BACKGROUND As a critical early event in hepatocellular carcinogenesis,telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma(HCC)patients,and its function in the genesis and tre...BACKGROUND As a critical early event in hepatocellular carcinogenesis,telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma(HCC)patients,and its function in the genesis and treatment of HCC has gained much attention over the past two decades.AIM To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase.METHODS The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to“articles”and“reviews”published in English.A total of 873 relevant publications related to HCC and telomerase were identified.We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications,such as the trends in the publications,citation counts,most prolific or influential writers,and most popular journals;to screen for keywords occurring at high frequency;and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences.VOSviewer was utilized to compile and visualize the bibliometric data.RESULTS A surge of 51 publications on HCC/telomerase research occurred in 2016,the most productive year from 1996 to 2023,accompanied by the peak citation count recorded in 2016.Up to December 2023,35226 citations were made to all publications,an average of 46.6 citations to each paper.The United States received the most citations(n=13531),followed by China(n=7427)and Japan(n=5754).In terms of national cooperation,China presented the highest centrality,its strongest bonds being to the United States and Japan.Among the 20 academic institutions with the most publications,ten came from China and the rest of Asia,though the University of Paris Cité,Public Assistance-Hospitals of Paris,and the National Institute of Health and Medical Research(INSERM)were the most prolific.As for individual contributions,Hisatomi H,Kaneko S,and Ide T were the three most prolific authors.Kaneko S ranked first by H-index,G-index,and overall publication count,while Zucman-Rossi J ranked first in citation count.The five most popular journals were the World Journal of Gastroenterology,Hepatology,Journal of Hepatology,Oncotarget,and Oncogene,while Nature Genetics,Hepatology,and Nature Reviews Disease Primers had the most citations.We extracted 2293 keywords from the publications,120 of which appeared more than ten times.The most frequent were HCC,telomerase and human telomerase reverse transcriptase(hTERT).Keywords such as mutational landscape,TERT promoter mutations,landscape,risk,and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years.CONCLUSION Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.展开更多
Objective:To investigate the effect of vascular endothelial growth factor(VEGF),P53 and telomerase on angiogenesis in gastric carcinoma tissue.Methods:A total of 95 surgical resection samples of gastric cancer tissue ...Objective:To investigate the effect of vascular endothelial growth factor(VEGF),P53 and telomerase on angiogenesis in gastric carcinoma tissue.Methods:A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF,P53 and telomerase expression using immunohistochemical methods.Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed.Results:Microvascular density(MVD)and the expression of VEGF,P53 and telomerase were positively correlated.Expression of VEGF and P53 protein were related to tumor type and lymph metastasis,and also a correlation was observed between P53 and VEGF.The telomerase expression had no correlation with VEGF,and P53.Conclusions:VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis.Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF.Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53.展开更多
AIM:To investigate telomerase activity and human telomerase reverse transcriptase(hTERT)expression in normal human gastric mucosal epithelial cells(nhGMECs)and fibroblasts(nhGMFs).METHODS:nhGMECs and nhGMFs were isola...AIM:To investigate telomerase activity and human telomerase reverse transcriptase(hTERT)expression in normal human gastric mucosal epithelial cells(nhGMECs)and fibroblasts(nhGMFs).METHODS:nhGMECs and nhGMFs were isolated and cultured from specimens obtained during routine surgery for bleeding peptic ulcer.Telomerase activity in nhGMFs,nhGMECs,and the tumor cell lines BGC-823,SGC-7901 and MKN-28 cells was analyzed using the telomeric repeat amplification protocol assay.hTERT protein was determined in nhGMECs,nhGMFs,BGC-823,SGC-7901 and MKN-28 cells by indirect immunofluorescence.served in nhGMECs,nhGMFs and BGC-823,SGC-7901,MKN-28 cell lines.Positive hTERT immunostaining was detected in nhGMECs,nhGMFs,BGC-823,SGC-7901and MKN-28 cell lines.CONCLUSION:The use of telomerase or hTERT as diagnostic markers for gastric cancer may require further studies.展开更多
AIM: To determine the mutation status of human telomerase reverse transcriptase gene(TERT) promoter region in hepatocellular carcinoma(HCC) from different geographical regions.METHODS: We analyzed the genomic DNA sequ...AIM: To determine the mutation status of human telomerase reverse transcriptase gene(TERT) promoter region in hepatocellular carcinoma(HCC) from different geographical regions.METHODS: We analyzed the genomic DNA sequences of 59 HCC samples comprising 15 cell lines and 44 primary tumors,collected from patients living in Asia,Europe and Africa.We amplified a 474 bp DNA fragment of the promoter region of TERT gene including the 1295228 and 1295250 sequence of chromosome 5 by using PCR.Amplicons were then sequenced by Sanger technique and the sequence data were analyzed with by using DNADynamo software in comparison with wild type TERT gene sequence as a reference.RESULTS: The TERT mutations were found highly frequent in HCC.Eight of the fifteen tested cell lines displayed C228 T mutation,and one had C250 T mutation