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Roy P, Kandel R, Sawant N, Singh KP. Estrogen-induced reactive oxygen species, through epigenetic reprogramming, causes increased growth in breast cancer cells. Mol Cell Endocrinol 2024; 579:112092. [PMID: 37858609 DOI: 10.1016/j.mce.2023.112092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/14/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
Despite the progress made in cancer diagnosis and treatment, breast cancer remains the second leading cause of cancer-related death among the women. Exposure to elevated levels of endogenous estrogen or environmental estrogenic chemicals is an important risk factor for breast cancer. Estrogen metabolites and ROS generated during estrogen metabolism are known to play a critical role in estrogen carcinogenesis. However, the molecular mechanisms through which estrogen-induced ROS regulate gene expression is not clear. Epigenetic changes of DNA methylation and histone modifications are known to regulate genes expression. Therefore, the objective of this study was to evaluate whether estrogen-induced ROS, through aberrant expression of epigenetic regulatory genes and epigenetic reprogramming, causes growth of breast cancer cells. Estrogen responsive MCF-7 and T47D human breast cancer cells were exposed to natural estrogen 17 beta-estradiol (E2) and synthetic estrogen Diethylstilbestrol (DES) both alone and in combination with antioxidant N-acetyl cysteine. Effects of NAC-mediated scavenging of estrogen-induced ROS on cell growth, gene expression, and histone modifications were measured. The result of MTT and cell cycle analysis revealed significant abrogation of E2 and DES-induced growth by scavenging ROS through NAC. E2 and DES caused significant changes in expression of epigenetic regulatory genes for DNA methylation and histone modifications as well as changes in both gene activating and repressive marks in the Histone H3. NAC restored the expression of epigenetic regulatory genes and changes in histone marks. Novel findings of this study suggest that estrogen can induce growth of breast cancer cells through ROS-dependent regulation of epigenetic regulatory genes and epigenetic reprogramming of histone marks.
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Affiliation(s)
- Priti Roy
- Department of Environmental Toxicology, Texas Tech University, Lubbock, TX, 79409, USA
| | - Ramji Kandel
- Department of Environmental Toxicology, Texas Tech University, Lubbock, TX, 79409, USA
| | - Neha Sawant
- Department of Environmental Toxicology, Texas Tech University, Lubbock, TX, 79409, USA
| | - Kamaleshwar P Singh
- Department of Environmental Toxicology, Texas Tech University, Lubbock, TX, 79409, USA.
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Castellanos G, Valbuena DS, Pérez E, Villegas VE, Rondón-Lagos M. Chromosomal Instability as Enabling Feature and Central Hallmark of Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:189-211. [PMID: 36923397 PMCID: PMC10010144 DOI: 10.2147/bctt.s383759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/11/2022] [Indexed: 03/11/2023]
Abstract
Chromosomal instability (CIN) has become a topic of great interest in recent years, not only for its implications in cancer diagnosis and prognosis but also for its role as an enabling feature and central hallmark of cancer. CIN describes cell-to-cell variation in the number or structure of chromosomes in a tumor population. Although extensive research in recent decades has identified some associations between CIN with response to therapy, specific associations with other hallmarks of cancer have not been fully evidenced. Such associations place CIN as an enabling feature of the other hallmarks of cancer and highlight the importance of deepening its knowledge to improve the outcome in cancer. In addition, studies conducted to date have shown paradoxical findings about the implications of CIN for therapeutic response, with some studies showing associations between high CIN and better therapeutic response, and others showing the opposite: associations between high CIN and therapeutic resistance. This evidences the complex relationships between CIN with the prognosis and response to treatment in cancer. Considering the above, this review focuses on recent studies on the role of CIN in cancer, the cellular mechanisms leading to CIN, its relationship with other hallmarks of cancer, and the emerging therapeutic approaches that are being developed to target such instability, with a primary focus on breast cancer. Further understanding of the complexity of CIN and its association with other hallmarks of cancer could provide a better understanding of the cellular and molecular mechanisms involved in prognosis and response to treatment in cancer and potentially lead to new drug targets.
