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Boniewska-Bernacka E, Pańczyszyn A, Głąb G, Goc A. Telomere Length, Telomerase Activity, and Vaginal Microbiome in Patients with HPV-Related Precancerous Lesions. Int J Mol Sci 2024; 25:8158. [PMID: 39125728 PMCID: PMC11311766 DOI: 10.3390/ijms25158158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/18/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.
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Affiliation(s)
- Ewa Boniewska-Bernacka
- Department of Biology and Genetics, Institute of Medical Sciences, Faculty of Medicine, University of Opole, Oleska 48, 45-052 Opole, Poland; (A.P.); (A.G.)
| | - Anna Pańczyszyn
- Department of Biology and Genetics, Institute of Medical Sciences, Faculty of Medicine, University of Opole, Oleska 48, 45-052 Opole, Poland; (A.P.); (A.G.)
| | - Grzegorz Głąb
- Department of Pathomorphology, Institute of Medical Sciences, Faculty of Medicine, University of Opole, Oleska 48, 45-052 Opole, Poland;
| | - Anna Goc
- Department of Biology and Genetics, Institute of Medical Sciences, Faculty of Medicine, University of Opole, Oleska 48, 45-052 Opole, Poland; (A.P.); (A.G.)
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Pańczyszyn A, Boniewska-Bernacka E, Włodarczyk K, Wertel I, Goc A. Telomeres and telomerase in endometrial cancer and hyperplasia. Arch Med Sci 2024; 20:682-685. [PMID: 38757009 PMCID: PMC11094811 DOI: 10.5114/aoms/186189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/17/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction The study aimed to measure telomeres length (TL) and telomerase expression in normal endometrium and endometrial hyperplasia and cancer. Methods Total RNA and DNA were isolated from endometrium samples of 117 patients. The RT-PCR method was used to determine telomerase expression and relative telomere length. Results The control group had the longest telomeres in comparison to the hyperplasia and endometrial cancer groups. Only in the endometrial cancer group was telomerase expressed and positively correlated with telomere length. Conclusions Telomere extension in endometrial cancer is mediated by telomerase, but telomere length may not be an indicator of endometrioid cancer development.
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Affiliation(s)
- Anna Pańczyszyn
- Institute of Medical Sciences, Department of Biology and Genetics, Faculty of Medicine, University of Opole, Opole, Poland
| | - Ewa Boniewska-Bernacka
- Institute of Medical Sciences, Department of Biology and Genetics, Faculty of Medicine, University of Opole, Opole, Poland
| | - Karolina Włodarczyk
- Independent Laboratory of Cancer Diagnostics and Immunology, Medical University of Lublin, Lublin, Poland
| | - Iwona Wertel
- Independent Laboratory of Cancer Diagnostics and Immunology, Medical University of Lublin, Lublin, Poland
| | - Anna Goc
- Institute of Medical Sciences, Department of Biology and Genetics, Faculty of Medicine, University of Opole, Opole, Poland
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Wang C, Qin X, Guo W, Wang J, Liu L, Fang Z, Yuan H, Fan Y, Xu D. The chromosomal instability 25 gene signature is identified in clear cell renal cell carcinoma and serves as a predictor for survival and Sunitinib response. Front Oncol 2023; 13:1133902. [PMID: 37197417 PMCID: PMC10183591 DOI: 10.3389/fonc.2023.1133902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/21/2023] [Indexed: 05/19/2023] Open
Abstract
Background Chromosomal instability (CIN) is a cancer hallmark and it is difficult to directly measure its phenotype, while a CIN25 gene signature was established to do so in several cancer types. However, it is currently unclear whether there exists this signature in clear cell renal cell carcinoma (ccRCC), and if so, which biological and clinical implications it has. Methods Transcriptomic profiling was performed on 10 ccRCC tumors and matched renal non-tumorous tissues (NTs) for CIN25 signature analyses. TCGA and E-MBAT1980 ccRCC cohorts were analyzed for the presence of CIN25 signature, CIN25 score-based ccRCC classification, and association with molecular alterations and overall or progression-free survival (OS or PFS). IMmotion150 and 151 cohorts of ccRCC patients treated with Sunitinib were analyzed for the CIN25 impact on Sunitinib response and survival. Results The transcriptomic analysis of 10 patient samples showed robustly upregulated expression of the CIN25 signature genes in ccRCC tumors, which were further confirmed in TCGA and E-MBAT1980 ccRCC cohorts. Based on their expression heterogeneity, ccRCC tumors were categorized into CIN25-C1 (low) and C2 (high) subtypes. The CIN25-C2 subtype was associated with significantly shorter patient OS and PFS, and characterized by increased telomerase activity, proliferation, stemness and EMT. The CIN25 signature reflects not only a CIN phenotype, but also levels of the whole genomic instability including mutation burden, microsatellite instability and homologous recombination deficiency (HRD). Importantly, the CIN25 score was significantly associated with Sunitinib response and survival. In IMmotion151 cohort, patients in the CIN25-C1 group exhibited 2-fold higher remission rate than those in the CIN25-C2 group (P = 0.0004) and median PFS in these two groups was 11.2 and 5.6 months, respectively (P = 7.78E-08). Similar results were obtained from the IMmotion150 cohort analysis. Higher EZH2 expression and poor angiogenesis, well characterized factors leading to Sunitinib resistance, were enriched in the CIN25-C2 tumors. Conclusion The CIN25 signature identified in ccRCC serves as a biomarker for CIN and other genome instability phenotypes and predicts patient outcomes and response to Sunitinib treatment. A PCR quantification is enough for the CIN25-based ccRCC classification, which holds great promises in clinical routine application.
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Affiliation(s)
- Chang Wang
- Department of Emergency, The Second Hospital of Shandong University, Jinan, China
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, China
| | - Xin Qin
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, China
| | - Wei Guo
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, China
| | - Jing Wang
- Department of Urologic Oncology, Division of Life Sciences and Medicine, University of Science and Technology of China, The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, China
| | - Li Liu
- School of Nursing, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiqing Fang
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, China
| | - Huiyang Yuan
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, China
- *Correspondence: Huiyang Yuan, ; Yidong Fan, ; Dawei Xu,
| | - Yidong Fan
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, China
- *Correspondence: Huiyang Yuan, ; Yidong Fan, ; Dawei Xu,
| | - Dawei Xu
- Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden
- *Correspondence: Huiyang Yuan, ; Yidong Fan, ; Dawei Xu,
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Association of Relative Telomere Length and Risk of High Human Papillomavirus Load in Cervical Epithelial Cells. Balkan J Med Genet 2022; 24:65-70. [PMID: 36249518 PMCID: PMC9524175 DOI: 10.2478/bjmg-2021-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Importunate high-risk HPV (HR-HPV) infection is the most common trigger for the cervical carcinogenesis process. In this respect, the presence of cancer can be imputed to telomere lengthening or shortening. This paper explores the possible correlation between relative telomere length and viral load in two groups of women, namely: those with high-risk HPV infection and those who do not have this infection. Thus, samples comprising of 50 women in each group were evaluated for this research. The Amplisens HPV HCR screen-titre-FRT PCR kite was employed for quantitative analysis. Relative telomere length was quantified by real-time PCR. In each of the two HPV load groups, there was no correlation between age and telomere length. Telomere shortening was found in the cervical cell samples of women with high HPV loads, compared with women in the control group. Telomere shortening is associated with elevated HPV loads.
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Wen J, Wang Y, Yuan M, Huang Z, Zou Q, Pu Y, Zhao B, Cai Z. Role of mismatch repair in aging. Int J Biol Sci 2021; 17:3923-3935. [PMID: 34671209 PMCID: PMC8495402 DOI: 10.7150/ijbs.64953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/07/2021] [Indexed: 01/10/2023] Open
Abstract
A common feature of aging is the accumulation of genetic damage throughout life. DNA damage can lead to genomic instability. Many diseases associated with premature aging are a result of increased accumulation of DNA damage. In order to minimize these damages, organisms have evolved a complex network of DNA repair mechanisms, including mismatch repair (MMR). In this review, we detail the effects of MMR on genomic instability and its role in aging emphasizing on the association between MMR and the other hallmarks of aging, serving to drive or amplify these mechanisms. These hallmarks include telomere attrition, epigenetic alterations, mitochondrial dysfunction, altered nutrient sensing and cell senescence. The close relationship between MMR and these markers may provide prevention and treatment strategies, to reduce the incidence of age-related diseases and promote the healthy aging of human beings.
