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Wang Q, Li QR, Xu L, Yuan ZC, Liu X, Tang MJ, Luo M, Zhong XW, Ma Q, Guo XL. BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation. World J Gastrointest Oncol 2025; 17:99376. [PMID: 39817136 PMCID: PMC11664625 DOI: 10.4251/wjgo.v17.i1.99376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 10/05/2024] [Accepted: 11/01/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high morbidity and mortality, and easy to develop resistance to chemotherapeutic agents. Telomeres are DNA-protein complexes located at the termini of chromosomes in eukaryotic cells, which are unreplaceable in maintaining the stability and integrity of genome. Telomerase, an RNA-dependent DNA polymerase, play vital role in telomere length maintain, targeting telomerase is a promising therapeutic strategy for cancer. AIM To investigate the efficacy and underlying mechanisms of BIBR1532, a telomerase inhibitor, in ESCC. METHODS KYSE150 and KYSE410 cells were cultured and exposed to various concentrations of BIBR1532. Cell viability was assessed at 48 hours and 72 hours to determine the IC50 values. The effects of BIBR1532 on ESCC cell proliferation, migration, and cellular senescence were evaluated using the cell counting kit-8 assay, plate colony formation assay, scratch assay, transwell assay, and β-galactosidase staining, respectively. Western blotting was performed to detect the expression of proteins in BIBR1532-treated ESCC cells, such as human telomerase reverse transcriptase (hTERT), key molecules involved in DNA damage response (DDR) or cellular senescence, as well as telomere-binding proteins. Additionally, a tumor-bearing nude mouse model was established to evaluate the anti-cancer effect of BIBR1532 in vivo. RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53 μM and 39.59 μM, respectively. These values decreased to 37.22 μM and 22.71 μM, respectively, following a longer exposure of 72 hours. BIBR1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells, including decreased hTERT expression, inhibition of proliferation and metastasis, and induction of cellular senescence. Mechanistically, BIBR1532 upregulated the expression of the DDR protein, γ-H2AX, and activated the ataxia telangiectasia and Rad3-related protein (ATR)/ check point kinase 1 (CHK-1) and ataxia-telangiectasia mutated gene (ATM)/CHK2 pathways. BIBR1532 downregulated the expression of telomere-binding proteins, including telomeric-repeat binding factor 1 (TRF1), TRF2, protection of telomeres 1, and TIN2-interacting protein 1. In a nude mouse xenograft model, BIBR1532 significantly suppressed tumor growth, reduced hTERT expression, and increased γ-H2AX protein levels. Hematoxylin and eosin staining of various organs, including the heart, liver, spleen, lungs, and kidneys, revealed no apparent adverse effects. CONCLUSION BIBR1532 exerts anti-cancer effects on ESCC by inducing DDR through the ATR/CHK1 and ATM/CHK2 pathways and downregulating the expression of telomere-binding proteins.
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Affiliation(s)
- Qin Wang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Qing-Rong Li
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Lei Xu
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zi-Chun Yuan
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao Liu
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Mao-Ju Tang
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Man Luo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Wu Zhong
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Lan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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Li XH, Sun MH, Jiang WJ, Zhou D, Lee SH, Heo G, Chen Z, Cui XS. ZSCAN4 Regulates Zygotic Genome Activation and Telomere Elongation in Porcine Parthenogenetic Embryos. Int J Mol Sci 2023; 24:12121. [PMID: 37569497 PMCID: PMC10418334 DOI: 10.3390/ijms241512121] [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: 06/26/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Zinc finger and SCAN domain-containing 4 (ZSCAN4), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells, including maintaining genomic stability and defying cellular senescence. However, the effect of ZSCAN4 in porcine parthenogenetic embryos remains unclear. To investigate the function of ZSCAN4 and the underlying mechanism in porcine embryo development, ZSCAN4 was knocked down via dsRNA injection in the one-cell stage. ZSCAN4 was highly expressed in the four- and five- to eight-cell stages in porcine embryos. The percentage of four-cell stage embryos, five- to eight-cell stage embryos, and blastocysts was lower in the ZSCAN4 knockdown group than in the control group. Notably, depletion of ZSCAN4 induced the protein expression of DNMT1 and 5-Methylcytosine (5mC, a methylated form of the DNA base cytosine) in the four-cell stage. The H3K27ac level and ZGA genes expression decreased following ZSCAN4 knockdown. Furthermore, ZSCAN4 knockdown led to DNA damage and shortened telomere compared with the control. Additionally, DNMT1-dsRNA was injected to reduce DNA hypermethylation in ZSCAN4 knockdown embryos. DNMT1 knockdown rescued telomere shortening and developmental defects caused by ZSCAN4 knockdown. In conclusion, ZSCAN4 is involved in the regulation of transcriptional activity and is essential for maintaining telomere length by regulating DNMT1 expression in porcine ZGA.
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Affiliation(s)
- Xiao-Han Li
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Ming-Hong Sun
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Wen-Jie Jiang
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Dongjie Zhou
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Song-Hee Lee
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Geun Heo
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Zhi Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiang-Shun Cui
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea
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Noto S. Perspectives on Aging and Quality of Life. Healthcare (Basel) 2023; 11:2131. [PMID: 37570372 PMCID: PMC10418952 DOI: 10.3390/healthcare11152131] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/27/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
The aging of the world's population and the health problems accompanying it are becoming increasingly severe. Healthcare policies in developed countries focus on how to prevent and treat diseases associated with aging and how to maintain quality of life. Typical age-related diseases include deafness, cataracts, osteoarthritis, chronic obstructive pulmonary disease, diabetes mellitus, and dementia. Although the mechanisms by which these diseases develop differ, they are all caused by the accumulation of molecular and cellular damage over time. In addition, age-related diseases can cause a decline in physical and mental functions and the ability to perform activities of daily living, as well as the loss of roles in society and a sense of fulfillment in life. Therefore, there is a need for treatment and measures to accurately grasp and maintain quality of life. This review aims to introduce areas and representative papers expected to be contributed to the special issue of "Aging and Quality of Life".
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Affiliation(s)
- Shinichi Noto
- Department of Rehabilitation, Niigata University of Health and Welfare, Niigata 9503198, Japan
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Zhao X, Luo D, Liu T, Zhang H, Xie Y, Kong W. BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling. Gynecol Obstet Invest 2023; 88:226-239. [PMID: 37429261 DOI: 10.1159/000530460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 02/27/2023] [Indexed: 07/12/2023]
Abstract
OBJECTIVES The effect of telomerase inhibitor BIBR1532 on endometriotic cells was investigated to explore the inhibitory effect of targeting telomerase on endometriosis. DESIGN In vitro primary cell culture study. Participants/Materials: Primary endometrial cells derived from eutopic and ectopic endometrium in patients with endometriosis. SETTING The study was conducted in the university hospital. METHODS Paired eutopic and ectopic endometrial cells were collected from 6 patients from January 2018 to July 2021. A TRAP assay was performed to detect the telomerase activity of the cells. MTT, cell cycle, apoptosis, migration, and invasion assays were performed to study the inhibitory effect of BIBR1532. Enrichment analysis was performed to identify the key pathways involved in endometriosis progression and telomerase action. Then, Western blotting was used to investigate the expression of related proteins. RESULTS BIBR1532 treatment significantly inhibited the growth of eutopic and ectopic endometrial cells, with apoptosis and cell cycle signaling involved. Migration and invasion, important characteristics for the establishment of ectopic lesions, were also inhibited by BIBR1532. The MAPK signaling cascade, related to telomerase and endometriosis, was decreased in eutopic and ectopic endometrial stromal cells with the treatment of BIBR1532. LIMITATIONS The severe side effects of telomerase inhibitors might be the main obstacle to clinical application, so it is necessary to find better drug delivery methods in vivo. CONCLUSIONS The telomerase inhibitor BIBR1532 affects endometrial cell proliferation, migration, and invasion in endometriosis.
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Affiliation(s)
- Xiaoling Zhao
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Dan Luo
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Tingting Liu
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - He Zhang
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Yunkai Xie
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Weimin Kong
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
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Yang K, Liang X, Wen K. Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review). Oncol Rep 2022; 48:175. [PMID: 36004472 PMCID: PMC9478986 DOI: 10.3892/or.2022.8390] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/27/2022] [Indexed: 11/05/2022] Open
Abstract
Genomic instability, a feature of most cancers, contributes to malignant cell transformation and cancer progression due to the accumulation of genetic alterations. Genomic instability is reflected at numerous levels, from single nucleotide to the chromosome levels. However, the exact molecular mechanisms and regulators of genomic instability in cancer remain unclear. Growing evidence indicates that the binding of long non-coding RNAs (lncRNAs) to protein chaperones confers a variety of regulatory functions, including managing of genomic instability. The aim of the present review was to examine the roles of mitosis, telomeres, DNA repair, and epigenetics in genomic instability, and the mechanisms by which lncRNAs regulate them by binding proteins in cancer cells. This review contributes to our understanding of the role of lncRNAs and genomic instability in cancer and can potentially provide entry points and molecular targets for cancer therapies.