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Affiliation(s)
- Giovanny Castellanos
- Maestría en Ciencias Biológicas, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia.,School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Duván Sebastián Valbuena
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Erika Pérez
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Victoria E Villegas
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Milena Rondón-Lagos
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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4
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Parvanov D, Ganeva R, Vidolova N, Stamenov G. Decreased number of p16-positive senescent cells in human endometrium as a marker of miscarriage. J Assist Reprod Genet 2021; 38:2087-2095. [PMID: 33821427 DOI: 10.1007/s10815-021-02182-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/29/2021] [Indexed: 10/21/2022] Open
Abstract
PURPOSE The aim of this study was to evaluate whether the number of p16-positive cells in the functional layer of the endometrium could be a useful biomarker to identify women with recurrent implantation failure (RIF) undergoing in vitro fertilization (IVF) at risk of miscarriage. METHODS Immunohistochemical staining was performed in 311 endometrial biopsies taken during mid-luteal phase using antibody against p16INK4A. The percentage of p16-positive cells was determined in luminal, glandular and stromal endometrial cells. After embryo transfer, women were divided into the following groups: unsuccessful embryo implantation (n = 151), miscarriage (n = 66) and live birth (n = 94). The percentage of p16-positive cells in all endometrial compartments was compared among these groups. RESULTS We found that the percentages of p16-positive glandular and luminal epithelial endometrial cells were significantly higher in patients with live births compared to women with miscarriage (9.3% vs. 2.9%, P < 0.001; and 35.2% vs. 11.7%, P = 0.001, respectively). This tendency was not confirmed in thе stroma. The cut-off values with p16-positive luminal cells lower than 12.5% and p16-positive glandular cells lower than 3.2% could be predictive factors for miscarriage (AUC 0.80 and 0.79; sensitivity 71.3% and 74.5%; specificity 74.2% and 71.2%, respectively). CONCLUSION A decreased number of senescent p16-positive cells could be involved in the implantation failures and aetiology of recurrent miscarriage. Women with history of RIF with reduced populations of p16-positive cells in the endometrial glandular and luminal epithelium may be at greater risk for unsuccessful implantation and miscarriage. The percentage of p16-positive luminal epithelial cells may be clinically useful as a biomarker of miscarriage.
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Affiliation(s)
- Dimitar Parvanov
- Nadezhda Women's Health Hospital, 3 "Blaga vest" Street, Sofia, Bulgaria.
| | - Rumiana Ganeva
- Nadezhda Women's Health Hospital, 3 "Blaga vest" Street, Sofia, Bulgaria
| | - Nina Vidolova
- Nadezhda Women's Health Hospital, 3 "Blaga vest" Street, Sofia, Bulgaria
| | - Georgi Stamenov
- Nadezhda Women's Health Hospital, 3 "Blaga vest" Street, Sofia, Bulgaria
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González-Gil C, Ribera J, Ribera JM, Genescà E. The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia. Genes (Basel) 2021; 12:genes12010079. [PMID: 33435487 PMCID: PMC7827355 DOI: 10.3390/genes12010079] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/13/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients.
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Affiliation(s)
- Celia González-Gil
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; (C.G.-G.); (J.R.); (J.M.R.)
| | - Jordi Ribera
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; (C.G.-G.); (J.R.); (J.M.R.)
| | - Josep Maria Ribera
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; (C.G.-G.); (J.R.); (J.M.R.)
- Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, 08916 Badalona, Spain
| | - Eulàlia Genescà
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; (C.G.-G.); (J.R.); (J.M.R.)
- Correspondence: ; Tel.: +34-93-557-28-08
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Zeng F, Heng J, Guo X, Wang Y, Wu W, Tang L, Chen M, Wang S, Deng H, Wang J. The novel TP53 3'-end methylation pattern associated with its expression would be a potential biomarker for breast cancer detection. Breast Cancer Res Treat 2020; 180:237-245. [PMID: 31983017 DOI: 10.1007/s10549-020-05536-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 01/14/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Deficiency or silence of TP53 is an early event in breast tumorigenesis. Aberrant methylation and mutation in regulatory regions were considered as crucial regulators of gene expression. METHODS Using multiplex-PCR and next-generation sequencing technology, we analyzed TP53 mutation spectrum in its promoter region. Using PCR target sequence enrichment and next-generation bisulfite sequencing technology, we analyzed the methylation profile of the promoter and 3'-end regions of TP53 gene in paired breast tumor and normal tissues from 120 breast cancer patients. The expression of TP53 and the flanking gene ATP1B2 was explored with qPCR method in the same cohort. RESULTS No promoter mutation of TP53 gene was found in the cohort of the 120 breast cancer patients. The 3'-end of TP53 gene was hyper-methylated (average 78.71%) compared with the promoter region (average less than 1%) in breast tumor tissues. TP53 was significantly lower expressed (P = 1.68E-15) and hyper-methylated in 3'-end (P = 1.82E-18) in tumor. Negative cis correlation was found between the TP53 expression and its 3'-end methylation (P = 9.02E-8, R = 0.337). TP53 expression was significantly associated with PR status (P = 0.0128), Ki67 level (P = 0.0091), and breast cancer subtypes (P = 0.0109). TP53 3'-end methylation and expression showed a good performance in discriminating breast cancer and normal tissues with an AUC of 0.930. CONCLUSIONS The 3'-end methylation of TP53 might be a crucial regulator for its expression in breast cancer, suggesting that TP53 3'-end hyper-methylation associated with its lower expression could be a potential biomarker for breast cancer diagnosis.