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Affiliation(s)
- Jie Wen
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China.,Department and Institute of Neurology, Guangdong Medical University, Guangdong, 524001, China.,Guangdong Key Laboratory of aging related cardio cerebral diseases, Guangdong, 524001, China
| | - Yangyang Wang
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China
| | - Minghao Yuan
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China
| | - Zhenting Huang
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China
| | - Qian Zou
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China
| | - Yinshuang Pu
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China
| | - Bin Zhao
- Department and Institute of Neurology, Guangdong Medical University, Guangdong, 524001, China.,Guangdong Key Laboratory of aging related cardio cerebral diseases, Guangdong, 524001, China
| | - Zhiyou Cai
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, China
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Yuan X, Dai M, Xu D. Telomere-related Markers for Cancer. Curr Top Med Chem 2020; 20:410-432. [PMID: 31903880 PMCID: PMC7475940 DOI: 10.2174/1568026620666200106145340] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/03/2019] [Accepted: 12/14/2019] [Indexed: 02/06/2023]
Abstract
Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomere-associated factors, and other telomere homeostasis-related signaling nodes. In the present review, these various strategies employed by malignant cells to regulate their telomere length, structure and function have been summarized, and potential implications of these findings in the rational development of telomere-based cancer therapy and other clinical applications for precision oncology have been discussed.
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Affiliation(s)
- Xiaotian Yuan
- Center for Reproductive Medicine, Shandong University, Jinan, 250012, China
| | - Mingkai Dai
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250033, China.,Karolinska Institute Collaborative Laboratory for Cancer and Stem Cell Research, Shandong University Second Hospital, Jinan, 250033, China
| | - Dawei Xu
- Karolinska Institute Collaborative Laboratory for Cancer and Stem Cell Research, Shandong University Second Hospital, Jinan, 250033, China.,Department of Medicine, Division of Hematology, Center for Molecular Medicine (CMM) and Bioclinicum, Karolinska Institute and Karolinska University Hospital Solna, Solna 171 64, Sweden
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Pańczyszyn A, Boniewska-Bernacka E, Głąb G. Telomere length in leukocytes and cervical smears of women with high-risk human papillomavirus (HR HPV) infection. Taiwan J Obstet Gynecol 2020; 59:51-55. [PMID: 32039800 DOI: 10.1016/j.tjog.2019.11.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2019] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Persistent high-risk HPV (HR HPV) infection leads to the development of squamous intraepithelial lesions, which in turn may progress to cervical cancer. Telomere elongation or shortening may indicate a carcinogenesis process. In the present study, we analyzed telomere length from blood and cervical smears of women without and with high-risk HPV infection. MATERIALS AND METHODS Telomere length was quantified by real-time PCR in blood and cervical smears from 48 women with high-risk HPV infection and HGSIL or LGSIL, 29 women HR-HPV positive without SIL, and 11 HPV-negative women. RESULTS No correlation was found between age and telomere length in blood and cervical smears. Women with high-risk HPV infection had shorter telomeres in cervical smears, but not in blood compared to the control group. CONCLUSION These findings suggest that telomere shortening occurs in cervical cells of women with HR HPV infection both with LGSIL and HGSIL and may indicate the onset of carcinogenesis. In turn, there is no correlation between leukocyte telomere length and cervical cancer risk in women with HR HPV infection.
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Affiliation(s)
| | | | - Grzegorz Głąb
- Public Higher Medical Professional School in Opole, Poland
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Yuan X, Liu T, Xu D. Telomerase reverse transcriptase promoter mutations in thyroid carcinomas: implications in precision oncology-a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1244. [PMID: 33178776 PMCID: PMC7607115 DOI: 10.21037/atm-20-5024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Telomerase is a ribonucleoprotein enzyme with telomerase reverse transcriptase (TERT) as a catalytic component. In normal human follicular thyroid cells or thyrocytes, telomerase is silent due to the TERT gene being tightly repressed. However, during the formation of thyroid carcinoma (TC), telomerase becomes activated via TERT induction. The TERT promoter’s gain-of-function mutation has recently been identified in TCs and many other malignancies. The mutation creates a de novo ETS-binding motif through which TERT transcription is de-repressed and telomerase is activated; through this, the mutant TERT promoter promotes the development of TC, contributes to disease aggressiveness and treatment resistance, and thereby leads to poor patient outcomes. From a clinical point of view, the strong association between the TERT promoter mutation and disease malignancy and aggressiveness holds great promise for its value in TC diagnostics, risk stratification, prognostication, treatment decision, and follow-up design. In the present review article, we summarize the recent findings of studies of TERT promoter mutations in TC and underscore the implications of TERT hyperactivity driven by genetic events in the pathogenesis and management of TC. Finally, the targeting of TERT promoter mutations and the disruption of telomere maintenance are considered as potential therapeutic strategies against TC.
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Affiliation(s)
- Xiaotian Yuan
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine (CMM), Karolinska Institutet and Karolinska University Hospital Solna, Solna, Sweden
| | - Tiantian Liu
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Dawei Xu
- Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine (CMM), Karolinska Institutet and Karolinska University Hospital Solna, Solna, Sweden.,Karolinska Institute-Shandong University Collaborative Laboratory for Cancer and Stem Cell Research, Jinan, China
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Shanta K, Nakayama K, Ishikawa M, Ishibashi T, Yamashita H, Sato S, Sasamori H, Sawada K, Kurose S, Mahmud HM, Razia S, Iida K, Ishikawa N, Kyo S. Prognostic Value of Peripheral Blood Lymphocyte Telomere Length in Gynecologic Malignant Tumors. Cancers (Basel) 2020; 12:cancers12061469. [PMID: 32512904 PMCID: PMC7352644 DOI: 10.3390/cancers12061469] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/22/2020] [Accepted: 06/02/2020] [Indexed: 01/22/2023] Open
Abstract
Background: Lymphocyte telomere length is strongly correlated with patient prognosis in several malignant tumor types and is thought to be related to tumor immunity. However, this correlation has not been studied in gynecological cancers. We determined the prognostic significance of peripheral blood lymphocyte telomere length in gynecologic cancers. Methods: Telomere length of lymphocytes from patients with gynecological malignant tumors (ovarian cancer (OC), N = 72; cervical cancer (CC), N = 63; endometrial cancer (EC), N = 87) was examined by quantitative reverse-transcription PCR of isolated mononuclear cells. Kaplan–Meier and Cox proportional hazard analyses were used to determine the association between lymphocyte telomere length and clinicopathological factors. Results: The overall survival (OS) and progression-free survival (PFS) of patients were based on the dichotomized lymphocyte telomere length using the median as a threshold (OC: 0.75, CC: 1.94, and EC: 1.09). A short telomere length was significantly correlated with residual tumors (≥1 cm) in OC and with advanced stage (III and IV) of CC. In OC and CC, patients with shorter relative lymphocyte telomere length (RLT) had significantly poorer OS and PFS than patients with longer RLT (p = 0.002, p = 0.003, and p = 0.001, p = 0.001, respectively). However, in EC, RLT was not significantly associated with OS or PFS (p = 0.567 and p = 0.304, log-rank test). Multivariate analysis showed that shorter RLT was a significant independent prognostic factor of PFS and OS for OC (p = 0.03 and p = 0.04, respectively) and CC (p = 0.02 and p = 0.03, respectively). Conclusions: Patients with OC and CC with shorter lymphocyte telomeres have significantly reduced survival; therefore, the peripheral blood lymphocyte telomere length is a prognostic biomarker in OC and CC.