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Affiliation(s)
- Kai Yang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xiaoxiang Liang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Kunming Wen
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Li P, Chen C, Li J, Yang L, Wang Y, Dong Z, Mi J, Zhang Y, Wang J, Wang H, Rodriguez R, Tian J, Wang Z. Homologous Recombination Related Signatures Predict Prognosis and Immunotherapy Response in Metastatic Urothelial Carcinoma. Front Genet 2022; 13:875128. [PMID: 35559013 PMCID: PMC9086193 DOI: 10.3389/fgene.2022.875128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: This study used homologous recombination (HR) related signatures to develop a clinical prediction model for screening immune checkpoint inhibitors (ICIs) advantaged populations and identify hub genes in advanced metastatic urothelial carcinoma. Methods: The single-sample gene enrichment analysis and weighted gene co-expression network analysis were applied to identify modules associated with immune response and HR in IMvigor210 cohort samples. The principal component analysis was utilized to determine the differences in HR-related module gene signature scores across different tissue subtypes and clinical variables. Risk prediction models and nomograms were developed using differential gene expression analysis associated with HR scores, least absolute shrinkage and selection operator, and multivariate proportional hazards model regression. Additionally, hub genes were identified by analyzing the contribution of HR-related genes to principal components and overall survival analysis. Finally, clinical features from GSE133624, GSE13507, the TCGA, and other data sets were analyzed to validate the relationship between hub genes and tumor growth and mutation. Results: The HR score was significantly higher in the complete/partial response group than in the stable/progressive disease group. The majority of genes associated with HR were discovered to be involved in the cell cycle and others. Genomically unstable, high tumor level, and high immune level samples all exhibited significantly higher HR score than other sample categories, and higher HR scores were related to improved survival following ICIs treatment. The risk scores for AUNIP, SEPT, FAM72D, CAMKV, CXCL9, and FOXN4 were identified, and the training and verification groups had markedly different survival times. The risk score, tumor neoantigen burden, mismatch repair, and cell cycle regulation were discovered to be independent predictors of survival time following immunotherapy. Patients with a high level of expression of hub genes such as EME1, RAD51AP1, and RAD54L had a greater chance of surviving following immunotherapy. These genes are expressed at significantly higher levels in tumors, high-grade cancer, and invasive cancer than other categories, and are associated with TP53 and RB1 mutations. Conclusion: HR-related genes are upregulated in genomically unstable samples, the survival time of mUC patients after treatment with ICIs can be predicted using a normogram model based on HR signature.
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Affiliation(s)
- Pan Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
| | - Chaohu Chen
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
| | - Jianpeng Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
| | - Li Yang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Gansu Province for Urological Diseases, Lanzhou, China.,Clinical Center of Gansu Province for Nephron-Urology, Lanzhou, China
| | - Yuhan Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
| | - Zhilong Dong
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Gansu Province for Urological Diseases, Lanzhou, China.,Clinical Center of Gansu Province for Nephron-Urology, Lanzhou, China
| | - Jun Mi
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Gansu Province for Urological Diseases, Lanzhou, China.,Clinical Center of Gansu Province for Nephron-Urology, Lanzhou, China
| | - Yunxin Zhang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Gansu Province for Urological Diseases, Lanzhou, China.,Clinical Center of Gansu Province for Nephron-Urology, Lanzhou, China
| | - Juan Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
| | - Hanzhang Wang
- Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Ronald Rodriguez
- Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Junqiang Tian
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Gansu Province for Urological Diseases, Lanzhou, China.,Clinical Center of Gansu Province for Nephron-Urology, Lanzhou, China
| | - Zhiping Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Gansu Province for Urological Diseases, Lanzhou, China.,Clinical Center of Gansu Province for Nephron-Urology, Lanzhou, China
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El Bairi K, Al Jarroudi O, Le Page C, Afqir S. Does the "Devil" originate from the fallopian tubes? Semin Cancer Biol 2021; 77:56-66. [PMID: 33766647 DOI: 10.1016/j.semcancer.2021.03.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/14/2021] [Accepted: 03/20/2021] [Indexed: 02/08/2023]
Abstract
Epithelial ovarian cancer (OC) is a heterogeneous disease and continues to be mostly diagnosed in advanced stages. The high lethality, the high rate of platinum-resistance, and the poor survival outcomes are the principal factors for categorizing OC among the most aggressive gynecological cancers. Only recently, a substantial progress has been made in our latest understanding of the origins of OC, particularly of high-grade serous histology. For a long time, the accumulation of genetic alterations in epithelial single layer cells of ovarian cysts caused by cyclic ovulations was considered as the most important driver and the long-standing dogma of ovarian tumorigenesis. Besides, the unique biological features and high histological heterogeneity of OC did not support this hypothesis. Indeed, various extra-ovarian cells of origin and multiple sites to each histotype were proposed, supported by cogent evidence from clinical cohorts and animal studies. In light of this enigma, this review was conducted to discuss the recent evidence supporting the revised origins of ovarian carcinoma histotypes with a particular focus on high-grade serous OC which may impact diagnostic and preventive approaches.
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Affiliation(s)
- Khalid El Bairi
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed I(st) University, Oujda, Morocco.
| | - Ouissam Al Jarroudi
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed I(st) University, Oujda, Morocco
| | - Cécile Le Page
- Research Institute of McGill University Health Center (RI-MUHC), Montréal, QC, Canada
| | - Said Afqir
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed I(st) University, Oujda, Morocco
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Chen M, Linstra R, van Vugt MATM. Genomic instability, inflammatory signaling and response to cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2021; 1877:188661. [PMID: 34800547 DOI: 10.1016/j.bbcan.2021.188661] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/02/2021] [Accepted: 11/13/2021] [Indexed: 02/08/2023]
Abstract
Genomic and chromosomal instability are hallmarks of cancer and shape the genomic composition of cancer cells, thereby determining their behavior and response to treatment. Various genetic and epigenetic alterations in cancer have been linked to genomic instability, including DNA repair defects, oncogene-induced replication stress, and spindle assembly checkpoint malfunction. A consequence of genomic and chromosomal instability is the leakage of DNA from the nucleus into the cytoplasm, either directly or through the formation and subsequent rupture of micronuclei. Cytoplasmic DNA subsequently activates cytoplasmic DNA sensors, triggering downstream pathways, including a type I interferon response. This inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors. However, cancers frequently evolve mechanisms to avoid immune clearance, including suppression of inflammatory signaling. In this review, we summarize inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy.
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Affiliation(s)
- Mengting Chen
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands
| | - Renske Linstra
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands
| | - Marcel A T M van Vugt
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands.
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9
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Sharif R, Shahar S, Rajab NF, Fenech M. Dietary Pattern, Genomic Stability and Relative Cancer Risk in Asian Food Landscape. Nutr Cancer 2021; 74:1171-1187. [PMID: 34282666 DOI: 10.1080/01635581.2021.1952627] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The incidence of cancer globally is increasing, partly due to lifestyle factors. Despite a better understanding of cancer biology and advancement in cancer management and therapies, current strategies in cancer treatment remain costly and cause socioeconomic burden especially in Asian countries. Hence, instead of putting more efforts in searches for new cancer cures, attention has now shifted to understanding how to mitigate cancer risk by modulating lifestyle factors. It has been established that carcinogenesis is multifactorial, and the important detrimental role of oxidative stress, chronic inflammation, and genomic instability is evident. To date, there is no study linking dietary pattern and genomic stability in cancer risk in the Asian food landscape. Thus, this present review article discusses recent literature on dietary pattern and genomic stability and its relationship with cancer risk in Asia.
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Affiliation(s)
- Razinah Sharif
- Centre of Healthy Ageing and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Suzana Shahar
- Centre of Healthy Ageing and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nor Fadilah Rajab
- Centre of Healthy Ageing and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Michael Fenech
- Centre of Healthy Ageing and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,Genome Health Foundation, Adelaide, Australia
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10
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Saini G, Ogden A, McCullough LE, Torres M, Rida P, Aneja R. Disadvantaged neighborhoods and racial disparity in breast cancer outcomes: the biological link. Cancer Causes Control 2019; 30:677-686. [PMID: 31111277 PMCID: PMC7043809 DOI: 10.1007/s10552-019-01180-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 05/09/2019] [Indexed: 02/07/2023]
Abstract
Neighborhoods encompass complex environments comprised of unique economic, physical, and social characteristics that have a profound impact on the residing individual's health and, collectively, on the community's wellbeing. Neighborhood disadvantage (ND) is one of several factors that prominently contributes to racial breast cancer (BC) health disparities in American women. African American (AA) women develop more aggressive breast cancer features, such as triple-negative receptor status and more advanced histologic grade and tumor stage, and suffer worse clinical outcomes than European American (EA) women. While the adverse effects of neighborhood disadvantage on health, including increased risk of cancer and decreased longevity, have recently come into focus, the specific molecular mechanisms by which neighborhood disadvantage increases BC risk and worsens BC outcomes (survivorship, recurrence, mortality) are not fully elucidated. This review illuminates the probable biological links between neighborhood disadvantage and predominantly BC risk, with an emphasis on stress reactivity and inflammation, epigenetics and telomere length in response to adverse neighborhood conditions.