with a mutation frequency up to 60%.All of the mutations were heterozygous and mutually exclusive.Ten out of forty-four tumors displayed C228 T mutation,and additional five tumors had C250 T mutation providing evidence for mutation frequency of 34% in primary tumors.Considering the geographic origins of HCC tumors tested,TERT promoter mutation frequencies were higher in African(53%),when compared to non-African(24%) tumors(P = 0.056).There was also a weak inverse correlation between TERT promoter mutations and murine double minute 2 single nucleotide polymorphism 309 TG polymorphism(P = 0.058).Mutation frequency was nearly two times higher in established HCC celllines(60%) compared to the primary tumors(34%).CONCLUSION: TERT promoter is one of most frequent mutational targets in liver cancer,and hepatocellular carcinogenesis is highly associated with the loss of telomere-dependent cellular senescence control.展开更多
Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep proce...Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.展开更多
This study investigated the effect of cadmium on the telomerase activity,the expression of TERT,c-myc and p53 and the apoptosis of rat hepatocytes.The rats were administrated 5,10 and 20 μmol/kg cadmium chloride intr...This study investigated the effect of cadmium on the telomerase activity,the expression of TERT,c-myc and p53 and the apoptosis of rat hepatocytes.The rats were administrated 5,10 and 20 μmol/kg cadmium chloride intraperitoneally and sacrificed 48 h after the initial treatment.The telomerase activity of the rat hepatocytes was measured by the telomeric repeat amplification protocol (TRAP),and apoptosis was detected by flow cytometry.The mRNA expressions of TERT,c-myc and p53 were measured by reverse transcription-polymerase chain reaction (RT-PCR).C-myc and P53 proteins were determined by immunochemistry.The results showed that cadmium chloride increased the hepatocellular telomerase activity in a dose-dependant manner and induced the apoptosis of hepatocytes significantly.The value of relative coefficient between the telomerase activity and the apoptosis rate was 0.9398.RT-PCR revealed that specific bands corresponding to the TERT mRNA,c-myc mRNA,and p53 mRNA were displayed at 185,342 and 538 bp respectively.Cadmium chloride could substantially increase the mRNA expressions of TERT,c-myc and p53 in rat hepatocytes,as compared with control.Moreover,cadmium chloride at the doses of 5,10 and 20 μmol/kg could increase the content of P53 protein in rat hepatocytes obviously,but only that at the doses of 10 and 20 μmol/kg substantially promoted the c-myc protein level in rat hepatocytes.Our study herein suggested that cadmium may contribute to the carcinogenesis by activating telomerase,and overexpressing the mRNAs of TERT,c-myc and p53,and causing apoptosis of normal cells.展开更多
BACKGROUND:Telomerase activity is reported to be specific and frequent in human pancreatic cancer.We conducted this study to assess the usefulness of monitoring telomerase activity in exfoliated cells obtained by panc...BACKGROUND:Telomerase activity is reported to be specific and frequent in human pancreatic cancer.We conducted this study to assess the usefulness of monitoring telomerase activity in exfoliated cells obtained by pancreatic duct brushing during endoscopic retrograde cholangiopancreatography(ERCP)for the diagnosis of pancreatic cancer. METHODS:Exfoliated cells obtained by pancreatic duct brushing during ERCP from 21 patients(18 with pancreatic cancer,3 with chronic pancreatitis) were examined.Telomerase activity was detected by polymerase chain reaction and telomeric repeat amplification protocol assay(PCR-TRAP-ELISA). RESULTS:D450 values of telomerase activity were 0.446± 0.2700 in pancreatic cancer and 0.041±0.0111 in chronic pancreatitis.77.8%(14/18)of patients with pancreatic cancer had cells with telomerase activity.None of the samples from patients with chronic pancreatitis showed telomerase activity,when the cutoff value of telomerase activity was set at 2.0.Cytological examination showed cancer cells in 66.7%(12/18)of the patients. CONCLUSIONS:Telomerase activity may be an early malignant event in pancreatic cancer development Cytology and telomerase activity in cells obtained bypancreatic duct brushing may complement each other for the diagnosis of pancreatic cancer.展开更多
Summary: The telomerse activity in condyloma acuminatum (CA) tissue with human papillomavirus (HPV) types of 6/11 and 16/18 was detected to investigate the function of telomerase in the occurrence, development and car...Summary: The telomerse activity in condyloma acuminatum (CA) tissue with human papillomavirus (HPV) types of 6/11 and 16/18 was detected to investigate the function of telomerase in the occurrence, development and carcinogenesis of genital CA. Forty-two biopsies from patients with gennital CA and 30 control tissue samples were tested for telomerase activity, HPV presence and types. The telomerase activity was determined by modified telomerase repeat amplification protocol (TRAP) assay and HPV typing by polymerase chain reaction (PCR) with typing-specific primers. Results showed that HPV-DNA was negative and the expression rate of telomerase was 16.7 % in all normal skin samples. All CA samples were positive for HPV (6/11 type was found in 32 cases, 16/18 in 3 and mixed type in 7). Telomerase activity was detectable in all CA patients. The telomerase activity in CA of 16/18 type was apparently higher than in CA of 6/11 type. It was concluded that the hyperplasia in CA might be increased as a result of HPV infection, suggesting that the activation of telomerase by HPV, especially by 16/18 type may play a role in the etiology and carcinogenesis of genital CA.展开更多