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Affiliation(s)
- Kamrunnahar Shanta
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Kentaro Nakayama
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
- Correspondence:
| | - Masako Ishikawa
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Tomoka Ishibashi
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Hitomi Yamashita
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Seiya Sato
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Hiroki Sasamori
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Kiyoka Sawada
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Sonomi Kurose
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Hossain Mohammad Mahmud
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Sultana Razia
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Kouji Iida
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
| | - Noriyoshi Ishikawa
- Department of Organ Pathology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan;
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (K.S.); (M.I.); (T.I.); (H.Y.); (S.S.); (H.S.); (K.S.); (S.K.); (H.M.M.); (S.R.); (K.I.); (S.K.)
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DNA Hypermethylation Downregulates Telomerase Reverse Transcriptase (TERT) during H. pylori-Induced Chronic Inflammation. JOURNAL OF ONCOLOGY 2019; 2019:5415761. [PMID: 32082377 PMCID: PMC7012206 DOI: 10.1155/2019/5415761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 08/29/2019] [Accepted: 09/27/2019] [Indexed: 12/16/2022]
Abstract
Helicobacter pylori infection causes chronic gastritis and is the major risk factor of gastric cancer. H. pylori induces a chronic inflammation-producing reactive oxygen species (ROS) which is a source of chromosome instabilities and contributes to the development of malignancy. H. pylori also promotes DNA hypermethylation, known to dysregulate essential genes that maintain genetic stability. The maintenance of telomere length by telomerase is essential for chromosome integrity. Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase activity and an important target during host-pathogen interaction. We aimed to investigate the consequences of H. pylori on the regulation of TERT gene expression and telomerase activity. In vitro, hTERT mRNA levels and telomerase activity were analysed in H. pylori-infected human gastric epithelial cells. In addition, C57BL/6 and INS-GAS mice were used to investigate the influence of H. pylori-induced inflammation on TERT levels. Our data demonstrated that, in vitro, H. pylori inhibits TERT gene expression and decreases the telomerase activity. The exposure of cells to lycopene, an antioxidant compound, restores TERT levels in infected cells, indicating that ROS are implicated in this downregulation. In vivo, fewer TERT-positive cells are observed in gastric tissues of infected mice compared to uninfected, more predominantly in the vicinity of large aggregates of lymphocytes, suggesting an inflammation-mediated regulation. Furthermore, H. pylori appears to downregulate TERT gene expression through DNA hypermethylation as shown by the restoration of TERT transcript levels in cells treated with 5′-azacytidine, an inhibitor of DNA methylation. This was confirmed in infected mice, by PCR-methylation assay of the TERT gene promoter. Our data unraveled a novel way for H. pylori to promote genome instabilities through the inhibition of TERT levels and telomerase activity. This mechanism could play an important role in the early steps of gastric carcinogenesis.
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Pańczyszyn A, Boniewska-Bernacka E, Głąb G. Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis. Mol Diagn Ther 2018; 22:421-430. [PMID: 29777397 PMCID: PMC6061425 DOI: 10.1007/s40291-018-0336-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Human papillomaviruses (HPVs) belong to a small spherical virus family and are transmitted through direct contact, most often through sexual behavior. More than 200 types of HPV are known, a dozen or so of which are classified as high-risk viruses (HR HPV) and may contribute to the development of cervical cancer. HPV is a small virus with a capsid composed of L1 and L2 proteins, which are crucial for entry to the cell. The infection begins at the basal cell layer and progresses to involve cells from higher layers of the cervical epithelium. E6 and E7 viral proteins are involved in the process of carcinogenesis. They interact with suppressors of oncogenesis, including p53 and Rb proteins. This leads to DNA replication and intensive cell divisions. The persistent HR HPV infection leads to the development of dysplasia and these changes may progress to invasive cancer. During the initial stage of carcinogenesis, telomeres shorten until telomerase activates. The activation of telomerase, the enzyme necessary to extend chromosome ends (telomeres) is the key step in cell immortalization. Analyzing the expression level of hTERT and hTERC genes encoding telomerase and telomere length measurement may constitute new markers of the early carcinogenesis.
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Affiliation(s)
- Anna Pańczyszyn
- Department of Biotechnology and Molecular Biology, University of Opole, ul. Kominka 6, 45-035, Opole, Poland.
| | - Ewa Boniewska-Bernacka
- Department of Biotechnology and Molecular Biology, University of Opole, ul. Kominka 6, 45-035, Opole, Poland
| | - Grzegorz Głąb
- Public Higher Medical Professional School in Opole, Opole, Poland
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12
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Bellon M, Nicot C. Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection. Viruses 2017; 9:v9100289. [PMID: 28981470 PMCID: PMC5691640 DOI: 10.3390/v9100289] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 09/28/2017] [Accepted: 09/29/2017] [Indexed: 02/06/2023] Open
Abstract
The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein–Barr virus (EBV), Hepatitis B/C/D virus (HBV/HCV/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1/2 (HSV-1/2), and Varicella–Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.
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Affiliation(s)
- Marcia Bellon
- Department of Pathology, Center for Viral Pathogenesis, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| | - Christophe Nicot
- Department of Pathology, Center for Viral Pathogenesis, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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13
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Wang PH, Chen GD, Chang H, Yang SF, Han CP, Lin LY, Ko JL. High Expression of Human Telomerase Reverse Transcriptase in High-Grade Intraepithelial Neoplasia and Carcinoma of Uterine Cervix and Its Correlation With Human Papillomavirus Infection. Reprod Sci 2016; 14:338-48. [PMID: 17644806 DOI: 10.1177/1933719107303986] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Most of cervical intraepithelial neoplasia 1 (CIN 1) will regress and 12% to 40% of high-grade CIN may progress to squamous cell carcinoma (SCC) of the uterine cervix. However, the differentiation of CIN 1 and high-grade CIN is sometimes controversial among pathologists. Human telomerase reverse transcriptase (hTERT) is therefore applied to detect the differences among normal, CIN 1, high-grade CIN, and SCC tissues of uterine cervix. One hundred six cervical specimens were collected for immunohistochemical study of hTERT. These data were compared with the human papillomavirus (HPV) DNA status. Expression of hTERT in high-grade CIN increased significantly compared to that in CIN 1 ( P < .001). A positive relationship was found between high hTERT expression and degree of malignant transformation ( P < .001). Most of the cases with high hTERT expression tested positive for the high-risk HPV groups. High hTERT expression was detected in 88.73% of the samples with cervical high-grade CIN or SCC. Low hTERT expression was found in 94.29% of low-grade CIN or normal tissues. Furthermore, 96.92% of the cervical tissues with high hTERT expression were high-grade CIN or SCC. A total of 80.49% of samples with low hTERT expression were low-grade CIN or normal tissues. A significantly increased hTERT expression between CIN 1 and high-grade CIN exhibits a critical progression in cervical carcinogenesis. hTERT can be offered as additional molecular information correlated with more severe dysplasia and SCC. Furthermore, this increased hTERT expression is correlated whigh-risk HPVs infection.
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Affiliation(s)
- Po-Hui Wang
- Department of Obstetrics and Gynecology, Chung Shan Medical University Taichung, Taiwan
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14
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Aghagolzadeh P, Radpour R. New trends in molecular and cellular biomarker discovery for colorectal cancer. World J Gastroenterol 2016; 22:5678-5693. [PMID: 27433083 PMCID: PMC4932205 DOI: 10.3748/wjg.v22.i25.5678] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/16/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, which is consequence of multistep tumorigenesis of several genetic and epigenetic events. Since CRC is mostly asymptomatic until it progresses to advanced stages, the early detection using effective screening approaches, selection of appropriate therapeutic strategies and efficient follow-up programs are essential to reduce CRC mortalities. Biomarker discovery for CRC based on the personalized genotype and clinical information could facilitate the classification of patients with certain types and stages of cancer to tailor preventive and therapeutic approaches. These cancer-related biomarkers should be highly sensitive and specific in a wide range of specimen(s) (including tumor tissues, patients’ fluids or stool). Reliable biomarkers which enable the early detection of CRC, can improve early diagnosis, prognosis, treatment response prediction, and recurrence risk. Advances in our understanding of the natural history of CRC have led to the development of different CRC associated molecular and cellular biomarkers. This review highlights the new trends and approaches in CRC biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches and follow-up of patients.