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Affiliation(s)
- Geetanjali Saini
- Department of Biology, Georgia State University, Atlanta, GA, 30303, USA
| | - Angela Ogden
- Department of Biology, Georgia State University, Atlanta, GA, 30303, USA
| | - Lauren E McCullough
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Mylin Torres
- Department of Radiation Oncology, Glenn Family Breast Center, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Padmashree Rida
- Department of Biology, Georgia State University, Atlanta, GA, 30303, USA
| | - Ritu Aneja
- Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
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11
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Alnafakh RAA, Adishesh M, Button L, Saretzki G, Hapangama DK. Telomerase and Telomeres in Endometrial Cancer. Front Oncol 2019; 9:344. [PMID: 31157162 PMCID: PMC6533802 DOI: 10.3389/fonc.2019.00344] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/15/2019] [Indexed: 12/11/2022] Open
Abstract
Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the “end replication problem” as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80–90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.
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Affiliation(s)
- Rafah A A Alnafakh
- Liverpool Women's Hospital NHS Foundation Trust, Liverpool, United Kingdom.,Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Meera Adishesh
- Liverpool Women's Hospital NHS Foundation Trust, Liverpool, United Kingdom.,Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Lucy Button
- Liverpool Women's Hospital NHS Foundation Trust, Liverpool, United Kingdom.,Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Gabriele Saretzki
- The Ageing Biology Centre and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Dharani K Hapangama
- Liverpool Women's Hospital NHS Foundation Trust, Liverpool, United Kingdom.,Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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12
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Thriveni K, Raju A, Kumar RV, Krishnamurthy S, Chaluvarayaswamy R. Patterns of Relative Telomere Length is Associated With hTERT Gene Expression in the Tissue of Patients With Breast Cancer. Clin Breast Cancer 2018; 19:27-34. [PMID: 30217473 DOI: 10.1016/j.clbc.2018.07.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/21/2018] [Accepted: 07/22/2018] [Indexed: 11/18/2022]
Abstract
BACKGROUND Homeostasis of telomere in breast cancer might be altered as a result of cumulative effects of various factors causing genomic instability and affecting prognosis. This study aimed to compare the relative telomere length (RTL) and hTERT mRNA expression in the tissue of patients with breast cancer along with the clinicopathologic parameters. PATIENTS AND METHODS Frozen tumor tissues and adjacent normal breast tissue from 98 patients with invasive ductal breast cancer were used for the analysis. RTL and hTERT mRNA expression were measured using quantitative real time polymerase chain reaction. RESULTS Among the 98 cases, 51% had an early-stage carcinoma, 66% were tumor size < 5 cm, 30% were node-negative, and 20% were low-grade tumors. In this study, 63% of cases showed higher hTERT gene expression with an odds ratio of 2.77 (P = .02). The median RTL for elongated telomere was 3.49, and the value was significantly elevated when compared with the shorter telomere. Shortened RTL was present in 60% of early-stage cancer cases, 55% where the tumor size was < 5 cm, 72% of the lymph node-negative cases, and 68% of low-grade carcinoma. Significantly elongated RTL, with median 4.22, 3.19, 3.17, and 3.28 was observed (P < .05) in the advanced stage, larger tumor size, node-positive, and high-grade cases respectively. CONCLUSION In this study, shortened telomere was observed in early-stage cancer, and elongated telomere was found in advanced diseases. However, 13% of patients with lower hTERT gene expression showed elongated telomeres, indicating relative telomere length measurement in tissue is different from blood leukocyte, showing the dynamic process of tumorigenesis in tissue.
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MESH Headings
- Adult
- Biomarkers, Tumor/genetics
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/surgery
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/surgery
- Carcinoma, Lobular/genetics
- Carcinoma, Lobular/pathology
- Carcinoma, Lobular/surgery
- Case-Control Studies
- Cross-Sectional Studies
- Female
- Follow-Up Studies
- Humans
- Neoplasm Grading
- Neoplasm Staging
- Receptor, ErbB-2/metabolism
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/metabolism
- Telomerase/genetics
- Telomere Shortening/genetics
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Affiliation(s)
- Karuvaje Thriveni
- Department of Biochemistry, Kidwai Cancer Institute, Bangalore, India.
| | - Anisha Raju
- Department of Biochemistry, Kidwai Cancer Institute, Bangalore, India
| | - Rekha V Kumar
- Department of Pathology, Kidwai Cancer Institute, Bangalore, India
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13
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Billet S, Landkocz Y, Martin PJ, Verdin A, Ledoux F, Lepers C, André V, Cazier F, Sichel F, Shirali P, Gosset P, Courcot D. Chemical characterization of fine and ultrafine PM, direct and indirect genotoxicity of PM and their organic extracts on pulmonary cells. J Environ Sci (China) 2018; 71:168-178. [PMID: 30195675 DOI: 10.1016/j.jes.2018.04.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 04/19/2018] [Accepted: 04/20/2018] [Indexed: 06/08/2023]
Abstract
Particulate matter in ambient air constitutes a complex mixture of fine and ultrafine particles composed of various chemical compounds including metals, ions, and organics. A multidisciplinary approach was developed by studying physico-chemical characteristics and mechanisms involved in the toxicity of particulate atmospheric pollution. PM0.3-2.5 and PM2.5 including ultrafine particles were sampled in Dunkerque, a French industrialized seaside city. PM samples were characterized from a chemical and toxicological point of view. Physico-chemical characterization evidenced that PM2.5 comes from several sources: natural ones, such as soil resuspension and marine sea-salt emissions, as well as anthropogenic ones, such as shipping traffic, road traffic, and industrial activities. Human BEAS-2B lung cells were exposed to PM0.3-2.5, or to the Extractable Organic Matter (EOM) of PM0.3-2.5 and PM2.5. These exposures induced several mechanisms of action implied in the genotoxicity, such as oxidative DNA adducts and DNA Damage Response. The toxicity of PM-EOM was higher for the sample including the ultrafine fraction (PM2.5) containing also higher concentrations of polycyclic aromatic hydrocarbons. These results evidenced the major role of organic compounds in the toxicity of PM.
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Affiliation(s)
- Sylvain Billet
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France.
| | - Yann Landkocz
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
| | - Perrine J Martin
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
| | - Anthony Verdin
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
| | - Frédéric Ledoux
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
| | - Capucine Lepers
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
| | | | - Fabrice Cazier
- University of the Littoral Opal Coast, Common Centre of Measurements, CCM, Dunkerque, France
| | - François Sichel
- Normandy Univ, UNICAEN, ABTE EA4651, Caen, France; Centre François Baclesse, Caen, France
| | - Pirouz Shirali
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
| | - Pierre Gosset
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France; Department of Anatomy and Pathological Cytology, Saint-Vincent Hospital, Catholic Hospital, Lille, France
| | - Dominique Courcot
- University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France
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14
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Joyce BT, Zheng Y, Nannini D, Zhang Z, Liu L, Gao T, Kocherginsky M, Murphy R, Yang H, Achenbach CJ, Roberts LR, Hoxha M, Shen J, Vokonas P, Schwartz J, Baccarelli A, Hou L. DNA Methylation of Telomere-Related Genes and Cancer Risk. Cancer Prev Res (Phila) 2018; 11:511-522. [PMID: 29895583 PMCID: PMC6800137 DOI: 10.1158/1940-6207.capr-17-0413] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 04/03/2018] [Accepted: 05/22/2018] [Indexed: 01/09/2023]
Abstract
Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (β = 1.0-6.93) and one protective CpG in MAD1L1 (β = -0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction. Cancer Prev Res; 11(8); 511-22. ©2018 AACR.
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Affiliation(s)
- Brian T Joyce
- Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| | - Yinan Zheng
- Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Drew Nannini
- Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Zhou Zhang
- Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lei Liu
- Division of Biostatistics, Washington University in St. Louis, St. Louis, Missouri
| | - Tao Gao
- Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Masha Kocherginsky
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Robert Murphy
- Center for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Hushan Yang
- Division of Population Science, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Chad J Achenbach
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Mirjam Hoxha
- Molecular Epidemiology and Environmental Epigenetics Laboratory, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Jincheng Shen
- Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, Utah
| | - Pantel Vokonas
- VA Normative Aging Study, VA Boston Healthcare System, Boston, Massachusetts
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Joel Schwartz
- Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
| | - Andrea Baccarelli
- Department of Environmental Health Science, Mailman School of Public Health, Columbia University, New York, New York
| | - Lifang Hou
- Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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15
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Aix E, Gallinat A, Flores I. Telomeres and telomerase in heart regeneration. Differentiation 2018; 100:26-30. [PMID: 29453108 DOI: 10.1016/j.diff.2018.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 01/19/2018] [Accepted: 01/23/2018] [Indexed: 01/08/2023]
Abstract
Although recent advances have overturned the old view of the human heart as an inert postmitotic organ, it is clear that the adult heart´s capacity to regenerate after an ischemic episode is very limited. Unlike humans, zebrafish and other lower vertebrates vigorously regenerate damaged myocardium after cardiac injury. Understanding how the zebrafish is able to conserve life-long cardiac regeneration capacity while mammals lose it soon after birth is crucial for the development of new treatments for myocardial infarction. Mammals and lower vertebrates differ markedly in their rates of cardiomyocyte proliferation and levels of telomerase activity. Here, we review recent discoveries identifying lack of telomerase activity and concomitant telomere dysfunction as natural barriers to cardiomyocyte proliferation and cardiac regeneration.