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Affiliation(s)
- Feng Zeng
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jianfu Heng
- Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Xinwu Guo
- Sansure Biotech Inc., Changsha, 410205, Hunan, China
| | - Yue Wang
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Wenhan Wu
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Lili Tang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Min Chen
- Sansure Biotech Inc., Changsha, 410205, Hunan, China
| | - Shouman Wang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Hongyu Deng
- Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Jun Wang
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China.
- Sansure Biotech Inc., Changsha, 410205, Hunan, China.
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Han P, Dang Z, Shen Z, Dai H, Bai Y, Li B, Shao Y. Association of SNPs in the OBFC1 gene and laryngeal carcinoma in Chinese Han male population. Int J Clin Oncol 2019; 24:1042-1048. [PMID: 31016429 DOI: 10.1007/s10147-019-01442-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 04/01/2019] [Indexed: 12/09/2022]
Abstract
BACKGROUND Laryngeal carcinoma (LC) is one of common diagnosed head and neck malignancies. Telomere length has been reported involved in malignant transformation and tumorigenesis. We speculate that single nucleotide polymorphisms (SNPs) in telomere length-related gene oligonucleotide/oligosaccharide-binding folds containing 1 (OBFC1) may have an association with LC in Chinese Han male population. METHODS To prove this hypothesis, we performed a case-control study to analyze the OBFC1 polymorphisms in 172 LC patients and 180 healthy controls. A total of five SNPs (i.e., rs9325507, rs3814220, rs12765878, rs11191865, rs9420707) were selected for further genotyping. RESULTS There was a significant difference in rs9325507 T allele frequency (OR = 0.88, 95% CI 0.64-1.21, P = 0.036) and rs11191865 A allele frequency (OR = 0.86, 95% CI 0.62-1.18, P = 0.009) between patient and control groups. In addition, the rs9325507 T/C genotype, rs3814220 G/A genotype, rs12765878 C/T genotype and rs11191865 A/G genotype had a lower risk of LC based on the results of logistic regression model analysis. CONCLUSIONS The results indicate a potential association between OBFC1 and LC risk in Chinese Han male population. Further work is required to confirm these results and explore the mechanisms of these effects.
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Affiliation(s)
- Peng Han
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, #227 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Zhongping Dang
- Department of Operation, Chang'an District Hospital of Xi'an Jiaotong University, Xi'an, 710100, Shaanxi, China
| | - Zhen Shen
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, #227 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Hao Dai
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, #227 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Yanxia Bai
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, #227 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Baiya Li
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, #227 Yanta West Road, Xi'an, 710061, Shaanxi, China.
| | - Yuan Shao
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, #227 Yanta West Road, Xi'an, 710061, Shaanxi, China.
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Abstract
Autophagy is a conserved process that degrades intracellular components through lysosomes, thereby maintaining energy homeostasis and renewal of organelles. Mounting evidence indicates that autophagy plays a key role in aging and aging-related diseases. Enhanced autophagy can delay aging and prolong life span. The absence of autophagy leads to the accumulation of mutant and misfolded proteins in the cell, which is the basis for the emergence and development of neurodegenerative diseases and other aging-related diseases. It will be of importance to develop approaches to extend the lifespan and improve the health of elderly individuals through the modulation of autophagy.
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Affiliation(s)
- Li Luo
- School of Physical Education and Sports Science, Soochow University, Suzhou, 215021, China
| | - Zheng-Hong Qin
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Aging and Nervous Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, China.
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Radpour R, Forouharkhou F. Single-cell analysis of tumors: Creating new value for molecular biomarker discovery of cancer stem cells and tumor-infiltrating immune cells. World J Stem Cells 2018; 10:160-171. [PMID: 30631391 PMCID: PMC6325074 DOI: 10.4252/wjsc.v10.i11.160] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/18/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
Biomarker-driven individualized treatment in oncology has made tremendous progress through technological developments, new therapeutic modalities and a deeper understanding of the molecular biology for tumors, cancer stem cells and tumor-infiltrating immune cells. Recent technical developments have led to the establishment of a variety of cancer-related diagnostic, prognostic and predictive biomarkers. In this regard, different modern OMICs approaches were assessed in order to categorize and classify prognostically different forms of neoplasia. Despite those technical advancements, the extent of molecular heterogeneity at the individual cell level in human tumors remains largely uncharacterized. Each tumor consists of a mixture of heterogeneous cell types. Therefore, it is important to quantify the dynamic cellular variations in order to predict clinical parameters, such as a response to treatment and or potential for disease recurrence. Recently, single-cell based methods have been developed to characterize the heterogeneity in seemingly homogenous cancer cell populations prior to and during treatment. In this review, we highlight the recent advances for single-cell analysis and discuss the challenges and prospects for molecular characterization of cancer cells, cancer stem cells and tumor-infiltrating immune cells.