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15
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Sano D, Oridate N. The molecular mechanism of human papillomavirus-induced carcinogenesis in head and neck squamous cell carcinoma. Int J Clin Oncol 2016; 21:819-826. [DOI: 10.1007/s10147-016-1005-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Accepted: 06/12/2016] [Indexed: 11/29/2022]
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16
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Modulation of DNA damage and repair pathways by human tumour viruses. Viruses 2015; 7:2542-91. [PMID: 26008701 PMCID: PMC4452920 DOI: 10.3390/v7052542] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023] Open
Abstract
With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved in the development of specific malignancies. It has long been known that the introduction of chromosomal aberrations is a common feature of viral infections. Intensive research over the past two decades has subsequently revealed that viruses specifically interact with cellular mechanisms responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). These interactions can involve activation and deactivation of individual DDR pathways as well as the recruitment of specific proteins to sites of viral replication. Since the DDR has evolved to protect the genome from the accumulation of deleterious mutations, deregulation is inevitably associated with an increased risk of tumour formation. This review summarises the current literature regarding the complex relationship between known human tumour viruses and the DDR and aims to shed light on how these interactions can contribute to genomic instability and ultimately the development of human cancers.
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Wang N, Liu T, Sofiadis A, Juhlin CC, Zedenius J, Höög A, Larsson C, Xu D. TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA. Cancer 2014; 120:2965-79. [PMID: 24898513 DOI: 10.1002/cncr.28800] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 03/31/2014] [Accepted: 04/03/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis. METHODS The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit. RESULTS The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival. CONCLUSIONS TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup.
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Affiliation(s)
- Na Wang
- Department of Oncology-Pathology and Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
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18
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Haghighi MM, Aghagolzadeh P, Zadeh SM, Molaei M, Zali MR, Radpour R. Telomere shortening: a biological marker of sporadic colorectal cancer with normal expression of p53 and mismatch repair proteins. Genet Test Mol Biomarkers 2014; 18:236-44. [PMID: 24495131 DOI: 10.1089/gtmb.2013.0436] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Uncontrolled growth of cells, a main criterion of cancer, is merged with pathologic telomere length alteration. Thereby, measurement of telomere length could provide important information on cell proliferation and senescence in cancer tissues. Telomere shortening and its potential correlation with clinicopathological predictive markers in sporadic colorectal cancer (CRC) with normal expression of mismatch repair (MMR) proteins (including Mlh1, Msh2, Pms2, and Msh6) and normal p53 expression was completely explored. Relative telomere length (RTL) was quantitatively measured in a cohort of 164 samples (68 patients with sporadic CRC and 96 healthy unrelated controls). Our results demonstrated a significant shortening of RTL in the tumor-derived tissue of patients compared with the control group (p<0.001). Interestingly, significant telomere shortening was observed in tumors from an ascending and sigmoid colon in comparison with tumors located in a descending colon. Additionally, the telomere length was significantly shorter in those with lymph node metastasis (p<0.05). The results suggest that pathological telomere shortening, leading to genome instability and lymphatic transformation, could serve as a potential sensitive detection and also as a classification marker for facilitating diagnosis and management of CRC.
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Affiliation(s)
- Mahdi Montazer Haghighi
- 1 Department of Biology, Science Faculty, Islamic Azad University , East Tehran Branch, Tehran, Iran
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19
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Chen X, Kamranvar SA, Masucci MG. Tumor viruses and replicative immortality--avoiding the telomere hurdle. Semin Cancer Biol 2014; 26:43-51. [PMID: 24486644 DOI: 10.1016/j.semcancer.2014.01.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 01/16/2014] [Indexed: 12/26/2022]
Abstract
Tumor viruses promote cell proliferation in order to gain access to an environment suitable for persistence and replication. The expression of viral products that promote growth transformation is often accompanied by the induction of multiple signs of telomere dysfunction, including telomere shortening, damage of telomeric DNA and chromosome instability. Long-term survival and progression to full malignancy require the bypassing of senescence programs that are triggered by the damaged telomeres. Here we review different strategies by which tumor viruses interfere with telomere homeostasis during cell transformation. This frequently involves the activation of telomerase, which assures both the integrity and functionality of telomeres. In addition, recent evidence suggests that oncogenic viruses may activate a recombination-based mechanism for telomere elongation known as Alternative Lengthening of Telomeres (ALT). This error-prone strategy promotes genomic instability and could play an important role in viral oncogenesis.
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Affiliation(s)
- Xinsong Chen
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | | | - Maria G Masucci
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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20
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Zhang W, Tian Y, Chen JJ, Zhao W, Yu X. A postulated role of p130 in telomere maintenance by human papillomavirus oncoprotein E7. Med Hypotheses 2012; 79:178-80. [PMID: 22595804 DOI: 10.1016/j.mehy.2012.04.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 04/18/2012] [Accepted: 04/18/2012] [Indexed: 11/28/2022]
Abstract
High-risk human papillomaviruses (HR-HPVs) infections is highly associated with the development of cervical cancer. It is now recognized that telomere length maintenance or extension is indispensable for carcinogenesis. The early oncoproteins E6 and E7 are the main malignant transformation factors of HR-HPVs and they maintain telomeres by different mechanisms, of which E6 protein activating telomerase is well documented. Reports showed that E7 protein utilized an alternative lengthen of telomere (ALT) mechanism to restore telomere length, yet the underlying molecular basis remains largely unknown. We propose that degradation of tumor suppressor pRb family member p130 plays an essential role in E7-regulated telomere extension by ALT. ALT is a mechanism based on homologous recombination (HR) between telomere sister chromatids, and a number of proteins involved in the HR pathway, such as MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex are required for the ALT pathway. Rb family member p130 could inhibit ALT by interacting with Rad50, while HPV E7 could activate ALT by degrading p130. We will make E7 mutants which are defective in p130 degradation to test whether these cells have a limited life span. Besides, immunofluorescence assay will show an ALT-related promyelocytic leukemia (PML) body (APBs) in E7-expressing cells. Although cervical cancer usually has high telomerase activities since the expressing of HPV E6, the anti-telomerase therapy will be unavailable for cervical cancer since it may activate E7-induced ALT. Our hypothesis not only enrich the knowledge of the regulation of ALT, but also indicate that p130 may serve as a potential suppressor of ALT, and gene therapy of p130 may be used in cervical cancers.
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Affiliation(s)
- WeiFang Zhang
- Department of Pathogenic Microbiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
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21
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A protein array screen for Kaposi's sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening. J Virol 2012; 86:5179-91. [PMID: 22379092 DOI: 10.1128/jvi.00169-12] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. To identify novel LANA protein-cell protein interactions that could contribute to these activities, we performed a proteomic screen in which purified, adenovirus-expressed Flag-LANA protein was incubated with an array displaying 4,192 nonredundant human proteins. Sixty-one interacting cell proteins were consistently detected. LANA interactions with high-mobility group AT-hook 1 (HMGA1), HMGB1, telomeric repeat binding factor 1 (TRF1), xeroderma pigmentosum complementation group A (XPA), pygopus homolog 2 (PYGO2), protein phosphatase 2A (PP2A)B subunit, Tat-interactive protein 60 (TIP60), replication protein A1 (RPA1), and RPA2 proteins were confirmed in coimmunoprecipitation assays. LANA-associated TIP60 retained acetyltransferase activity and, unlike human papillomavirus E6 and HIV-1 TAT proteins, LANA did not reduce TIP60 stability. The LANA-bound PP2A B subunit was associated with the PP2A A subunit but not the catalytic C subunit, suggesting a disruption of PP2A phosphatase activity. This is reminiscent of the role of simian virus 40 (SV40) small t antigen. Chromatin immunoprecipitation (ChIP) assays showed binding of RPA1 and RPA2 to the KSHV terminal repeats. Interestingly, LANA expression ablated RPA1 and RPA2 binding to the cell telomeric repeats. In U2OS cells that rely on the alternative mechanism for telomere maintenance, LANA expression had minimal effect on telomere length. However, LANA expression in telomerase immortalized endothelial cells resulted in telomere shortening. In KSHV-infected cells, telomere shortening may be one more mechanism by which LANA contributes to the development of malignancy.