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Affiliation(s)
- Esther Aix
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernandez Almagro 3, Madrid E-28029, Spain
| | - Alex Gallinat
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernandez Almagro 3, Madrid E-28029, Spain
| | - Ignacio Flores
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernandez Almagro 3, Madrid E-28029, Spain.
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16
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Martin U. Genome stability of programmed stem cell products. Adv Drug Deliv Rev 2017; 120:108-117. [PMID: 28917518 DOI: 10.1016/j.addr.2017.09.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 08/31/2017] [Accepted: 09/07/2017] [Indexed: 01/23/2023]
Abstract
Inherited and acquired genomic abnormalities are known to cause genetic diseases and contribute to cancer formation. Recent studies demonstrated a substantial mutational load in mouse and human embryonic and induced pluripotent stem cells (ESCs and iPSCs). Single nucleotide variants, copy number variations, and larger chromosomal abnormalities may influence the differentiation capacity of pluripotent stem cells and the functionality of their derivatives in disease modeling and drug screening, and are considered a serious risk for cellular therapies based on ESC or iPSC derivatives. This review discusses the types and origins of different genetic abnormalities in pluripotent stem cells, methods for their detection, and the mechanisms of development and enrichment during reprogramming and culture expansion.
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Affiliation(s)
- Ulrich Martin
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH Cluster of Excellence, German Center for Lung Research, Hannover Medical School, Germany.
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17
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Using human artificial chromosomes to study centromere assembly and function. Chromosoma 2017; 126:559-575. [DOI: 10.1007/s00412-017-0633-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/12/2017] [Accepted: 06/13/2017] [Indexed: 12/13/2022]
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18
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Garland J. Unravelling the complexity of signalling networks in cancer: A review of the increasing role for computational modelling. Crit Rev Oncol Hematol 2017; 117:73-113. [PMID: 28807238 DOI: 10.1016/j.critrevonc.2017.06.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 06/01/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023] Open
Abstract
Cancer induction is a highly complex process involving hundreds of different inducers but whose eventual outcome is the same. Clearly, it is essential to understand how signalling pathways and networks generated by these inducers interact to regulate cell behaviour and create the cancer phenotype. While enormous strides have been made in identifying key networking profiles, the amount of data generated far exceeds our ability to understand how it all "fits together". The number of potential interactions is astronomically large and requires novel approaches and extreme computation methods to dissect them out. However, such methodologies have high intrinsic mathematical and conceptual content which is difficult to follow. This review explains how computation modelling is progressively finding solutions and also revealing unexpected and unpredictable nano-scale molecular behaviours extremely relevant to how signalling and networking are coherently integrated. It is divided into linked sections illustrated by numerous figures from the literature describing different approaches and offering visual portrayals of networking and major conceptual advances in the field. First, the problem of signalling complexity and data collection is illustrated for only a small selection of known oncogenes. Next, new concepts from biophysics, molecular behaviours, kinetics, organisation at the nano level and predictive models are presented. These areas include: visual representations of networking, Energy Landscapes and energy transfer/dissemination (entropy); diffusion, percolation; molecular crowding; protein allostery; quinary structure and fractal distributions; energy management, metabolism and re-examination of the Warburg effect. The importance of unravelling complex network interactions is then illustrated for some widely-used drugs in cancer therapy whose interactions are very extensive. Finally, use of computational modelling to develop micro- and nano- functional models ("bottom-up" research) is highlighted. The review concludes that computational modelling is an essential part of cancer research and is vital to understanding network formation and molecular behaviours that are associated with it. Its role is increasingly essential because it is unravelling the huge complexity of cancer induction otherwise unattainable by any other approach.
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Affiliation(s)
- John Garland
- Manchester Interdisciplinary Biocentre, Manchester University, Manchester, UK.
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19
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Potapova T, Gorbsky GJ. The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis. BIOLOGY 2017; 6:biology6010012. [PMID: 28208750 PMCID: PMC5372005 DOI: 10.3390/biology6010012] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/24/2017] [Accepted: 01/26/2017] [Indexed: 12/21/2022]
Abstract
Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects is change in the relative dosage of products from genes located on the missegregated chromosomes. Abnormal expression of transcriptional regulators can also impact genes on the properly segregated chromosomes. The consequences of these perturbations in gene expression depend on the specific chromosomes affected and on the interplay of the aneuploid phenotype with the environment. Most often, these novel chromosome distributions are detrimental to the health and survival of the organism. However, in a changed environment, alterations in gene copy number may generate a more highly adapted phenotype. Chromosome segregation errors also have important implications in human health. They may promote drug resistance in pathogenic microorganisms. In cancer cells, they are a source for genetic and phenotypic variability that may select for populations with increased malignance and resistance to therapy. Lastly, chromosome segregation errors during gamete formation in meiosis are a primary cause of human birth defects and infertility. This review describes the consequences of mitotic and meiotic errors focusing on novel concepts and human health.
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Affiliation(s)
- Tamara Potapova
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
| | - Gary J Gorbsky
- Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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20
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Jezek M, Gast A, Choi G, Kulkarni R, Quijote J, Graham-Yooll A, Park D, Green EM. The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance. Epigenetics 2016; 12:93-104. [PMID: 27911222 DOI: 10.1080/15592294.2016.1265712] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Genes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir protein-independent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.
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Affiliation(s)
- Meagan Jezek
- a Department of Biological Sciences , University of Maryland Baltimore County , Baltimore , MD , USA
| | - Alison Gast
- a Department of Biological Sciences , University of Maryland Baltimore County , Baltimore , MD , USA
| | - Grace Choi
- b Department of Mathematics and Statistics , University of Maryland Baltimore County , Baltimore , MD , USA
| | - Rushmie Kulkarni
- a Department of Biological Sciences , University of Maryland Baltimore County , Baltimore , MD , USA
| | - Jeremiah Quijote
- b Department of Mathematics and Statistics , University of Maryland Baltimore County , Baltimore , MD , USA
| | - Andrew Graham-Yooll
- a Department of Biological Sciences , University of Maryland Baltimore County , Baltimore , MD , USA
| | - DoHwan Park
- b Department of Mathematics and Statistics , University of Maryland Baltimore County , Baltimore , MD , USA
| | - Erin M Green
- a Department of Biological Sciences , University of Maryland Baltimore County , Baltimore , MD , USA
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21
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G-Quadruplex ligands: Potent inhibitors of telomerase activity and cell proliferation in Plasmodium falciparum. Mol Biochem Parasitol 2016; 207:33-8. [DOI: 10.1016/j.molbiopara.2016.05.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 04/10/2016] [Accepted: 05/19/2016] [Indexed: 12/11/2022]
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22
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Ceja-Rangel HA, Sánchez-Suárez P, Castellanos-Juárez E, Peñaroja-Flores R, Arenas-Aranda DJ, Gariglio P, Benítez-Bribiesca L. Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines. Tumour Biol 2016; 37:11917-11926. [PMID: 27072825 DOI: 10.1007/s13277-016-5045-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 04/01/2016] [Indexed: 12/12/2022] Open
Abstract
Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers-telomere length and telomerase activity-could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.
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Affiliation(s)
- Hugo A Ceja-Rangel
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico.,Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Patricia Sánchez-Suárez
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Emilio Castellanos-Juárez
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Rubicelia Peñaroja-Flores
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Diego J Arenas-Aranda
- Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
| | - Patricio Gariglio
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico.
| | - Luis Benítez-Bribiesca
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico.