Objective: To evaluate whether arsenic trioxide (AS2O3) could downregulate human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity during induction of apoptosis of HL-60 cells. Methods: ...Objective: To evaluate whether arsenic trioxide (AS2O3) could downregulate human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity during induction of apoptosis of HL-60 cells. Methods: Apoptosis was detected by morphological observation and flow cytomertric cell cycle analysis. The expression of hTERT at mRNA and protein levels was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence using fluoresce isothiocyanate (FITC) label, respectively. Telomerase activity was determined by polymerase chain reaction enzyme-linked immunoassay (PCR-ELISA). Results: Treatment of 2 祄ol/L at As2O3 could induce apoptosis of HL-60 cells. hTERT was decreased at both mRNA and protein levels during apoptosis of HL-60 cells. Telomerase activity of HL-60 cells was significantly inhibited. Conclusion:It is suggested that telomerase activity of HL-60 cells might be specifically inhibited by AS2O3 through the downregulation of hTERT gene expression.展开更多
The effects of combined RNA interference(RNAi) of human telomerase RNA(hTR) and human telomerase reverse transcriptase(hTERT) genes on telomerase activity in a bladder cancer cell line(BIU-87 cells) were investigated ...The effects of combined RNA interference(RNAi) of human telomerase RNA(hTR) and human telomerase reverse transcriptase(hTERT) genes on telomerase activity in a bladder cancer cell line(BIU-87 cells) were investigated by using gene chip technology in vitro with an attempt to evaluate the role of RNAi in the gene therapy of bladder transitional cell cancer(BTCC).Three TR-specific double-stranded small interfering RNAs(siRNAs) and three TERT-specific double-stranded siRNAs were designed to target different regions of TR and TERT mRNA.The phTR-siRNA,phTERT-siRNA,and the combination of both plasmids phTR+phTERT-siRNA were transfected into BIU-87 cells.The expression of hTR and hTERT mRNA was detected by quantitative fluorescent reverse transcription-polymerase chain reaction,and a telomeric repeat amplification protocol was applied to detect telomerase activity.Growth inhibition of BIU-87 cells was measured by MTT assay.Gene chip analysis was performed to evaluate the effects of the combined RNAi of hTR+hTERT genes on telomerase activity and growth of BIU-87 cells in vitro.The results showed that the expression of hTERT and hTR mRNA was inhibited by pRNAT-hTERT-Ⅲ,pRNAT-hTR-Ⅲ,and pRNAT-hTR-Ⅲ+hTERT-Ⅲ in BIU-87 cells.The inhibition efficiency of pRNAT-hTERT-Ⅲ,pRNAT-hTR-Ⅲ,pRNAT-hTERT-Ⅲ+pRNAT-hTR-Ⅲ was 67% for TERT mRNA,41% for TR mRNA,57% for TR mRNA and 70% for TERT mRNA in BIU-87 cells respectively.The growth of BIU-87 cells was inhibited and telomerase activity was considerably decreased,especially in the cells treated with combined RNAi-hTR and-hTERT.Gene chip analysis revealed that 21 genes were down-regulated(ATM,BAX,BCL2,BCL2L1,BIRC5,CD44,CTNNB1,E2F1,JUN,MCAM,MTA1,MYC,NFKB1,NFKBIA,NME4,PNN,PNN,SERPINE1,THBS1,TNFRSF1A,and UCC1).The results indicated that hTR-siRNA and hTERT-siRNA,especially their combination,siRNA hTR+hTERT,specifically and effectively suppressed the expression of both hTR and hTERT mRNA and telomerase activity.Molecular biological mechanism by which combined siRNA-TR and-TERT inhibited telomerase activity and growth of BIU-87 cells in vitro may involve the down-regulation of the 21 genes.展开更多
Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were pres...Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2-5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.展开更多
Mixed gliomas, primarily oligoastrocytomas, account for about 5%-10% of all gliomas. Distinguishing oligoastrocytoma based on histological features alone has limitations in predicting the exact biological behavior, ne...Mixed gliomas, primarily oligoastrocytomas, account for about 5%-10% of all gliomas. Distinguishing oligoastrocytoma based on histological features alone has limitations in predicting the exact biological behavior, necessitating ancillary markers for greater specificity. In this case report, human telomerase reverse transcriptase(hT ERT) and high mobility group-A1(HMGA1); markers of proliferation and stemness, have been quantitatively analyzed in formalin-fixed paraffin-embedded tissue samples of a 34 years old patient with oligoastrocytoma. Customized florescence-based immunohistochemistry protocol with enhanced sensitivity and specificity is used in the study. The patient presented with a history of generalized seizures and his magnetic resonance imaging scans revealed infiltrative ill-defined mass lesion with calcified foci within the left frontal white matter, suggestive of glioma. He was surgically treated at our center for four consecutive clinical events. Histopathologically, the tumor was identified as oligoastrocytoma-grade Ⅱ followed by two recurrence events and final progression to grade Ⅲ. Overall survival of the patient without adjuvant therapy was more than 9 years. Glial fibrillary acidic protein, p53, Ki-67, nuclear atypia index, pre-operative neutrophillymphocyte ratio, are the other parameters assessed. Findings suggest that hT ERT and HMGA1 are linked to tumor recurrence and progression. Established markers can assist in defining precise histopathological grade in conjuction with conventional markers in clinical setup.展开更多