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Affiliation(s)
- Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Farzad Forouharkhou
- Department for Bioinformatics, Persian Bioinformatics System, Tehran 14166, Iran
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Kim G, Kim JY, Lim SC, Lee KY, Kim O, Choi HS. SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development. FASEB J 2018; 32:5647-5660. [PMID: 29750576 DOI: 10.1096/fj.201700645rrrrr] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Melanoma is among the most aggressive and treatment-resistant human cancers. Aberrant histone H3 methylation at Lys 9 (H3K9) correlates with carcinogenic gene silencing, but the significance of suppressor of variegation 3-9 homolog 1 (SUV39H1), an H3K9-specific methyltransferase, in melanoma initiation and progression remains unclear. Here, we show that SUV39H1-mediated H3K9 trimethylation facilitates retinoblastoma ( RB) 1 promoter CpG island methylation by interacting with DNA methyltransferase 3A and decreasing RB mRNA and protein in melanoma cells. Reduced RB abundance, in turn, impairs E2F1 transcriptional inhibition, leading to increased peptidyl-prolyl cis-trans isomerase never-in-mitosis A (NIMA)-interacting 1 (PIN1) levels, human keratinocyte neoplastic cell transformation, and melanoma tumorigenesis via enhanced rapidly accelerated fibrosarcoma 1(RAF1)-MEK-ERK signaling pathway activation. In a synergistic model with B16-F1 murine melanoma cells, SUV39H1 and PIN1 overexpression increased melanoma growth, which was abrogated by their inhibition in SUV39H1-overexpressing B16-F1 mice. SUV39H1 also positively correlated with PIN1 expression in human melanoma. Our studies establish SUV39H1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.-Kim, G., Kim, J.-Y., Lim, S.-C., Lee, K. Y., Kim, O., Choi, H. S. SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.
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Affiliation(s)
- Garam Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - Jin-Young Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - Sung-Chul Lim
- Department of Pathology, School of Medicine, Chosun University, Gwangju, South Korea
| | - Kwang Youl Lee
- College of Pharmacy, Chonnam National University, Gwangju, South Korea
| | - Okyun Kim
- College of Pharmacy, Chosun University, Gwangju, South Korea
| | - Hong Seok Choi
- College of Pharmacy, Chosun University, Gwangju, South Korea
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The synthetic antihyperlipidemic drug potassium piperate selectively kills breast cancer cells through inhibiting G1-S-phase transition and inducing apoptosis. Oncotarget 2018; 8:47250-47268. [PMID: 28467790 PMCID: PMC5564562 DOI: 10.18632/oncotarget.16872] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/14/2017] [Indexed: 01/09/2023] Open
Abstract
Piper longum L. is a well-known traditional antihyperlipidemic medicine in China, containing medicinal constituents of piperine, pipernonaline and piperlonguminine in its fruit. However, the antitumor properties of these constituents have not yet been studied. We found that potassium piperate (GBK), a derivative of piperine, inhibited proliferation of cancer cells. GBK selectively inhibited the G1-S-phase transition in breast cancer cells and the G1 arrest was correlated with induction of p27 expression, which is an inhibitor for cyclin-dependent kinases, and inhibition of cyclin A, cyclin E and cyclin B expression. Moreover, GBK treatment led to a downregulation of the mini-chromosome maintenance protein expression and induction of mitochondrial-dependent cell apoptosis in breast cancer cells. Our results also suggested that GBK might also inhibit cancer cell proliferation through epigenetic signaling pathways. A synergistic effect in inhibition of cancer cell proliferation was found when GBK was combined with chemotherapy medicines etoposide phosphate or cisplatin at middle or low doses in vitro. These results show that GBK is a novel potential anti-breast cancer drug that inhibits cell proliferation and promotes cell apoptosis.