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23
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Stepanenko A, Dmitrenko V. HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution. Gene 2015; 569:182-90. [DOI: 10.1016/j.gene.2015.05.065] [Citation(s) in RCA: 208] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 05/11/2015] [Accepted: 05/26/2015] [Indexed: 01/18/2023]
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Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci AM, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams GP, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi A, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D’Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, et alGoodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci AM, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams GP, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi A, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D’Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez Guzman MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar P, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Leung PS, Nangia-Makker P, Cheng Q(S, Robey R, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Hamid RA, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell W, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, Hu Z. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015; 36 Suppl 1:S254-S296. [PMID: 26106142 PMCID: PMC4480130 DOI: 10.1093/carcin/bgv039] [Show More Authors] [Citation(s) in RCA: 186] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 01/23/2015] [Accepted: 01/31/2015] [Indexed: 02/07/2023] Open
Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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Affiliation(s)
- William H. Goodson
- *To whom correspondence should be addressed. William H.Goodson III, California Pacific Medical Center Research Institute, 2100 Webster Street #401, San Francisco, CA 94115, USA. Tel: +41 59 233925; Fax: +41 57 761977;
| | - Leroy Lowe
- Getting to Know Cancer, Room 229A, 36 Arthur Street, Truro, Nova Scotia B2N 1X5, Canada
- Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK
| | - David O. Carpenter
- Institute for Health and the Environment, University at Albany, 5 University Pl., Rensselaer, NY 12144, USA
| | | | - Abdul Manaf Ali
- School of Biotechnology, Faculty of Agriculture Biotechnology and Food Sciences, Sultan Zainal Abidin University, Tembila Campus, 22200 Besut, Terengganu, Malaysia
| | | | - Ahmed Lasfar
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Cientificas. Hospital Universitario Virgen del Rocio, Univ. de Sevilla., Avda Manuel Siurot sn. 41013 Sevilla, Spain
| | - Amaya Azqueta
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31008, Spain
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
| | - Amelia K. Charles
- School of Biological Sciences, University of Reading, Hopkins Building, Reading, Berkshire RG6 6UB, UK
| | | | - Andrew Ward
- Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Anna C. Salzberg
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Anna Maria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - Ann-Karin Olsen
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway
| | - Arthur Berg
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | | | - Binhua P. Zhou
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA
| | - Carmen Blanco-Aparicio
- Spanish National Cancer Research Centre, CNIO, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain
| | - Carolyn J. Baglole
- Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Chenfang Dong
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA
| | - Chiara Mondello
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - Chia-Wen Hsu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA
| | - Christian C. Naus
- Department of Cellular and Physiological Sciences, Life Sciences Institute, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
| | - Clement Yedjou
- Department of Biology, Jackson State University, Jackson, MS 39217, USA
| | - Colleen S. Curran
- Department of Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Dale W. Laird
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada
| | - Daniel C. Koch
- Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA
| | - Danielle J. Carlin
- Superfund Research Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27560, USA
| | - Dean W. Felsher
- Department of Medicine, Oncology and Pathology, Stanford University,Stanford, CA 94305, USA
| | - Debasish Roy
- Department of Natural Science, The City University of New York at Hostos Campus, Bronx, NY 10451, USA
| | - Dustin G. Brown
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523–1680, USA
| | - Edward Ratovitski
- Department of Head and Neck Surgery/Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Elizabeth P. Ryan
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523–1680, USA
| | - Emanuela Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Emilio Rojas
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Eun-Yi Moon
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143–747, Korea
| | - Ezio Laconi
- Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Fabio Marongiu
- Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Firouz Darroudi
- Human Safety and Environmental Research, Department of Health Sciences, College of North Atlantic, Doha 24449, State of Qatar
| | - Francis L. Martin
- Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK
| | - Frederik J. Van Schooten
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht 6200, The Netherlands
| | - Gary S. Goldberg
- Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Gerard Wagemaker
- Hacettepe University, Center for Stem Cell Research and Development, Ankara 06640, Turkey
| | - Gladys N. Nangami
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Gloria M. Calaf
- Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA
- Instituto de Alta Investigacion, Universidad de Tarapaca, Arica, Chile
| | - Graeme P. Williams
- School of Biological Sciences, University of Reading, Reading, RG6 6UB, UK
| | - Gregory T. Wolf
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Gudrun Koppen
- Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium
| | - Gunnar Brunborg
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway
| | - H. Kim Lyerly
- Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Harini Krishnan
- Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Hasiah Ab Hamid
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Hemad Yasaei
- Department of Life Sciences, College of Health and Life Sciences and the Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK
| | - Hideko Sone
- National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan
| | - Hiroshi Kondoh
- Department of Geriatric Medicine, Kyoto University Hospital 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto, 606–8507, Japan
| | - Hosni K. Salem
- Department of Urology, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 11559, Egypt
| | - Hsue-Yin Hsu
- Department of Life Sciences, Tzu-Chi University, Hualien 970, Taiwan
| | - Hyun Ho Park
- School of Biotechnology, Yeungnam University, Gyeongbuk 712-749, South Korea
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - A.Ivana Scovassi
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - James E. Klaunig
- Department of Environmental Health, Indiana University, School of Public Health, Bloomington, IN 47405, USA
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics Academy of Sciences of the Czech Republic, Brno, CZ-61265, Czech Republic
| | - Jayadev Raju
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada
| | - Jesse Roman
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, Louisville, KY 40202, USA
| | - John Pierce Wise
- Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA
| | - Jonathan R. Whitfield
- Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Joseph A. Christopher
- Cancer Research UK. Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK
| | - Josiah Ochieng
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | | | - Judith Weisz
- Departments of Obstetrics and Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey PA 17033, USA
| | - Julia Kravchenko
- Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Jun Sun
- Department of Biochemistry, Rush University, Chicago, IL 60612, USA
| | - Kalan R. Prudhomme
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | | | - Karine A. Cohen-Solal
- Department of Medicine/Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Kim Moorwood
- Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Laetitia Gonzalez
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Laura Soucek
- Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain
| | - Le Jian
- School of Public Health, Curtin University, Bentley, WA 6102, Australia
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Leandro S. D’Abronzo
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Lin Li
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People’s Republic of China
| | - Linda Gulliver
- Faculty of Medicine, University of Otago, Dunedin 9054, New Zealand
| | - Lisa J. McCawley
- Department of Biomedical Engineering and Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy
| | - Louis Vermeulen
- Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
| | - Luc Leyns
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
| | - Mahara Valverde
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Mahin Khatami
- Inflammation and Cancer Research, National Cancer Institute (NCI) (Retired), National Institutes of Health, Bethesda, MD 20892, USA
| | - Maria Fiammetta Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Marion Chapellier
- Centre De Recherche En Cancerologie,De Lyon, Lyon, U1052-UMR5286, France
| | - Marc A. Williams
- United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA
| | - Mark Wade
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Via Adamello 16, 20139 Milano, Italy
| | - Masoud H. Manjili
- Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
| | - Matilde E. Lleonart
- Institut De Recerca Hospital Vall D’Hebron, Passeig Vall d’Hebron, 119–129, 08035 Barcelona, Spain
| | - Menghang Xia
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA
| | - Michael J. Gonzalez Guzman
- University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan 00921, Puerto Rico
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, University of Athens, Institute of Molecular Medicine and Biomedical Research, 10676 Athens, Greece
| | | | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George’s Medical University, Lucknow, Uttar Pradesh 226 003, India
| | - Nichola Cruickshanks
- Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Nicole Kleinstreuer
- Integrated Laboratory Systems Inc., in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, RTP, NC 27709, USA
| | - Nik van Larebeke
- Analytische, Milieu en Geochemie, Vrije Universiteit Brussel, Brussel B1050, Belgium
| | - Nuzhat Ahmed
- Department of Obstetrics and Gynecology, University of Melbourne, Victoria 3052, Australia
| | - Olugbemiga Ogunkua
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - P.K. Krishnakumar
- Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 3126, Saudi Arabia
| | - Pankaj Vadgama
- School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, UK
| | - Paola A. Marignani
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
| | - Paramita M. Ghosh
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Patricia Ostrosky-Wegman
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Patricia A. Thompson
- Department of Pathology, Stony Brook School of Medicine, Stony Brook University, The State University of New York, Stony Brook, NY 11794-8691, USA
| | - Paul Dent
- Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Petr Heneberg
- Charles University in Prague, Third Faculty of Medicine, CZ-100 00 Prague 10, Czech Republic
| | - Philippa Darbre
- School of Biological Sciences, The University of Reading, Whiteknights, Reading RG6 6UB, England
| | - Po Sing Leung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People’s Republic of China
| | | | - Qiang (Shawn) Cheng
- Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA
| | - R.Brooks Robey
- White River Junction Veterans Affairs Medical Center, White River Junction, VT 05009, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Rabeah Al-Temaimi
- Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Jabriya 13110, Kuwait
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Rafaela Andrade-Vieira
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
| | - Ranjeet K. Sinha
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Rekha Mehta
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada
| | - Renza Vento
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Riccardo Di Fiore
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy
| | | | - Rita Dornetshuber-Fleiss
- Department of Pharmacology and Toxicology, University of Vienna, Vienna A-1090, Austria
- Institute of Cancer Research, Department of Medicine, Medical University of Vienna, Wien 1090, Austria
| | - Rita Nahta
- Departments of Pharmacology and Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA
| | - Robert C. Castellino
- Division of Hematology and Oncology, Department of Pediatrics, Children’s Healthcare of Atlanta, GA 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Roberta Palorini
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Roslida A. Hamid
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Sabine A.S. Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium
| | - Sakina E. Eltom
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Samira A. Brooks
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Sandra Ryeom
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sandra S. Wise
- Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA
| | - Sarah N. Bay
- Program in Genetics and Molecular Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA
| | - Shelley A. Harris
- Population Health and Prevention, Research, Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, M5G 2L7, Canada
- Departments of Epidemiology and Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada
| | - Silvana Papagerakis
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Simona Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Sofia Pavanello
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
| | - Staffan Eriksson
- Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences, PO Box 7011, VHC, Almas Allé 4, SE-756 51, Uppsala, Sweden
| | - Stefano Forte
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy
| | - Stephanie C. Casey
- Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA
| | - Sudjit Luanpitpong
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tae-Jin Lee
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705–717, South Korea,
| | - Takemi Otsuki
- Department of Hygiene, Kawasaki Medical School, Matsushima Kurashiki, Okayama 701-0192, Japan,
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA
| | - Thierry Massfelder
- INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France
| | - Thomas Sanderson
- INRS-Institut Armand-Frappier, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada,
| | - Tiziana Guarnieri
- Department of Biology, Geology and Environmental Sciences, Alma Mater Studiorum Università di Bologna, Via Francesco Selmi, 3, 40126 Bologna, Italy
- Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Via Massarenti, 9, 40126 Bologna, Italy
- National Institute of Biostructures and Biosystems, Viale Medaglie d’ Oro, 305, 00136 Roma, Italy
| | - Tove Hultman
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden
| | - Valérian Dormoy
- INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France
- Department of Cell and Developmental Biology, University of California, Irvine, CA 92697, USA
| | - Valerie Odero-Marah
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Venkata Sabbisetti
- Harvard Medical School/Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Veronique Maguer-Satta
- United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA
| | - W.Kimryn Rathmell
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Wilhelm Engström
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden
| | | | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | - Yon Rojanasakul
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown,WV, 26506,USA
| | - Yunus Luqmani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait and
| | - Zhenbang Chen
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Zhiwei Hu
- Department of Surgery, The Ohio State University College of Medicine, The James Comprehensive Cancer Center, Columbus, OH 43210, USA
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Langie SA, Koppen G, Desaulniers D, Al-Mulla F, Al-Temaimi R, Amedei A, Azqueta A, Bisson WH, Brown D, Brunborg G, Charles AK, Chen T, Colacci A, Darroudi F, Forte S, Gonzalez L, Hamid RA, Knudsen LE, Leyns L, Lopez de Cerain Salsamendi A, Memeo L, Mondello C, Mothersill C, Olsen AK, Pavanello S, Raju J, Rojas E, Roy R, Ryan E, Ostrosky-Wegman P, Salem HK, Scovassi I, Singh N, Vaccari M, Van Schooten FJ, Valverde M, Woodrick J, Zhang L, van Larebeke N, Kirsch-Volders M, Collins AR. Causes of genome instability: the effect of low dose chemical exposures in modern society. Carcinogenesis 2015; 36 Suppl 1:S61-S88. [PMID: 26106144 PMCID: PMC4565613 DOI: 10.1093/carcin/bgv031] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 12/08/2014] [Accepted: 12/11/2014] [Indexed: 12/17/2022] Open
Abstract
Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.