Most people associate the enzyme telomerase with its role in maintaining telomeres,which is its best-known canonical role.For this important function,two main components are required:the protein telomerase reve rse tr...Most people associate the enzyme telomerase with its role in maintaining telomeres,which is its best-known canonical role.For this important function,two main components are required:the protein telomerase reve rse transcriptase(TERT)and the telomerase RNA component.In addition,over the last decades,an ever-growing number of othe r,non-telomeric,non-canonical functions for the telomerase protein TERT has been established.These reach from tumor promotion to decreasing oxidative stress and apoptosis as well as activating autophagy.These functions are more and more recognized as being important in many tissues and physiological as well as pathological conditions.The role of telomerase in brain development and neuronal cells has been investigated for more than 20 years.However,the non-telomeric role in non-dividing neurons of the brain for telomerase and the TERT-protein has only recently been highlighted by extensive research.Moreover,these developments promoted the suggestion of a beneficial and protective role of TERT against neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.This review summarizes the most important findings in the field of telomerase in neuro ns and gives an outlook onto possible therapeutic applications of boosting telomerase/TERT levels with telomerase activators to prevent or ameliorate various neurodegene rative diseases.展开更多
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Te-lomerase is reactivated in various types of malignant tumors and may contribute to the development of HCC. To evalua...BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Te-lomerase is reactivated in various types of malignant tumors and may contribute to the development of HCC. To evaluate the role of telomerase in formation and development of HCC, we analyzed its expression status in different parts of HCC tissues and peripheral blood mono-nuclear cells (PBMCs) , and explored its clinical implications for diagnosis of HCC. METHODS: Total RNAs and telomerase were extracted from HCC and their non-cancerous tissues, and both relationships were analyzed between them. The expression of telomerase reverse transcriptase (hTERT) mRNA and telomerase activities in liver tissues and PBMCs were detected by RT-PCR and telomeric repeat amplification protocol (TRAP)-ELISA, respectively. The diagnostic values of telomerase in PBMCs were investigated in the diagnosis and differentiation of HCC. RESULTS: The specific activities of telomerase were 18.25 ±15.02 A/μg RNA in HCC tissues, and significantly higher than those in their non-cancerous tissues (8.16 ± 6.22 A/μg RNA, P 【0. 05). But total RNA levels in HCC were 12.40 ±7.34 μg/mg wet liver and lower than 53.77 ± 52.02 μg/mg wet liver in their non-cancerous parts (P 【 0.01). The different telomerase levels could be detected in PBMCs from patients with chronic liver diseases and control group. The enzyme activities were significantly higher in HCC than in any other groups (P 【0.01). However, circulating telomerase levels were more obviously decreased in HCC patients after transcatheter arterial embolization treatment than before the treatment (P 【0.01). The analysis of combined serum alpha-fetoprotein level and PBMCs telomerase was more sensitive and specific for the diagnosis of HCC. CONCLUSION: The abnormal expression of telomerase in HCC tissues and circulating PBMCs could be a useful marker to the diagnosis and prognosis of HCC.展开更多
Objective: To investigate the roles of telomerase activity (TA) in relation to hamster buccal pouch tumor progression. Methods: male hamster were treated three times weekly with 0.5% of 7, 12-dimethyl- benzanthracene ...Objective: To investigate the roles of telomerase activity (TA) in relation to hamster buccal pouch tumor progression. Methods: male hamster were treated three times weekly with 0.5% of 7, 12-dimethyl- benzanthracene (DMBA) over a 15 weeks experimental period. Hamsters were sacrificed at 3, 6, 9, 12 and 15 weeks after treatment. Telomerase activity of hamster buccal pouch tissue were measured along with the analyses of the formation of DMBA-induced hamster buccal pouch tumors. Results: DMBA-induced squamous cell carcinomas were found at the 6th week after dosing. Telomerase activity elevation began at the 3rd week and was increasing to a plateau at the 12th week. Conclusion: Our results show that telomerase activity in the target tissue may be detected at the early stage of the DMBA-induced hamster buccal pouch tumor formation and suggests that telomerase activity may be used as a biomarker for an early clinical detection of buccal pouch cancer.展开更多
Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint ...Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.展开更多
The pathogenesis of liver cirrhosis is not completely elucidated.Although in the majority of patients,the risk factors may be identified in B and C viral hepatitis,alcohol intake,drugs or fatty liver disease,there is ...The pathogenesis of liver cirrhosis is not completely elucidated.Although in the majority of patients,the risk factors may be identified in B and C viral hepatitis,alcohol intake,drugs or fatty liver disease,there is a small percentage of patients with no apparent risk factors.In addition,the evolution of chronic liver disease is highly heterogeneous from one patient to another.Among patient with identical risk factors,some rapidly progress to cirrhosis and hepatocellular carcinoma(HCC)whereas others have a benign course.Therefore,a genetic predisposition may contribute to the development of cirrhosis and HCC.Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years.In addition to the results from epidemiological studies,polymorphisms studies and data on twins,the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed.Here we review the literature on telomerase mutations,telomere shortening and liver disease including hepatocellular carcinoma.展开更多
基金the Beijing Hope Run Special Fund of Cancer Foundation of China,No.LC2020L05.