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22
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Liu L, Liu C, Lou F, Zhang G, Wang X, Fan Y, Yan K, Wang K, Xu Z, Hu S, Björkholm M, Xu D. Activation of telomerase by seminal plasma in malignant and normal cervical epithelial cells. J Pathol 2011; 225:203-11. [PMID: 21590772 DOI: 10.1002/path.2914] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2011] [Revised: 03/01/2011] [Accepted: 11/15/2010] [Indexed: 01/11/2023]
Abstract
Seminal fluids are involved in the development of cervical cancer but the underlying mechanism is unclear. Because cellular transformation requires telomerase activation by expression of the telomerase reverse transcriptase (hTERT) gene, we examined the role of seminal fluids in telomerase activation. Significantly elevated hTERT mRNA and telomerase activity were observed in cervical cell lines (HeLa, SiHa and Caski) treated with seminal plasma. Normal cervical epithelial cells expressed minimal levels of hTERT mRNA and telomerase activity, and seminal plasma substantially enhanced both expression and activity. The hTERT promoter activity was similarly increased in seminal plasma-treated HeLa cells and this effect was closely correlated with increased Sp1 expression and binding to the hTERT promoter. Cyclooxygenase-2 (COX-2) was simultaneously increased in HeLa cells exposed to seminal plasma, and blockade of COX-2 induction abolished seminal plasma stimulation of the hTERT promoter activity, hTERT expression and telomerase activity. Prostaglandin E2 (PGE2) mimics the effect of seminal plasma, stimulating Sp1 expression, enhancing Sp1 occupancy on the hTERT promoter and promoter activity. Moreover, tumour growth was robustly enhanced when HeLa cells together with seminal plasma were injected into nude-mice. Taken together, seminal plasma stimulates COX-2-PGE2-Sp1-dependent hTERT transcription, which provides insights into the putative mechanism underlying telomerase activation in cervical epithelial and cancer cells.
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Affiliation(s)
- Li Liu
- Ageing and Health Centre, Nursing School, Shandong University, Jinan, People's Republic of China
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Abstract
An association between human papillomavirus (HPV) infection and the development of cervical cancer was initially reported over 30 years ago, and today there is overwhelming evidence that certain subtypes of HPV are the causative agents of these malignancies. The p53 and retinoblastoma proteins are well-characterized targets of the HPV E6 and E7 oncoproteins, but recent studies have shown that the alteration of additional pathways are equally important for transformation. These additional factors are crucial regulators of cell cycle progression, telomere maintenance, apoptosis and chromosomal stability. Understanding how HPV oncoproteins modify these activities provides novel insights into the basic mechanisms of oncogenesis.
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Affiliation(s)
- Cary A Moody
- Department of MicrobiologyImmunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
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Correlation of telomere length shortening with promoter methylation profile of p16/Rb and p53/p21 pathways in breast cancer. Mod Pathol 2010; 23:763-72. [PMID: 20081803 DOI: 10.1038/modpathol.2009.195] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Unregulated cell growth, a major hallmark of cancer, is coupled with telomere shortening. Measurement of telomere length could provide important information on cell replication and proliferation state in cancer tissues. Telomere shortening and its potential correlation with downregulation of cell-cycle regulatory elements were studied by the examination of relative telomere length and methylation status of the TP53, P21 and P16 promoters in tissues from breast cancer patients. Telomere length was measured in 104 samples (52 tumors and paired adjacent normal breast tissues) by quantitative PCR. Methylation profile of selected genes was analyzed in all samples using a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Our results demonstrated a significant shortening of tumor telomere regions compared with paired adjacent normal tissues (P<0.001). Similarly, telomere lengths were significantly shorter in advanced stage cases and in those with higher histological grades (P<0.05). Telomere shortening in cancer tissues was correlated with a different level of hypermethylation in the TP53, P21 and P16 promoters (r=-0.33, P=0.001; r=-0.70, P<0.0001 and r=-0.71, P<0.0001, respectively). The results suggested that inactivation of p16/Rb and/or p53/p21 pathways by hypermethylation may be linked to critical telomere shortening, leading to genome instability and ultimately to malignant transformation. Thus, telomere shortening and promoter hypermethylation of related genes both might serve as breast cancer biomarkers.
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25
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Xing J, Ajani JA, Chen M, Izzo J, Lin J, Chen Z, Gu J, Wu X. Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p is associated with an increased risk for esophageal cancer. Cancer Prev Res (Phila) 2009; 2:459-65. [PMID: 19401529 PMCID: PMC2701666 DOI: 10.1158/1940-6207.capr-08-0227] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Shortened telomere length may cause chromosomal instability in Barrett's esophagus and thus promote tumorigenesis. However, whether short telomere length in all chromosomes or just some of them is associated with increased esophageal cancer (EC) risk is largely unknown. To address this question, we examined the overall and chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q and assessed their associations with EC risk. In a case-control study with 94 EC cases and 94 matched controls, the overall telomere length and the chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q in peripheral blood lymphocytes were determined by a real-time PCR and a modified single telomere length analysis assay, respectively. Multivariate logistic regression analysis was used to assess the association between telomere length and EC risk. Compared with controls, EC patients had significantly shorter overall telomere lengths (P = 0.004) and chromosome-specific telomere lengths of 17p (P = 0.003) and 12q (P = 0.006) but not of 11q (P = 0.632) and 2p (P = 0.972). Furthermore, the multivariate logistic regression analysis showed that the short overall telomere length and chromosome-specific telomere lengths of 17p and 12q were associated with a dose-dependent increase in EC risk. Our study provides the first epidemiologic evidence that short telomere length of 17p and 12q plays an important role in esophageal carcinogenesis, suggesting that short telomere length of specific chromosomes is associated with the etiology of different cancer types.
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Affiliation(s)
- Jinliang Xing
- Department of Epidemiology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Jaffer A. Ajani
- Department of GI Medical Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Meng Chen
- Department of Epidemiology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Julie Izzo
- Department of Experimental Therapeutics, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Jie Lin
- Department of Epidemiology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhinan Chen
- Cell Engineering Research Center, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, P.R. China
| | - Jian Gu
- Department of Epidemiology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Xifeng Wu
- Department of Epidemiology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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26
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Tu Z, Zhang A, Wu R, Jiang J, Li Y, Wulan N, Li J, Zhang Y, Li Y, Chen Z, Wei L. Genomic amplification of the human telomerase RNA gene for differential diagnosis of cervical disorders. CANCER GENETICS AND CYTOGENETICS 2009; 191:10-16. [PMID: 19389503 DOI: 10.1016/j.cancergencyto.2009.01.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2008] [Revised: 01/02/2009] [Accepted: 01/05/2009] [Indexed: 12/30/2022]
Abstract
To evaluate genomic amplification of the human telomerase RNA gene (TERC) as a supportive approach to cytopathology or histopathology in diagnosis of low-grade and high-grade uterine cervical lesions, 1,033 Chinese women at three medical centers had liquid-based thin-layer cytopathologic examination and TERC detection by fluorescence in situ hybridization (FISH). Human papillomavirus DNA testing, colposcopy with or without biopsy, and histopathologic examination were conducted as needed. In cytopathologic examination, genomic amplification of TERC was found in 30 of 659 (4.6%) normal or benign cellular changes; in 23 of 170 (13.5%) atypical squamous cells of undetermined significance (ASCUS); in 8 of 28 (28.6%) atypical squamous cells with high-grade squamous intraepithelial lesion possible (ASC-H); and in 26 of 103 (25.2%) low-grade (LSIL) and 64 of 73 (87.7%) high-grade (HSIL) squamous intraepithelial lesions; with pairwise significant difference (P< 0.05) in each, except ASC-H and LSIL (chi(2) = 0.127, P = 0.72). In histopathologic examination, TERC was amplified in 28 of 671 (4.2%) normal, inflammatory, or wart cases; in 17 of 233 (7.3%) cervical intraepithelial neoplasia grade 1 cases (CIN 1); in 27 of 39 (69.2%) CIN 2 cases; in 57 of 67 (85.1%) CIN 3 cases; and in 22 of 23 (95.7%) cervical cancer cases; with pairwise significant difference in each (P < 0.05). The number of cells with abnormal signals increased and the abnormal signal patterns were diversified with increasing severity of cervical dysplasia. FISH detection of TERC amplification may provide an effective, noninvasive approach in conjunction with cytopathologic or histopathologic evaluation for differential diagnosis of low- and high-grade cervical disorders.