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Affiliation(s)
- Sabine A.S. Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Boeretang 200, 2400 Mol, Belgium
- Health Canada, Environmental Health Sciences and Research Bureau, Environmental Health Centre, Ottawa, Ontario K1A0K9, Canada
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31009, Spain
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
- Hopkins Building, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6UB, UK
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Human and Environmental Safety Research, Department of Health Sciences, College of North Atlantic, Doha, State of Qatar
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra, Serdang 43400, Selangor, Malaysia
- University of Copenhagen, Department of Public Health, Copenhagen 1353, Denmark
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
- Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200MD, PO Box 61, Maastricht, The Netherlands
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
- Laboratory for Analytical and Environmental Chemistry, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Study Centre for Carcinogenesis and Primary Prevention of Cancer, Ghent University, Ghent 9000, Belgium
- Department of Nutrition, University of Oslo, Oslo 0316, Norway
| | - Gudrun Koppen
- *To whom correspondence should be addressed. Tel: +32 14335165; Fax: +32 14580523
| | - Daniel Desaulniers
- Health Canada, Environmental Health Sciences and Research Bureau, Environmental Health Centre, Ottawa, Ontario K1A0K9, Canada
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
| | - Amaya Azqueta
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31009, Spain
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Dustin Brown
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Gunnar Brunborg
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
| | - Amelia K. Charles
- Hopkins Building, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6UB, UK
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Firouz Darroudi
- Human and Environmental Safety Research, Department of Health Sciences, College of North Atlantic, Doha, State of Qatar
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Laetitia Gonzalez
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Roslida A. Hamid
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra, Serdang 43400, Selangor, Malaysia
| | - Lisbeth E. Knudsen
- University of Copenhagen, Department of Public Health, Copenhagen 1353, Denmark
| | - Luc Leyns
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | | | - Lorenzo Memeo
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Carmel Mothersill
- Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
| | - Ann-Karin Olsen
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
| | - Sofia Pavanello
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Emilio Rojas
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Elizabeth Ryan
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Patricia Ostrosky-Wegman
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Frederik J. Van Schooten
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200MD, PO Box 61, Maastricht, The Netherlands
| | - Mahara Valverde
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
| | - Nik van Larebeke
- Laboratory for Analytical and Environmental Chemistry, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Study Centre for Carcinogenesis and Primary Prevention of Cancer, Ghent University, Ghent 9000, Belgium
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Chene G, Ouellet V, Rahimi K, Barres V, Caceres K, Meunier L, Cyr L, De Ladurantaye M, Provencher D, Mes Masson AM. DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma. Int J Gynecol Cancer 2015; 25:761-9. [PMID: 24987917 DOI: 10.1097/igc.0000000000000196] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC. METHODS/MATERIALS A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E. RESULTS The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different. CONCLUSIONS These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.
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Affiliation(s)
- Gautier Chene
- *Centre de Recherche du Centre hospitalier de l'Université de Montréal; †Institut du Cancer de Montréal, Montreal, Quebec, Canada; ‡Department of Gynecology, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Departments of §Pathology, and ∥Gynecology, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
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Blood Telomere Length Attrition and Cancer Development in the Normative Aging Study Cohort. EBioMedicine 2015; 2:591-6. [PMID: 26288820 PMCID: PMC4535161 DOI: 10.1016/j.ebiom.2015.04.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/09/2015] [Accepted: 04/10/2015] [Indexed: 11/12/2022] Open
Abstract
Background Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence. Methods We included 792 Normative Aging Study participants with 1–4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis. Findings Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (pdifference = 0.017); all participants had similar age-adjusted BTL 8–14 years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p = 0.003) and four (p = 0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR = 1.79, p = 0.03), and longer BTL measured ≤ 4 years pre-diagnosis with any (OR = 3.27, p < 0.001) and prostate cancers (OR = 6.87, p < 0.001). Interpretation Age-related BTL attrition was faster in cancer cases but their age-adjusted BTL attrition began decelerating as diagnosis approached. This may explain prior inconsistencies and help develop BTL as a cancer detection biomarker.
Normal, age-related telomere attrition is faster in subjects who later developed cancer. Telomere attrition began decelerating before cancer diagnosis, resulting in longer telomeres 3–4 years pre-diagnosis. Longer telomeres measured within four years of diagnosis were associated with all-cancer incidence.
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28
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Gonzalez-Vasconcellos I, Alonso-Rodríguez S, López-Baltar I, Fernández JL. Telomere Chromatin Condensation Assay (TCCA): a novel approach to study structural telomere integrity. Mutat Res 2015; 771:51-55. [PMID: 25771980 DOI: 10.1016/j.mrfmmm.2014.12.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 12/02/2014] [Accepted: 12/16/2014] [Indexed: 06/04/2023]
Abstract
Telomeres, the DNA-protein complexes located at the end of linear eukaryotic chromosomes are essential for genome stability. Improper higher-order chromatin organization at the chromosome ends can give rise to telomeric recombination and genomic instability. We report the development of an assay to quantify differences in the condensation of telomeric chromatin, thereby offering new opportunities to study telomere biology and stability. We have combined a DNA nuclease digestion with a quantitative PCR (qPCR) assay of telomeric DNA, which we term the Telomere Chromatin Condensation Assay (TCCA). By quantifying the relative quantities of telomeric DNA that are progressively digested with the exonuclease Bal 31 the method can discriminate between different levels of telomeric chromatin condensation. The structural chromatin packaging at telomeres shielded against exonuclease digestion delivered an estimate, which we term Chromatin Protection Factor (CPF) that ranged from 1.7 to 2.3 fold greater than that present in unpacked DNA. The CPF was significantly decreased when cell cultures were incubated with the DNA hypomethylating agent 5-azacytidine, demonstrating the ability of the TCCA assay to discriminate between packaging levels of telomeric DNA.
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Affiliation(s)
- Iria Gonzalez-Vasconcellos
- INIBIC-Complejo Hospitalario Universitario A Coruña, Unidad de Genética, As Xubias, 84, 15006 A Coruña, Spain
| | - Silvia Alonso-Rodríguez
- INIBIC-Complejo Hospitalario Universitario A Coruña, Unidad de Genética, As Xubias, 84, 15006 A Coruña, Spain
| | - Isidoro López-Baltar
- Laboratorio de Genética Molecular y Radiobiología, Centro Oncológico de Galicia, 15009 A Coruña, Spain
| | - José Luis Fernández
- INIBIC-Complejo Hospitalario Universitario A Coruña, Unidad de Genética, As Xubias, 84, 15006 A Coruña, Spain; Laboratorio de Genética Molecular y Radiobiología, Centro Oncológico de Galicia, 15009 A Coruña, Spain.
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Moir JAG, White SA, Mann J. Arrested development and the great escape--the role of cellular senescence in pancreatic cancer. Int J Biochem Cell Biol 2014; 57:142-8. [PMID: 25461770 DOI: 10.1016/j.biocel.2014.10.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 10/14/2014] [Accepted: 10/15/2014] [Indexed: 12/26/2022]
Abstract
The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro-tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes.
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Affiliation(s)
- John A G Moir
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Steven A White
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Jelena Mann
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom.