文摘BACKGROUND As a critical early event in hepatocellular carcinogenesis,telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma(HCC)patients,and its function in the genesis and treatment of HCC has gained much attention over the past two decades.AIM To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase.METHODS The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to“articles”and“reviews”published in English.A total of 873 relevant publications related to HCC and telomerase were identified.We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications,such as the trends in the publications,citation counts,most prolific or influential writers,and most popular journals;to screen for keywords occurring at high frequency;and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences.VOSviewer was utilized to compile and visualize the bibliometric data.RESULTS A surge of 51 publications on HCC/telomerase research occurred in 2016,the most productive year from 1996 to 2023,accompanied by the peak citation count recorded in 2016.Up to December 2023,35226 citations were made to all publications,an average of 46.6 citations to each paper.The United States received the most citations(n=13531),followed by China(n=7427)and Japan(n=5754).In terms of national cooperation,China presented the highest centrality,its strongest bonds being to the United States and Japan.Among the 20 academic institutions with the most publications,ten came from China and the rest of Asia,though the University of Paris Cité,Public Assistance-Hospitals of Paris,and the National Institute of Health and Medical Research(INSERM)were the most prolific.As for individual contributions,Hisatomi H,Kaneko S,and Ide T were the three most prolific authors.Kaneko S ranked first by H-index,G-index,and overall publication count,while Zucman-Rossi J ranked first in citation count.The five most popular journals were the World Journal of Gastroenterology,Hepatology,Journal of Hepatology,Oncotarget,and Oncogene,while Nature Genetics,Hepatology,and Nature Reviews Disease Primers had the most citations.We extracted 2293 keywords from the publications,120 of which appeared more than ten times.The most frequent were HCC,telomerase and human telomerase reverse transcriptase(hTERT).Keywords such as mutational landscape,TERT promoter mutations,landscape,risk,and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years.CONCLUSION Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.
基金supported by Handan City Technology Bureau Scientific Research Project(No 1023108101-8)
文摘Objective:To investigate the effect of vascular endothelial growth factor(VEGF),P53 and telomerase on angiogenesis in gastric carcinoma tissue.Methods:A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF,P53 and telomerase expression using immunohistochemical methods.Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed.Results:Microvascular density(MVD)and the expression of VEGF,P53 and telomerase were positively correlated.Expression of VEGF and P53 protein were related to tumor type and lymph metastasis,and also a correlation was observed between P53 and VEGF.The telomerase expression had no correlation with VEGF,and P53.Conclusions:VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis.Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF.Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53.
基金Supported by National Natural Science Foundation of China,No.30270609
文摘AIM:To investigate telomerase activity and human telomerase reverse transcriptase(hTERT)expression in normal human gastric mucosal epithelial cells(nhGMECs)and fibroblasts(nhGMFs).METHODS:nhGMECs and nhGMFs were isolated and cultured from specimens obtained during routine surgery for bleeding peptic ulcer.Telomerase activity in nhGMFs,nhGMECs,and the tumor cell lines BGC-823,SGC-7901 and MKN-28 cells was analyzed using the telomeric repeat amplification protocol assay.hTERT protein was determined in nhGMECs,nhGMFs,BGC-823,SGC-7901 and MKN-28 cells by indirect immunofluorescence.served in nhGMECs,nhGMFs and BGC-823,SGC-7901,MKN-28 cell lines.Positive hTERT immunostaining was detected in nhGMECs,nhGMFs,BGC-823,SGC-7901and MKN-28 cell lines.CONCLUSION:The use of telomerase or hTERT as diagnostic markers for gastric cancer may require further studies.