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Affiliation(s)
- Zheng Tu
- Department of Gynecology, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing 100044, China
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27
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Spardy N, Duensing A, Hoskins EE, Wells SI, Duensing S. HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies. Cancer Res 2009; 68:9954-63. [PMID: 19047177 DOI: 10.1158/0008-5472.can-08-0224] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Expression of the high-risk human papillomavirus (HPV-16) E7 oncoprotein extends the life span of primary human keratinocytes and partially restores telomere length in the absence of telomerase. The molecular basis of this activity is incompletely understood. Here, we show that HPV-16 E7 induces an increased formation of alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies (APBs) in early passage primary human keratinocytes as well as HPV-negative tumor cells. This activity was found to require sequences of HPV-16 E7 involved in degradation of the retinoblastoma tumor suppressor protein as well as regions in the COOH terminus. HPV-16 E7-induced APBs contained ssDNA and several proteins that are involved in the response to DNA replication stress, most notably the Fanconi anemia D2 protein (FANCD2) as well as BRCA2 and MUS81. In line with these results, we found that FANCD2-containing APBs form in an ATR-dependent manner in HPV-16 E7-expressing cells. To directly show a role of FANCD2 in ALT, we provide evidence that knockdown of FANCD2 rapidly causes telomere dysfunction in cells that rely on ALT to maintain telomeres. Taken together, our results suggest a novel link between replication stress and recombination-based telomere maintenance that may play a role in HPV-16 E7-mediated extension of host cell life span and immortalization.
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Affiliation(s)
- Nicole Spardy
- Biochemistry and Molecular Genetics Graduate Program, and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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28
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Deng W, Tsao SW, Kwok YK, Wong E, Huang XR, Liu S, Tsang CM, Ngan HYS, Cheung ANY, Lan HY, Guan XY, Cheung ALM. Transforming growth factor beta1 promotes chromosomal instability in human papillomavirus 16 E6E7-infected cervical epithelial cells. Cancer Res 2008; 68:7200-9. [PMID: 18757436 DOI: 10.1158/0008-5472.can-07-6569] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Uterine cervical cancer, the second most frequently occurring cancer in women worldwide, is tightly associated with the expression of high-risk human papillomavirus [mainly human papillomavirus (HPV)-16 and HPV18] oncogenes E6 and E7 and characteristically exhibits chromosomal instability. However, the mechanisms underlying chromosomal instability in cervical cancer are still not fully understood. In this study, we observed that two of three human cervical epithelial cell lines expressing HPV16 E6E7 became immortalized without extensive chromosomal instability and crisis. The introduction of transforming growth factor (TGF)-beta1, a multiple functional cytokine/growth factor, in the culture medium induced crisis, which was associated with massive chromosomal end-to-end fusions and other structural aberrations. The distributions of structural aberrations on individual chromosomes were significantly correlated with the profiles of telomere signal-free ends. The immortalized cells that emerged from the TGF-beta1-induced crisis showed multiple clonal structural aberrations that were not observed in cells without TGF-beta1 treatment. Overexpression of the catalytic subunit of telomerase (hTERT) abolished the effects of TGF-beta1 on chromosomal instability. Interestingly, another HPV16 E6E7-expressing cervical cell line that experienced crisis and telomere dysfunction under ordinary culture condition had a higher level of autocrine TGF-beta1 production than the other two crisis-free immortalized cell lines. Blocking the TGF-beta1 pathway by an inhibitor of TGF-beta1 receptor type I prevented the crisis and telomere-mediated chromosomal instability. In addition, more dramatic telomere shortening was observed in cervical intraepithelial neoplasias having higher expression of TGF-beta1 in vivo. These results together suggest an important role of TGF-beta1 in the early process of cervical carcinogenesis.
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Affiliation(s)
- Wen Deng
- Department of Anatomy, The University of Hong Kong, Hong Kong, SAR, China
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29
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Bellon M, Nicot C. Regulation of telomerase and telomeres: human tumor viruses take control. J Natl Cancer Inst 2008; 100:98-108. [PMID: 18182620 DOI: 10.1093/jnci/djm269] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Human tumor viruses are responsible for one-fifth of all cancers worldwide. These viruses have evolved multiple strategies to evade immune defenses and to persist in the host by establishing a latent infection. Proliferation is necessary for pretumor cells to accumulate genetic alterations and to acquire a transformed phenotype. However, each cell division is associated with a progressive shortening of the telomeres, which can suppress tumor development by initiating senescence and irreversible cell cycle arrest. Therefore, the ability of virus-infected cells to circumvent the senescence program is essential for the long-term survival and proliferation of infected cells and the likelihood of transformation. We review the multiple strategies used by human DNA and RNA tumor viruses to subvert telomerase functions during cellular transformation and carcinogenesis. Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus, human papillomavirus, hepatitis B virus, hepatitis C virus, and human T-cell leukemia virus-1 each can increase transcription of the telomerase reverse transcriptase. Several viruses appear to mediate cis-activation or enhance epigenetic activation of telomerase transcription. Epstein-Barr virus and human papillomavirus have each developed posttranscriptional mechanisms to regulate the telomerase protein. Finally, some tumor virus proteins can also negatively regulate telomerase transcription or activity. It is likely that, as future studies further expose the strategies used by viruses to deregulate telomerase activity and control of telomere length, novel mechanisms will emerge and underscore the importance of increased telomerase activity in sustaining virus-infected cells and its potential in therapeutic targeting.
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Affiliation(s)
- Marcia Bellon
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, 3025 Wahl Hall West, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
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30
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Gabet AS, Accardi R, Bellopede A, Popp S, Boukamp P, Sylla BS, Londoño-Vallejo JA, Tommasino M. Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38. FASEB J 2007; 22:622-32. [PMID: 17898088 DOI: 10.1096/fj.07-8389com] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The skin human papillomavirus (HPV) types belonging to the genus beta of the HPV phylogenetic tree appear to be associated with nonmelanoma skin cancer. We previously showed that the beta HPV type 38 E6 and E7 oncoproteins are able to inactivate the tumor suppressors p53 and retinoblastoma. Here, both viral proteins were expressed in primary human skin keratinocytes in order to study their effects on the telomere/telomerase system. We show that immortalization of skin keratinocytes induced by HPV38 E6/E7 is associated with hTERT gene overexpression. This event is, in part, explained by the accumulation of the p53-related protein, DeltaNp73. Despite elevated levels of hTERT mRNA, the telomerase activity detected in HPV38 E6/E7 keratinocytes was lower than that observed in HPV16 E6/E7 keratinocytes. The low telomerase activation in highly proliferative HPV38 E6/E7 keratinocytes resulted in the presence of extremely short and unstable telomeres. In addition, we observed anaphase bridges, mitotic multipolarity, and dramatic genomic aberrations. Interestingly, the ectopic expression of hTERT prevents both telomere erosion and genomic instability. Thus, we showed that in HPV38 E6/E7 keratinocytes characterized by unscheduled proliferation, suboptimal activation of telomerase and subsequent extensive telomere shortening result in genomic instability facilitating cellular immortalization.
