Department of Hebei Province of China,No.20120056,20140314the Funding Project for Introduced Abroad Study Personnel of Hebei Province of China,No.C2011003039
文摘An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43（GAP-43） is closely associated with neurite outgrowth and axon regeneration during neural development. We speculate that an enriched environment can reduce damage to dopaminergic neurons by affecting the expression of GAP-43. This study is designed to test this hypothesis. Three-month-old female senescence-accelerated mouse prone 8（SAMP8） mice were housed for 3 months in an enriched environment or a standard environment. These mice were then subcutaneously injected in the abdomen with 14 mg/kg MPTP four times at 2-hour intervals. Morris water maze testing demonstrated that learning and memory abilities were better in the enriched environment group than in the standard environment group. Reverse-transcription polymerase chain reaction, immunohistochemistry and western blot assays showed that m RNA and protein levels of GAP-43 in the substantia nigra were higher after MPTP application in the enriched environment group compared with the standard environment group. These findings indicate that an enriched environment can increase GAP-43 expression in SAMP8 mice. The upregulation of GAP-43 may be a mechanism by which an enriched environment protects against MPTP-induced neuronal damage.
文摘In order to unravel the biochemical pathways and understand the molecular mechanisms involved in leaf senescence, suppression subtractive hybridization (SSH) was used to generate a cDNA library enriched for transcripts differentially expressed in developmental senescence cotyledons of upland cotton. After differential screening by membrane- based hybridization and subsequent confirmation by reverse Northern blot analysis, selected 678 clones were sequenced and analyzed. Sequencing of these cDNA fragments reveals that 216 of expressed se- quence tags (ESTs) represented unique genes. Of these 216 cDNAs, 151 clones (69.9%) show signifi- cant homologies to previously known genes, while the remaining 65 do not match any known sequences. 151 unique ESTs are assigned to twelve different categories based on their putative functions gener- ated by BLAST analysis. These SAG-encoded pro- teins are likely to participate in macromolecule deg- radation, nutrient recycling, detoxification of oxidative metabolites, and signaling and regulatory events. The expression pattern of selection of genes was confirmed using northern hybridization. Northern hybridization confirmed several distinct patterns, from expression at a very early stage to the terminal phase of the senescence syndrome. Clones encod- ing proteases and proteins involved in macromole- cule degradation and gluconeogenesis, as well as stress-related genes, are up regulated in senescence cotyledons.