基金Supported by TUBITAK,the Scientific and Technological Research Council of Turkey,No.113S389TUBITAK(BIDEB-2211)+1 种基金TUBITAK(BIDEB-2211 and BIDEB-2214)EMBO short term fellowships
文摘AIM: To determine the mutation status of human telomerase reverse transcriptase gene(TERT) promoter region in hepatocellular carcinoma(HCC) from different geographical regions.METHODS: We analyzed the genomic DNA sequences of 59 HCC samples comprising 15 cell lines and 44 primary tumors,collected from patients living in Asia,Europe and Africa.We amplified a 474 bp DNA fragment of the promoter region of TERT gene including the 1295228 and 1295250 sequence of chromosome 5 by using PCR.Amplicons were then sequenced by Sanger technique and the sequence data were analyzed with by using DNADynamo software in comparison with wild type TERT gene sequence as a reference.RESULTS: The TERT mutations were found highly frequent in HCC.Eight of the fifteen tested cell lines displayed C228 T mutation,and one had C250 T mutation with a mutation frequency up to 60%.All of the mutations were heterozygous and mutually exclusive.Ten out of forty-four tumors displayed C228 T mutation,and additional five tumors had C250 T mutation providing evidence for mutation frequency of 34% in primary tumors.Considering the geographic origins of HCC tumors tested,TERT promoter mutation frequencies were higher in African(53%),when compared to non-African(24%) tumors(P = 0.056).There was also a weak inverse correlation between TERT promoter mutations and murine double minute 2 single nucleotide polymorphism 309 TG polymorphism(P = 0.058).Mutation frequency was nearly two times higher in established HCC celllines(60%) compared to the primary tumors(34%).CONCLUSION: TERT promoter is one of most frequent mutational targets in liver cancer,and hepatocellular carcinogenesis is highly associated with the loss of telomere-dependent cellular senescence control.
基金Supported by A grant from Cariparo,Project"Tumour mi-croenvironment and tumour spread in gastrointestinal cancers",2013/2014,No.6421 to Rampazzo E
文摘Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.
基金supported by the National Natural Sciences Foundation of China(No.30271110)Scientific Foundation(No.2006GGW01)Teacher's Foundation of Guangdong Pharmaceutical University,China
文摘This study investigated the effect of cadmium on the telomerase activity,the expression of TERT,c-myc and p53 and the apoptosis of rat hepatocytes.The rats were administrated 5,10 and 20 μmol/kg cadmium chloride intraperitoneally and sacrificed 48 h after the initial treatment.The telomerase activity of the rat hepatocytes was measured by the telomeric repeat amplification protocol (TRAP),and apoptosis was detected by flow cytometry.The mRNA expressions of TERT,c-myc and p53 were measured by reverse transcription-polymerase chain reaction (RT-PCR).C-myc and P53 proteins were determined by immunochemistry.The results showed that cadmium chloride increased the hepatocellular telomerase activity in a dose-dependant manner and induced the apoptosis of hepatocytes significantly.The value of relative coefficient between the telomerase activity and the apoptosis rate was 0.9398.RT-PCR revealed that specific bands corresponding to the TERT mRNA,c-myc mRNA,and p53 mRNA were displayed at 185,342 and 538 bp respectively.Cadmium chloride could substantially increase the mRNA expressions of TERT,c-myc and p53 in rat hepatocytes,as compared with control.Moreover,cadmium chloride at the doses of 5,10 and 20 μmol/kg could increase the content of P53 protein in rat hepatocytes obviously,but only that at the doses of 10 and 20 μmol/kg substantially promoted the c-myc protein level in rat hepatocytes.Our study herein suggested that cadmium may contribute to the carcinogenesis by activating telomerase,and overexpressing the mRNAs of TERT,c-myc and p53,and causing apoptosis of normal cells.
文摘BACKGROUND:Telomerase activity is reported to be specific and frequent in human pancreatic cancer.We conducted this study to assess the usefulness of monitoring telomerase activity in exfoliated cells obtained by pancreatic duct brushing during endoscopic retrograde cholangiopancreatography(ERCP)for the diagnosis of pancreatic cancer. METHODS:Exfoliated cells obtained by pancreatic duct brushing during ERCP from 21 patients(18 with pancreatic cancer,3 with chronic pancreatitis) were examined.Telomerase activity was detected by polymerase chain reaction and telomeric repeat amplification protocol assay(PCR-TRAP-ELISA). RESULTS:D450 values of telomerase activity were 0.446± 0.2700 in pancreatic cancer and 0.041±0.0111 in chronic pancreatitis.77.8%(14/18)of patients with pancreatic cancer had cells with telomerase activity.None of the samples from patients with chronic pancreatitis showed telomerase activity,when the cutoff value of telomerase activity was set at 2.0.Cytological examination showed cancer cells in 66.7%(12/18)of the patients. CONCLUSIONS:Telomerase activity may be an early malignant event in pancreatic cancer development Cytology and telomerase activity in cells obtained bypancreatic duct brushing may complement each other for the diagnosis of pancreatic cancer.
文摘Summary: The telomerse activity in condyloma acuminatum (CA) tissue with human papillomavirus (HPV) types of 6/11 and 16/18 was detected to investigate the function of telomerase in the occurrence, development and carcinogenesis of genital CA. Forty-two biopsies from patients with gennital CA and 30 control tissue samples were tested for telomerase activity, HPV presence and types. The telomerase activity was determined by modified telomerase repeat amplification protocol (TRAP) assay and HPV typing by polymerase chain reaction (PCR) with typing-specific primers. Results showed that HPV-DNA was negative and the expression rate of telomerase was 16.7 % in all normal skin samples. All CA samples were positive for HPV (6/11 type was found in 32 cases, 16/18 in 3 and mixed type in 7). Telomerase activity was detectable in all CA patients. The telomerase activity in CA of 16/18 type was apparently higher than in CA of 6/11 type. It was concluded that the hyperplasia in CA might be increased as a result of HPV infection, suggesting that the activation of telomerase by HPV, especially by 16/18 type may play a role in the etiology and carcinogenesis of genital CA.