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Religa AA, Ramesar J, Janse CJ, Scherf A, Waters AP. P. berghei telomerase subunit TERT is essential for parasite survival. PLoS One 2014; 9:e108930. [PMID: 25275500 PMCID: PMC4183507 DOI: 10.1371/journal.pone.0108930] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/04/2014] [Indexed: 11/29/2022] Open
Abstract
Telomeres define the ends of chromosomes protecting eukaryotic cells from chromosome instability and eventual cell death. The complex regulation of telomeres involves various proteins including telomerase, which is a specialized ribonucleoprotein responsible for telomere maintenance. Telomeres of chromosomes of malaria parasites are kept at a constant length during blood stage proliferation. The 7-bp telomere repeat sequence is universal across different Plasmodium species (GGGTTT/CA), though the average telomere length varies. The catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), is present in all sequenced Plasmodium species and is approximately three times larger than other eukaryotic TERTs. The Plasmodium RNA component of TERT has recently been identified in silico. A strategy to delete the gene encoding TERT via double cross-over (DXO) homologous recombination was undertaken to study the telomerase function in P. berghei. Expression of both TERT and the RNA component (TR) in P. berghei blood stages was analysed by Western blotting and Northern analysis. Average telomere length was measured in several Plasmodium species using Telomere Restriction Fragment (TRF) analysis. TERT and TR were detected in blood stages and an average telomere length of ∼950 bp established. Deletion of the tert gene was performed using standard transfection methodologies and we show the presence of tert− mutants in the transfected parasite populations. Cloning of tert- mutants has been attempted multiple times without success. Thorough analysis of the transfected parasite populations and the parasite obtained from extensive parasite cloning from these populations provide evidence for a so called delayed death phenotype as observed in different organisms lacking TERT. The findings indicate that TERT is essential for P. berghei cell survival. The study extends our current knowledge on telomere biology in malaria parasites and validates further investigations to identify telomerase inhibitors to induce parasite cell death.
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Affiliation(s)
- Agnieszka A. Religa
- Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Jai Ramesar
- Leiden Malaria Research Group, Parasitology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Chris J. Janse
- Leiden Malaria Research Group, Parasitology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Artur Scherf
- Biology of Host-Parasite Interactions Unit, Institut Pasteur, Paris, France
| | - Andrew P. Waters
- Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
- * E-mail:
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Cornélio DA, Tavares JCM, Pimentel TVCDA, Cavalcanti GB, Batistuzzo de Medeiros SR. Cytokinesis-block micronucleus assay adapted for analyzing genomic instability of human mesenchymal stem cells. Stem Cells Dev 2014; 23:823-38. [PMID: 24328548 DOI: 10.1089/scd.2013.0383] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Human mesenchymal stem cells (hMSCs) are multipotent cells used in cell therapy research. One of the problems involving hMSCs is the possibility of genetic instability during in vitro expansion required to obtain a suitable number of cells for clinical applications. The cytokinesis-block micronucleus (CBMN) assay measures genetic instability by analyzing the presence of micronucleus (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) in binucleated cells. The present study describes modifications in the CBMN assay methodology to analyze genetic instability in hMSCs isolated from the umbilical vein and in vitro expanded. The best protocol to achieve binucleated hMSCs with preserved cytoplasm was as follows: cytochalasin B concentration (4.0 μg/mL), use of hypotonic treatment (3 min), and the fixative solution (9 methanol:1 acetic acid). These adaptations were reproduced in three hMSC primary cell cultures and also in XP4PA and A549 cell lines. The frequency of hMSCs treated with mitomycin-C presenting MN was lower than that with other nuclear alterations, indicating that the hMSCs contain mechanisms to avoid a high level of chromosomal breaks. However, a high frequency of cells with NPBs was detected and spontaneous anaphase bridges under normal hMSC in vitro culture were observed. Considering that anaphase bridges are characteristic alterations in tumor cells, the CBMN assay is indicated as an important tool associated with other genetic analyses in order to ensure the safe clinical use of hMSCs in cell therapy.
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Affiliation(s)
- Déborah Afonso Cornélio
- 1 Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte , Natal, Brazil
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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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Abstract
Telomere erosion may be counteracted by telomerase. Here we explored telomere length (TL) and telomerase activity (TA) in primary cutaneous T-cell lymphoma (CTCL) by using quantitative polymerase chain reaction and interphase quantitative fluorescence in situ hybridization assays. Samples from patients with Sézary syndrome (SS), transformed mycosis fungoides (T-MF), and cutaneous anaplastic large cell lymphoma were studied in parallel with corresponding cell lines to evaluate the relevance of TL and TA as target candidates for diagnostic and therapeutic purposes. Compared with controls, short telomeres were observed in aggressive CTCL subtypes such as SS and T-MF and were restricted to neoplastic cells in SS. While no genomic alteration of the hTERT (human telomerase catalytic subunit) locus was observed in patients' tumor cells, TA was detected. To understand the role of telomerase in CTCL, we manipulated its expression in CTCL cell lines. Telomerase inhibition rapidly impeded in vitro cell proliferation and led to cell death, while telomerase overexpression stimulated in vitro proliferation and clonogenicity properties and favored tumor development in immunodeficient mice. Our data indicate that, besides maintenance of TL, telomerase exerts additional functions in CTCL. Therefore, targeting these functions might represent an attractive therapeutic strategy, especially in aggressive CTCL.
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Han X, Liu D, Zhang Y, Li Y, Lu W, Chen J, Songyang Z. Akt regulates TPP1 homodimerization and telomere protection. Aging Cell 2013; 12:1091-9. [PMID: 23862686 DOI: 10.1111/acel.12137] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2013] [Indexed: 12/01/2022] Open
Abstract
Telomeres are specialized structures at the ends of eukaryotic chromosomes that are important for maintaining genome stability and integrity. Telomere dysfunction has been linked to aging and cancer development. In mammalian cells, extensive studies have been carried out to illustrate how core telomeric proteins assemble on telomeres to recruit the telomerase and additional factors for telomere maintenance and protection. In comparison, how changes in growth signaling pathways impact telomeres and telomere-binding proteins remains largely unexplored. The phosphatidylinositol 3-kinase (PI3-K)/Akt (also known as PKB) pathway, one of the best characterized growth signaling cascades, regulates a variety of cellular function including cell proliferation, survival, metabolism, and DNA repair, and dysregulation of PI3-K/Akt signaling has been linked to aging and diseases such as cancer and diabetes. In this study, we provide evidence that the Akt signaling pathway plays an important role in telomere protection. Akt inhibition either by chemical inhibitors or small interfering RNAs induced telomere dysfunction. Furthermore, we found that TPP1 could homodimerize through its OB-fold, a process that was dependent on the Akt kinase. Telomere damage and reduced TPP1 dimerization as a result of Akt inhibition was also accompanied by diminished recruitment of TPP1 and POT1 to the telomeres. Our findings highlight a previously unknown link between Akt signaling and telomere protection.
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Affiliation(s)
- Xin Han
- Key Laboratory of Gene Engineering of the Ministry of Education; School of Life Sciences and Key Laboratory of Reproductive Medicine of Guangdong Province; the First Affiliated Hospital; Sun Yat-Sen University; Guangzhou Guangzhou China
| | - Dan Liu
- Verna and Marrs Mclean Department of Biochemistry and Molecular Biology; Baylor College of Medicine; One Baylor Plaza; Houston TX 77030 USA
| | - Yi Zhang
- Verna and Marrs Mclean Department of Biochemistry and Molecular Biology; Baylor College of Medicine; One Baylor Plaza; Houston TX 77030 USA
| | - Yujing Li
- Key Laboratory of Gene Engineering of the Ministry of Education; School of Life Sciences and Key Laboratory of Reproductive Medicine of Guangdong Province; the First Affiliated Hospital; Sun Yat-Sen University; Guangzhou Guangzhou China
| | - Weisi Lu
- Key Laboratory of Gene Engineering of the Ministry of Education; School of Life Sciences and Key Laboratory of Reproductive Medicine of Guangdong Province; the First Affiliated Hospital; Sun Yat-Sen University; Guangzhou Guangzhou China
| | - Junjie Chen
- Department of Experimental Radiation Oncology; The University of Texas M D Anderson Cancer Center; Houston TX 77030 USA
| | - Zhou Songyang
- Key Laboratory of Gene Engineering of the Ministry of Education; School of Life Sciences and Key Laboratory of Reproductive Medicine of Guangdong Province; the First Affiliated Hospital; Sun Yat-Sen University; Guangzhou Guangzhou China
- Verna and Marrs Mclean Department of Biochemistry and Molecular Biology; Baylor College of Medicine; One Baylor Plaza; Houston TX 77030 USA
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Pal J, Gold JS, Munshi NC, Shammas MA. Biology of telomeres: importance in etiology of esophageal cancer and as therapeutic target. Transl Res 2013; 162:364-70. [PMID: 24090770 PMCID: PMC3834232 DOI: 10.1016/j.trsl.2013.09.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 09/05/2013] [Accepted: 09/06/2013] [Indexed: 11/17/2022]
Abstract
The purpose of this review is to highlight the importance of telomeres, the mechanisms implicated in their maintenance, and their role in the etiology as well as the treatment of human esophageal cancer. We will also discuss the role of telomeres in the maintenance and preservation of genomic integrity, the consequences of telomere dysfunction, and the various factors that may affect telomere health in esophageal tissue predisposing it to oncogenesis. There has been growing evidence that telomeres, which can be affected by various intrinsic and extrinsic factors, contribute to genomic instability, oncogenesis, as well as proliferation of cancer cells. Telomeres are the protective DNA-protein complexes at chromosome ends. Telomeric DNA undergoes progressive shortening with age leading to cellular senescence and/or apoptosis. If senescence/apoptosis is prevented as a consequence of specific genomic changes, continued proliferation leads to very short (ie, dysfunctional) telomeres that can potentially cause genomic instability, thus, increasing the risk for activation of telomere maintenance mechanisms and oncogenesis. Like many other cancers, esophageal cancer cells have short telomeres and elevated telomerase, the enzyme that maintains telomeres in most cancer cells. Homologous recombination, which is implicated in the alternate pathway of telomere elongation, is also elevated in Barrett's-associated esophageal adenocarcinoma. Evidence from our laboratory indicates that both telomerase and homologous recombination contribute to telomere maintenance, DNA repair, and the ongoing survival of esophageal cancer cells. This indicates that telomere maintenance mechanisms may potentially be targeted to make esophageal cancer cells static. The rate at which telomeres in healthy cells shorten is determined by a number of intrinsic and extrinsic factors, including those associated with lifestyle. Avoidance of factors that may directly or indirectly injure esophageal tissue including its telomeric and other genomic DNA can not only reduce the risk of development of esophageal cancer but may also have positive impact on overall health and lifespan.