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Affiliation(s)
- Anne-Sophie Gabet
- Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, 69372 Lyon, France
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31
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Tresnasari K, Takakuwa T, Ham MF, Rahadiani N, Nakajima H, Aozasa K. Telomere dysfunction and inactivation of the p16(INK4a)/Rb pathway in pyothorax-associated lymphoma. Cancer Sci 2007; 98:978-84. [PMID: 17428253 PMCID: PMC11158100 DOI: 10.1111/j.1349-7006.2007.00482.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Previous studies have indicated that genome instability is involved in the lymphomagenesis of pyothorax-associated lymphoma (PAL), which develops in patients with a long-standing history of pyothorax. One of the well-known causes of genome instability is telomere dysfunction. In the present study, the condition of telomeres was analyzed in the cell lines and clinical samples from PAL. Telomere length (TL) in PAL cell lines was extremely short (<4.5 kbp). TL in tumor samples was broad in range, and shorter than that in the peripheral blood leukocytes from the matched patients. Three of five PAL cell lines showed frequent loss of telomere signals (telomere erosion); however, telomerase activity in PAL cell lines was similar to that in Burkitt lymphoma cell lines. Rb expression was detected in three PAL cell lines and four of 15 clinical samples, respectively. Rb protein expressed in three PAL cell lines was heavily phosphorylated, indicating that function of Rb protein was suppressed. p16(INK4a) expression was not detected in either cell lines or clinical samples. The promoter region in p16(INK4a) was heavily methylated in all cell lines as well as the clinical samples. Inactivation of the p16(INK4a)/Rb pathway may allow continuous cell division and critical telomere shortening, which induce genome instability, finally leading to malignant transformation. Taken together, telomere dysfunction and inactivation of the p16(INK4a)/Rb pathway might play a role for PAL development.
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32
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Hsu CG, Wang PH, Ko JL, Chen GD, Chang H, Yang SF, Chen SC, Lin LY. Concurrent high expression of human telomerase reverse transcriptase and human nonmetastatic clone 23 in high-grade squamous intraepithelial neoplasia and squamous cell carcinoma of uterine cervix. Int J Gynecol Cancer 2007; 17:851-7. [PMID: 17359290 DOI: 10.1111/j.1525-1438.2007.00894.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Human telomerase reverse transcriptase (hTERT) and human nonmetastatic clone 23 (nm23-H1) may be separately involved in tumor progression of uterine cervix. We therefore investigate the correlations of hTERT and nm23-H1 in cervical carcinogenesis and further check their application. One hundred and twenty-eight cervical tissues, including 48 squamous cell carcinoma (SCC), 36 high-grade cervical intraepithelial neoplasia (CIN) (CIN 2 and CIN 3), 20 low-grade CIN 1, and 24 normal cases, were collected for immunohistochemical expression of hTERT and nm23-H1. Spearman rank correlation analysis was applied to assess their correlation in these samples. The Fisher exact or Chi-square test was used to evaluate the expression of hTERT or nm23-H1 among each subgroup. The sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy of hTERT and/or nm23-H1 were calculated for the prediction of high-grade CIN and SCC. We found normal cervix and CIN 1 samples had concurrent low expression of hTERT and nm23-H1, whereas high-grade CIN and SCC samples had concurrent high immunoreactivities. The hTERT alone and hTERT or nm23-H1 in combination had better sensitivity, NPV, and accuracy. The nm23-H1 alone as well as hTERT and nm23-H1 in combination had better specificity and PPV. Our results reveal a significantly positive relationship between expression of hTERT and nm23-H1 in normal and neoplastic tissues of uterine cervix. We suggest high expression of hTERT alone and hTERT or nm23-H1 in combination can be offered additional molecular information correlated with high-grade CIN and SCC.
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Affiliation(s)
- C-G Hsu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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33
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Elgui de Oliveira D. DNA viruses in human cancer: An integrated overview on fundamental mechanisms of viral carcinogenesis. Cancer Lett 2007; 247:182-96. [PMID: 16814460 DOI: 10.1016/j.canlet.2006.05.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2006] [Revised: 05/17/2006] [Accepted: 05/18/2006] [Indexed: 11/18/2022]
Abstract
The first experimental data suggesting that neoplasm development in animals might be influenced by infectious agents were published in the early 1900s. However, conclusive evidence that DNA viruses play a role in the pathogenesis of some human cancers only emerged in the 1950s, when Epstein-Barr virus (EBV) was discovered within Burkitt lymphoma cells. Besides EBV, other DNA viruses consistently associated with human cancers are the hepatitis B virus (HBV), human papillomavirus (HPV), and Kaposi sarcoma herpesvirus (KSHV). Although each virus has unique features, it is becoming clearer that all these oncogenic agents target multiple cellular pathways to support malignant transformation and tumor development.
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Affiliation(s)
- Deilson Elgui de Oliveira
- Department of Pathology, Botucatu School of Medicine, State University of Sao Paulo (UNESP), Brazil.
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34
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Branca M, Giorgi C, Ciotti M, Santini D, Di Bonito L, Costa S, Benedetto A, Bonifacio D, Di Bonito P, Paba P, Accardi L, Mariani L, Ruutu M, Syrjänen S, Favalli C, Syrjänen K. Upregulation of telomerase (hTERT) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus, virus persistence, or disease outcome in cervical cancer. Diagn Cytopathol 2006; 34:739-748. [PMID: 17041957 DOI: 10.1002/dc.20554] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Telomerase activation and telomere maintenance are essential for cell immortalization and represent a rate-limiting step in cancer progression. The E6 oncoprotein of high-risk human papillomavirus (HPV) is known to activate telomerase, but its expression in CIN lesions and its prognostic value in cervical cancer (CC) are still incompletely understood. As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for hTERT (telomerase reverse transcriptase), and tested for HPV using PCR with three primer sets (MY09/11, GP5(+)/GP6(+), SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment. Expression of hTERT was increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 18.81; 95% CI 8.48-41.69; P = 0.0001). Positive hTERT expression was 90% specific indicator of CIN, with 98.7% PPV, but suffers from low sensitivity (57.5%) and NPV (14.3%). hTERT expression was also significantly associated to HR-HPV with OR 3.38 (95% CI 1.90-6.02; P = 0.0001), but this association was confounded by the histological grade (Mantel-Haenszel common OR = 1.83; 95% CI 0.92-3.79; P = 0.086). Expression of hTERT did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in cervical cancer in univariate or multivariate survival analysis. It was concluded that up-regulation of hTERT was closely associated with HR-HPV, due to activation by the E6 oncoprotein. hTERT is a late marker of cervical carcinogenesis, significantly associated with progression to CIN3. Theoretically, a combination of hTERT assay (showing high SP and PPV) with another test showing high SE and high NPV (e.g. Hybrid Capture 2 for HPV), should provide an ideal screening tool capable of high-performance detection of CIN lesions.
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Affiliation(s)
- M Branca
- Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), Rome, Italy
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35
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Wang PH, Ko JL. Implication of human telomerase reverse transcriptase in cervical carcinogenesis and cancer recurrence. Int J Gynecol Cancer 2006; 16:1873-9. [PMID: 17009985 DOI: 10.1111/j.1525-1438.2006.00659.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The objective of this study was to evaluate the implication of human telomerase reverse transcriptase (hTERT) in cervical carcinogenesis and cancer recurrence. One hundred three cases of uterine cervix, including 20 normal, 13 low-grade squamous intraepithelial lesion (LSIL), 30 high-grade squamous intraepithelial lesion (HSIL), and 40 squamous cell carcinoma (SCC) tissues, were evaluated for hTERT immunoreactivity. The expressions of hTERT in normal, LSIL, HSIL, and SCC tissues were compared by Fisher exact or Chi-square test. The relationships between hTERT and clinicopathologic variables of SCC were also assessed. Furthermore, SCC patients were subdivided into negative and positive hTERT expression subgroups, and Kaplan-Meier curves were used to plot the cumulative recurrence hazard for 5 years. There was a significant difference for hTERT expression between LSIL and HSIL subgroups (P < 0.001) but no significant difference between normal and LSIL as well as HSIL and SCC subgroups. For SCC patients, hTERT expression was positive in lymph nodes, vagina, and parametrium metastastic cases. However, it did not reach a significant difference. The cumulative recurrence hazard for 5 years was about 29% in positive hTERT expression subgroup compared to 0% in negative hTERT subgroup (P = 0.2866). In conclusion, a point stage of HSIL exists in the progression of cervical carcinogenesis when the hTERT expression increases significantly. Moreover, SCC patients with positive hTERT expression may have higher cumulative recurrence hazard.