基金This work was supported by the Guangdong Provincial Key Foundation of Science and Technology Program (99M01204G) and the Guangzhou City Key Foundation of Science and Technology Program (2001-Z-037-01).
文摘Objective: To evaluate whether arsenic trioxide (AS2O3) could downregulate human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity during induction of apoptosis of HL-60 cells. Methods: Apoptosis was detected by morphological observation and flow cytomertric cell cycle analysis. The expression of hTERT at mRNA and protein levels was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence using fluoresce isothiocyanate (FITC) label, respectively. Telomerase activity was determined by polymerase chain reaction enzyme-linked immunoassay (PCR-ELISA). Results: Treatment of 2 祄ol/L at As2O3 could induce apoptosis of HL-60 cells. hTERT was decreased at both mRNA and protein levels during apoptosis of HL-60 cells. Telomerase activity of HL-60 cells was significantly inhibited. Conclusion:It is suggested that telomerase activity of HL-60 cells might be specifically inhibited by AS2O3 through the downregulation of hTERT gene expression.
文摘The effects of combined RNA interference(RNAi) of human telomerase RNA(hTR) and human telomerase reverse transcriptase(hTERT) genes on telomerase activity in a bladder cancer cell line(BIU-87 cells) were investigated by using gene chip technology in vitro with an attempt to evaluate the role of RNAi in the gene therapy of bladder transitional cell cancer(BTCC).Three TR-specific double-stranded small interfering RNAs(siRNAs) and three TERT-specific double-stranded siRNAs were designed to target different regions of TR and TERT mRNA.The phTR-siRNA,phTERT-siRNA,and the combination of both plasmids phTR+phTERT-siRNA were transfected into BIU-87 cells.The expression of hTR and hTERT mRNA was detected by quantitative fluorescent reverse transcription-polymerase chain reaction,and a telomeric repeat amplification protocol was applied to detect telomerase activity.Growth inhibition of BIU-87 cells was measured by MTT assay.Gene chip analysis was performed to evaluate the effects of the combined RNAi of hTR+hTERT genes on telomerase activity and growth of BIU-87 cells in vitro.The results showed that the expression of hTERT and hTR mRNA was inhibited by pRNAT-hTERT-Ⅲ,pRNAT-hTR-Ⅲ,and pRNAT-hTR-Ⅲ+hTERT-Ⅲ in BIU-87 cells.The inhibition efficiency of pRNAT-hTERT-Ⅲ,pRNAT-hTR-Ⅲ,pRNAT-hTERT-Ⅲ+pRNAT-hTR-Ⅲ was 67% for TERT mRNA,41% for TR mRNA,57% for TR mRNA and 70% for TERT mRNA in BIU-87 cells respectively.The growth of BIU-87 cells was inhibited and telomerase activity was considerably decreased,especially in the cells treated with combined RNAi-hTR and-hTERT.Gene chip analysis revealed that 21 genes were down-regulated(ATM,BAX,BCL2,BCL2L1,BIRC5,CD44,CTNNB1,E2F1,JUN,MCAM,MTA1,MYC,NFKB1,NFKBIA,NME4,PNN,PNN,SERPINE1,THBS1,TNFRSF1A,and UCC1).The results indicated that hTR-siRNA and hTERT-siRNA,especially their combination,siRNA hTR+hTERT,specifically and effectively suppressed the expression of both hTR and hTERT mRNA and telomerase activity.Molecular biological mechanism by which combined siRNA-TR and-TERT inhibited telomerase activity and growth of BIU-87 cells in vitro may involve the down-regulation of the 21 genes.
文摘Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2-5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.
基金Supported by M.P.Biotech Council,M.P.for financial assistanceBMHRC for infrastructural facilities,No.249
文摘Mixed gliomas, primarily oligoastrocytomas, account for about 5%-10% of all gliomas. Distinguishing oligoastrocytoma based on histological features alone has limitations in predicting the exact biological behavior, necessitating ancillary markers for greater specificity. In this case report, human telomerase reverse transcriptase(hT ERT) and high mobility group-A1(HMGA1); markers of proliferation and stemness, have been quantitatively analyzed in formalin-fixed paraffin-embedded tissue samples of a 34 years old patient with oligoastrocytoma. Customized florescence-based immunohistochemistry protocol with enhanced sensitivity and specificity is used in the study. The patient presented with a history of generalized seizures and his magnetic resonance imaging scans revealed infiltrative ill-defined mass lesion with calcified foci within the left frontal white matter, suggestive of glioma. He was surgically treated at our center for four consecutive clinical events. Histopathologically, the tumor was identified as oligoastrocytoma-grade Ⅱ followed by two recurrence events and final progression to grade Ⅲ. Overall survival of the patient without adjuvant therapy was more than 9 years. Glial fibrillary acidic protein, p53, Ki-67, nuclear atypia index, pre-operative neutrophillymphocyte ratio, are the other parameters assessed. Findings suggest that hT ERT and HMGA1 are linked to tumor recurrence and progression. Established markers can assist in defining precise histopathological grade in conjuction with conventional markers in clinical setup.