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Affiliation(s)
- Jagannath Pal
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
| | - Jason S. Gold
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women’s Hospital, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
| | - Nikhil C. Munshi
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
| | - Masood A. Shammas
- Harvard (Dana Farber) Cancer Institute, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
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Penfield JD, Anderson M, Lutzke L, Wang KK. The role of cellular senescence in the gastrointestinal mucosa. Gut Liver 2013; 7:270-7. [PMID: 23710306 PMCID: PMC3661957 DOI: 10.5009/gnl.2013.7.3.270] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Revised: 01/06/2013] [Accepted: 01/07/2013] [Indexed: 12/21/2022] Open
Abstract
Cellular senescence is a biologically irreversible state of cell-growth arrest that occurs following either a replicative or an oncogenic stimulus. This phenomenon occurs as a response to the presence of premalignant cells and appears to be an important anticancer mechanism that keeps these transformed cells at bay. Many exogenous and endogenous triggers for senescence have been recognized to act via genomic or epigenomic pathways. The most common stimulus for senescence is progressive loss of telomeric DNA, which results in the loss of chromosomal stability and eventual unregulated growth and malignancy. Senescence is activated through an interaction between the p16 and p53 tumor-suppressor genes. Senescent cells can be identified in vitro because they express senescence-associated β-galactosidase, a marker of increased lysosomal activity. Cellular senescence plays an integral role in the prevention and development of both benign and malignant gastrointestinal diseases. The senescence cascade and the cell-cycle checkpoints that dictate the progression and maintenance of senescence are important in all types of gastrointestinal cancers, including pancreatic, liver, gastric, colon, and esophageal cancers. Understanding the pathogenic mechanisms involved in cellular senescence is important for the development of agents targeted toward the treatment of gastrointestinal tumors.
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Affiliation(s)
- Joshua D Penfield
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Lima FM, Souza RT, Santori FR, Santos MF, Cortez DR, Barros RM, Cano MI, Valadares HMS, Macedo AM, Mortara RA, da Silveira JF. Interclonal variations in the molecular karyotype of Trypanosoma cruzi: chromosome rearrangements in a single cell-derived clone of the G strain. PLoS One 2013; 8:e63738. [PMID: 23667668 PMCID: PMC3646811 DOI: 10.1371/journal.pone.0063738] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 04/11/2013] [Indexed: 12/22/2022] Open
Abstract
Trypanosoma cruzi comprises a pool of populations which are genetically diverse in terms of DNA content, growth and infectivity. Inter- and intra-strain karyotype heterogeneities have been reported, suggesting that chromosomal rearrangements occurred during the evolution of this parasite. Clone D11 is a single-cell-derived clone of the T. cruzi G strain selected by the minimal dilution method and by infecting Vero cells with metacyclic trypomastigotes. Here we report that the karyotype of clone D11 differs from that of the G strain in both number and size of chromosomal bands. Large chromosomal rearrangement was observed in the chromosomes carrying the tubulin loci. However, most of the chromosome length polymorphisms were of small amplitude, and the absence of one band in clone D11 in relation to its reference position in the G strain could be correlated to the presence of a novel band migrating above or below this position. Despite the presence of chromosomal polymorphism, large syntenic groups were conserved between the isolates. The appearance of new chromosomal bands in clone D11 could be explained by chromosome fusion followed by a chromosome break or interchromosomal exchange of large DNA segments. Our results also suggest that telomeric regions are involved in this process. The variant represented by clone D11 could have been induced by the stress of the cloning procedure or could, as has been suggested for Leishmania infantum, have emerged from a multiclonal, mosaic parasite population submitted to frequent DNA amplification/deletion events, leading to a 'mosaic' structure with different individuals having differently sized versions of the same chromosomes. If this is the case, the variant represented by clone D11 would be better adapted to survive the stress induced by cloning, which includes intracellular development in the mammalian cell. Karyotype polymorphism could be part of the T. cruzi arsenal for responding to environmental pressure.
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Affiliation(s)
- Fabio Mitsuo Lima
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Renata Torres Souza
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Fábio Rinaldo Santori
- Skirball Institute of Biomolecular Medicine, New York University Cancer Center, New York University School of Medicine, New York, New York, United States of America
| | - Michele Fernandes Santos
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Danielle Rodrigues Cortez
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Roberto Moraes Barros
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Maria Isabel Cano
- Departamento de Genética, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, São Paulo, Brazil
| | - Helder Magno Silva Valadares
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Campus Centro-Oeste Dona Lindu, Universidade Federal de São João del-Rey, Divinópolis, Minas Gerais, Brazil
| | - Andréa Mara Macedo
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Renato Arruda Mortara
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - José Franco da Silveira
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
- * E-mail:
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Yasaei H, Gozaly-Chianea Y, Slijepcevic P. Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition. Genome Integr 2013; 4:2. [PMID: 23521760 PMCID: PMC3614538 DOI: 10.1186/2041-9414-4-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 03/18/2013] [Indexed: 11/15/2022] Open
Abstract
Background Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response and acting as a regulator of telomere length maintenance by telomerase, an enzyme that elongates telomeres. Telomere dysfunction manifests in different forms including chromosomal end-to-end fusion, telomere shortening and p53-dependent apoptosis and/or senescence. An important shelterin-associated protein with critical role in telomere protection in human and mouse cells is the catalytic subunit of DNA-protein kinase (DNA-PKcs). DNA-PKcs deficiency in mouse cells results in elevated levels of spontaneous telomeric fusion, a marker of telomere dysfunction, but does not cause telomere length shortening. Similarly, inhibition of DNA-PKcs with chemical inhibitor, IC86621, prevents chromosomal end protection through mechanism reminiscent of dominant-negative reduction in DNA-PKcs activity. Results We demonstrate here that the IC86621 mediated inhibition of DNA-PKcs in two mouse lymphoma cell lines results not only in elevated frequencies of chromosome end-to-end fusions, but also accelerated telomere shortening in the presence of telomerase. Furthermore, we observed increased levels of spontaneous telomeric fusions in Artemis defective human primary fibroblasts in which DNA-PKcs was inhibited, but no significant changes in telomere length. Conclusion These results confirm that DNA-PKcs plays an active role in chromosome end protection in mouse and human cells. Furthermore, it appears that DNA-PKcs is also involved in telomere length regulation, independently of telomerase activity, in mouse lymphoma cells but not in human cells.
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Affiliation(s)
- Hemad Yasaei
- Division of Biosciences, Brunel Institute of Cancer Genetics and Pharmacogenomics, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex, UB8 3PH, UK.
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Wang L, Li PF, Geng M, Cao YC, Yin YC. Correlation between chemosensitivity to anticancer drugs and telomerase reverse transcriptase mRNA expression in gastric cancer. Diagn Pathol 2013; 8:33. [PMID: 23432846 PMCID: PMC3599120 DOI: 10.1186/1746-1596-8-33] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 01/30/2013] [Indexed: 01/08/2023] Open
Abstract
Background The determination of sensitive chemotherapy drugs for gastric cancer (GC) is one of the greatest challenges of adjuvant therapy. Here we evaluated the chemosensitivity of GC to anticancer drugs and the telomerase reverse transcriptase (hTERT) mRNA expression, and investigated the relationship of them. Methods The GC cells which were collected from 68 patients with primary GC were primary cultured. The chemosensitivity of GC cells to anticancer drugs was evaluated successfully using the MTT assay for 60 cases of GC cells, and the hTERT mRNA expression was examined in 60 cases of GC tissues and corresponding normal gastric mucosa and 6 cases of chronic superficial gastritis mucosa by in situ hybridization. Results Taxol, Cisplatin and 5-Fluorouracil were in general more effective than Adriamycin and Mitomycin for GC cells, and the chemosensitivity to anticancer drugs was associated with tumor histological types and a worse tumor grade. Compared to normal gastric mucosa tissues, hTERT mRNA expression was significantly increased in GC (P<0.05), which was related with a worse differentiation and drug-resistance to 5-Fluorouracil or Adriamycin in GC. Conclusions These data demonstrate for the first time that examinations of hTERT mRNA expression as an important factor could be used to select the chemotherapeutic drugs for GC patients. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793217009875483
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Affiliation(s)
- Lin Wang
- Department of Pathology, General Hospital of Jinan Military Command, Jinan, Shandong Province, China.
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