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Affiliation(s)
- P-H Wang
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
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36
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Maida Y, Kyo S, Forsyth NR, Takakura M, Sakaguchi J, Mizumoto Y, Hashimoto M, Nakamura M, Nakao S, Inoue M. Distinct telomere length regulation in premalignant cervical and endometrial lesions: implications for the roles of telomeres in uterine carcinogenesis. J Pathol 2006; 210:214-23. [PMID: 16909412 DOI: 10.1002/path.2038] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Mouse models show that progressive shortening of telomeres with ageing causes chromosomal instability, which can lead to the initiation of cancer. However, it is unclear what roles telomere shortening plays in human carcinogenesis. The present study has investigated the involvement of telomere dynamics in uterine carcinogenesis. Using telomere-FISH (telo-FISH) assays, telomere lengths in premalignant and malignant cervical and endometrial lesions were measured and compared with chromosomal arm loss or gain. Telo-FISH signals were visualized with Cy3-labelled telomere-specific probes and presented as telomere intensity (TI). Early-stage cervical intraepithelial neoplasias (CINs), especially CIN2, had significantly shorter telomeres than corresponding normal squamous epithelia (p = 0.019), together with increased rates of chromosomal arm loss/gain (p < 0.001). Cervical cancers had relatively short telomeres, but they also showed greater heterogeneity than other sampled tissues, including those with long telomeres. In contrast, there was no significant difference between the telomere length of normal endometrium and of endometrial hyperplasia and endometrial cancer. There was no significant difference in the rate of chromosomal arm loss/gain between normal endometrium and endometrial hyperplasia. These findings suggest that progressive shortening of telomeres occurs in CIN, in association with chromosomal instability, which may play critical roles in cervical carcinogenesis. In contrast, endometrial hyperplasias have relatively stable telomeres without widespread chromosome alteration, implying that endometrial carcinogenesis involves mechanisms distinct from those of cervical carcinogenesis, possibly including microsatellite instability.
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Affiliation(s)
- Y Maida
- Department of Obstetrics and Gynaecology, Graduate School of Medical Science, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641, Japan
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37
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Shin JS, Hong A, Solomon MJ, Lee CS. The role of telomeres and telomerase in the pathology of human cancer and aging. Pathology 2006; 38:103-13. [PMID: 16581649 DOI: 10.1080/00313020600580468] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cellular senescence, the state of permanent growth arrest, is the inevitable fate of replicating normal somatic cells. Postulated to underlie this finite replicative span is the physiology of telomeres, which constitute the ends of chromosomes. The repetitive sequences of these DNA-protein complexes progressively shorten with each mitosis. When the critical length is bridged, telomeres trigger DNA repair and cell cycle checkpoint mechanisms that result in chromosomal fusions, cell cycle arrest, senescence and/or apoptosis. Should senescence be bypassed at such time, continued cell divisions in the face of dysfunctional telomeres and activated DNA repair machinery can result in the genomic instability favourable for oncogenesis. The longevity and malignant progression of the thus transformed cell requires coincident telomerase expression or other means to negate the constitutional telomeric loss. Practically then, telomeres and telomerase may represent plausible prognostic and screening cancer markers. Furthermore, if the argument is extended, with assumptions that telomeric attrition is indeed the basis of cellular senescence and that accumulation of the latter equates to aging at the organismal level, then telomeres may well explain the increased incidence of cancer with human aging.
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Affiliation(s)
- Joo-Shik Shin
- Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, Australia.
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38
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Brunori M, Mathieu N, Ricoul M, Bauwens S, Koering CE, Roborel de Climens A, Belleville A, Wang Q, Puisieux I, Décimo D, Puisieux A, Sabatier L, Gilson E. TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts. Oncogene 2006; 25:990-7. [PMID: 16205637 DOI: 10.1038/sj.onc.1209135] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to gamma-radiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.
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Affiliation(s)
- M Brunori
- Laboratoire de Biologie Moléculaire de la Cellule of Ecole Normale Supérieure de Lyon, UMR CNRS/INRA/ENS, Lyon, France
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39
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Wang JL, Andersson S, Li X, Hellström AC, Auer G, Angström T, Lindström MS, Wallin KL. p16INK4a and laminin-5gamma2 chain expression during the progression of cervical neoplasia. Acta Oncol 2006; 45:676-84. [PMID: 16938810 DOI: 10.1080/02841860600617092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
p16INK4a, laminin-5gamma2 chain, and PCNA were investigated to compare the expression levels in relation to histological diagnosis and time for progression. The material consisted of 37 normal cervical tissues, 35 with different grades of CIN, and 11 invasive cervical cancers. Our results showed a reduction of basement membrane staining for laminin-5gamma2 chain from 78.4% in normal squamous epithelium to 27.8% in CIN3 (p < 0.001). The intracytoplasmic staining for laminin-5gamma2 chain increases with severity of lesion. The same trend was observed with p16INK4a and PCNA expression (p < 0.001). Co-expression of p16INK4a and PCNA was seen in 85.7% of samples. Cases that were laminin-5gamma2 chain BM - /p16INK4a+/PCNA+ have the shortest interval time (average: 46.8+/-36.3 months) for progression, while cases with laminin-5gamma2 chain BM + /p16INK4a-/PCNAPCNA--have the longest time interval (average: 110.2+/-52.7 months) (p < 0.05). Thus co-expression of p16INK4a, laminin-5gamma2 chain and PCNA may be valuable for the prediction progression of cervical neoplasia.
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Affiliation(s)
- Jian-Liu Wang
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
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40
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Escoffier E, Rezza A, Roborel de Climens A, Belleville A, Gazzolo L, Gilson E, Duc Dodon M. A balanced transcription between telomerase and the telomeric DNA-binding proteins TRF1, TRF2 and Pot1 in resting, activated, HTLV-1-transformed and Tax-expressing human T lymphocytes. Retrovirology 2005; 2:77. [PMID: 16354306 PMCID: PMC1343578 DOI: 10.1186/1742-4690-2-77] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2005] [Accepted: 12/15/2005] [Indexed: 01/30/2023] Open
Abstract
Background The functional state of human telomeres is controlled by telomerase and by a protein complex named shelterin, including the telomeric DNA-binding proteins TRF1, TRF2 and Pot1 involved in telomere capping functions. The expression of hTERT, encoding the catalytic subunit of telomerase, plays a crucial role in the control of lymphocyte proliferation by maintaining telomere homeostasis. It has been previously found that hTERT activity is down-regulated by the human T cell leukaemia virus type 1 (HTLV-1) Tax protein in HTLV-1 transformed T lymphocytes. In this study, we have examined the effects of Tax expression on the transcriptional profile of telomerase and of shelterin in human T lymphocytes. Results We first provide evidence that the up-regulation of hTERT transcription in activated CD4+ T lymphocytes is associated with a down-regulation of that of TERF1, TERF2 and POT1 genes. Next, the down-regulation of hTERT transcription by Tax in HTLV-1 transformed or in Tax-expressing T lymphocytes is found to correlate with a significant increase of TRF2 and/or Pot1 mRNAs. Finally, ectopic expression of hTERT in one HTLV-1 T cell line induces a marked decrease in the transcription of the POT1 gene. Collectively, these observations predict that the increased transcriptional expression of shelterin genes is minimizing the impact on telomere instability induced by the down-regulation of hTERT by Tax. Conclusion These findings support the notion that Tax, telomerase and shelterin play a critical role in the proliferation of HTLV-1 transformed T lymphocytes.
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Affiliation(s)
- Emmanuelle Escoffier
- Virologie Humaine INSERM-U412, Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46 Allée d'Italie 69364 Lyon Cedex 07, France
| | - Amélie Rezza
- Virologie Humaine INSERM-U412, Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46 Allée d'Italie 69364 Lyon Cedex 07, France
| | - Aude Roborel de Climens
- Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5161 Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46, allée d'Italie 69364 Lyon Cedex 07, France
| | - Aurélie Belleville
- Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5161 Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46, allée d'Italie 69364 Lyon Cedex 07, France
| | - Louis Gazzolo
- Virologie Humaine INSERM-U412, Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46 Allée d'Italie 69364 Lyon Cedex 07, France
| | - Eric Gilson
- Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5161 Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46, allée d'Italie 69364 Lyon Cedex 07, France
| | - Madeleine Duc Dodon
- Virologie Humaine INSERM-U412, Ecole Normale Supérieure de Lyon, IFR 128 BioSciences Lyon-Gerland, 46 Allée d'Italie 69364 Lyon Cedex 07, France
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