文摘Most people associate the enzyme telomerase with its role in maintaining telomeres,which is its best-known canonical role.For this important function,two main components are required:the protein telomerase reve rse transcriptase(TERT)and the telomerase RNA component.In addition,over the last decades,an ever-growing number of othe r,non-telomeric,non-canonical functions for the telomerase protein TERT has been established.These reach from tumor promotion to decreasing oxidative stress and apoptosis as well as activating autophagy.These functions are more and more recognized as being important in many tissues and physiological as well as pathological conditions.The role of telomerase in brain development and neuronal cells has been investigated for more than 20 years.However,the non-telomeric role in non-dividing neurons of the brain for telomerase and the TERT-protein has only recently been highlighted by extensive research.Moreover,these developments promoted the suggestion of a beneficial and protective role of TERT against neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.This review summarizes the most important findings in the field of telomerase in neuro ns and gives an outlook onto possible therapeutic applications of boosting telomerase/TERT levels with telomerase activators to prevent or ameliorate various neurodegene rative diseases.
基金This study was supported in part by a grant from the Key Projects of Medical Sciences of Jiangsu Province, China (RC2003100).
文摘BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Te-lomerase is reactivated in various types of malignant tumors and may contribute to the development of HCC. To evaluate the role of telomerase in formation and development of HCC, we analyzed its expression status in different parts of HCC tissues and peripheral blood mono-nuclear cells (PBMCs) , and explored its clinical implications for diagnosis of HCC. METHODS: Total RNAs and telomerase were extracted from HCC and their non-cancerous tissues, and both relationships were analyzed between them. The expression of telomerase reverse transcriptase (hTERT) mRNA and telomerase activities in liver tissues and PBMCs were detected by RT-PCR and telomeric repeat amplification protocol (TRAP)-ELISA, respectively. The diagnostic values of telomerase in PBMCs were investigated in the diagnosis and differentiation of HCC. RESULTS: The specific activities of telomerase were 18.25 ±15.02 A/μg RNA in HCC tissues, and significantly higher than those in their non-cancerous tissues (8.16 ± 6.22 A/μg RNA, P 【0. 05). But total RNA levels in HCC were 12.40 ±7.34 μg/mg wet liver and lower than 53.77 ± 52.02 μg/mg wet liver in their non-cancerous parts (P 【 0.01). The different telomerase levels could be detected in PBMCs from patients with chronic liver diseases and control group. The enzyme activities were significantly higher in HCC than in any other groups (P 【0.01). However, circulating telomerase levels were more obviously decreased in HCC patients after transcatheter arterial embolization treatment than before the treatment (P 【0.01). The analysis of combined serum alpha-fetoprotein level and PBMCs telomerase was more sensitive and specific for the diagnosis of HCC. CONCLUSION: The abnormal expression of telomerase in HCC tissues and circulating PBMCs could be a useful marker to the diagnosis and prognosis of HCC.
文摘Objective: To investigate the roles of telomerase activity (TA) in relation to hamster buccal pouch tumor progression. Methods: male hamster were treated three times weekly with 0.5% of 7, 12-dimethyl- benzanthracene (DMBA) over a 15 weeks experimental period. Hamsters were sacrificed at 3, 6, 9, 12 and 15 weeks after treatment. Telomerase activity of hamster buccal pouch tissue were measured along with the analyses of the formation of DMBA-induced hamster buccal pouch tumors. Results: DMBA-induced squamous cell carcinomas were found at the 6th week after dosing. Telomerase activity elevation began at the 3rd week and was increasing to a plateau at the 12th week. Conclusion: Our results show that telomerase activity in the target tissue may be detected at the early stage of the DMBA-induced hamster buccal pouch tumor formation and suggests that telomerase activity may be used as a biomarker for an early clinical detection of buccal pouch cancer.
文摘Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.
文摘The pathogenesis of liver cirrhosis is not completely elucidated.Although in the majority of patients,the risk factors may be identified in B and C viral hepatitis,alcohol intake,drugs or fatty liver disease,there is a small percentage of patients with no apparent risk factors.In addition,the evolution of chronic liver disease is highly heterogeneous from one patient to another.Among patient with identical risk factors,some rapidly progress to cirrhosis and hepatocellular carcinoma(HCC)whereas others have a benign course.Therefore,a genetic predisposition may contribute to the development of cirrhosis and HCC.Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years.In addition to the results from epidemiological studies,polymorphisms studies and data on twins,the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed.Here we review the literature on telomerase mutations,telomere shortening and liver disease including hepatocellular carcinoma.