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12
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Integrated analysis of promoter methylation and expression of telomere related genes in breast cancer. Oncotarget 2018; 8:25442-25454. [PMID: 28424414 PMCID: PMC5421942 DOI: 10.18632/oncotarget.16036] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 02/07/2017] [Indexed: 11/25/2022] Open
Abstract
Telomeres at the ends of eukaryotic chromosomes play a critical role in tumorgenesis. Using microfluidic PCR and next-generation bisulfite sequencing technology, we investigated the promoter methylation of 29 telomere related genes in paired tumor and normal tissues from 184 breast cancer patients. The expression of significantly differentially methylated genes was quantified using qPCR method.We observed that the average methylation level of the 29 telomere related genes was significant higher in tumor than that in normal tissues (P = 4.30E-21). A total of 4 genes (RAD50, RTEL, TERC and TRF1) showed significant hyper-methylation in breast tumor tissues. RAD51D showed significant methylation difference among the four breast cancer subtypes. The methylation of TERC showed significant association with ER status of breast cancer. The expression profiles of the 4 hyper-methylated genes showed significantly reduced expression in tumor tissues. The integration analysis of methylation and expression of these 4 genes showed a good performance in breast cancer prediction (AUC = 0.947).Our results revealed the methylation pattern of telomere related genes in breast cancer and suggested a novel 4-gene panel might be a valuable biomarker for breast cancer diagnosis.
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Wang L, Zhan X, Shen X, Li M, Yang J, Yu W, Chen H, Jin B, Mao Z. P16 promotes the growth and mobility potential of breast cancer both in vitro and in vivo: the key role of the activation of IL-6/JAK2/STAT3 signaling. Mol Cell Biochem 2018; 446:137-148. [PMID: 29388151 DOI: 10.1007/s11010-018-3281-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 01/16/2018] [Indexed: 11/25/2022]
Abstract
P16 is the product of cyclin-dependent kinase 2 (CDKN2A) gene and plays multi-pronged roles in the cancer progression. Breast cancer (BC) is the most commonly diagnosed cancer type among females. In the current study, the potential function of P16 in the growth and metastasis of BC was investigated. Firstly, the expression statuses of P16 in different cancer types were investigated using Oncomine database and validated with corresponding cancer cell lines. Afterwards, the expression of P16 was knocked down in BC cell line BT-549 and the effect on the cell proliferation, sensitivity to paclitaxel (TAX), apoptosis, migration, and invasion abilities was assessed using CCK-8, Edu, flow cytometry, scratch, and transwell assays, respectively. The influence of P16 inhibition and P16 overexpression on the activity of IL-6/JAK/STAT3 signaling was explored. Additionally, the effect of P16 inhibition on the tumor growth was verified with a BC xenograft mice model. The abnormal expression of P16 was detected in BC cell line BT-549 as well as colorectal cancer and osteosarcoma cell lines. The inhibition of P16 suppressed the cell proliferation, invasion, and migration abilities while induced the apoptosis and sensitivity to TAX in BT-549 cells. At molecular level, P16 knockdown inhibited the expression of IL6ST and Survivin, and the phosphorylation of JAK2 and STAT3. However, the induced expression of P16 in P16-knockdown BT-549 cells restored the activity of IL-6/JAK2/STAT3 pathway. The results of in vitro assays were confirmed with BC xenograft models: the inhibition of P16 decreased the tumor growth rate. Findings outlined in the current study demonstrated that the inhibition of P16 decreased the growth and metastasis potential of BC cells by inhibiting IL-6/JAK2/STAT3 signaling.
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Affiliation(s)
- Le Wang
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Xiangwen Zhan
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Xiaomeng Shen
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Mingzhe Li
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Jianming Yang
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Wenhua Yu
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Hao Chen
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Bo Jin
- Department of Clinical Laboratory, Peking University First Hospital, 8 Xishiku Road, Beijing, 100034, China.
| | - Zebin Mao
- The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
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14
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Tahara T, Shibata T, Okubo M, Kawamura T, Horiguchi N, Ishizuka T, Nakano N, Nagasaka M, Nakagawa Y, Ohmiya N. Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa. Oncotarget 2018; 7:43989-43996. [PMID: 27259265 PMCID: PMC5190073 DOI: 10.18632/oncotarget.9764] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 05/02/2016] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa. METHODS Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive elementResults: We identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=-0.39, P<0.0001) and four of these locus (IGF2: R=-0.35, P=0.0003, SLC16A12: R=-0.35, P=0.0002, P2RX7: R=-0.29, P=0.003, and MYOD1: R=-0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016). CONCLUSION Potential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tomoyuki Shibata
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Masaaki Okubo
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tomohiko Kawamura
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Noriyuki Horiguchi
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Takamitsu Ishizuka
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Naoko Nakano
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Mitsuo Nagasaka
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yoshihito Nakagawa
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Naoki Ohmiya
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
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15
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Romagnolo DF, Daniels KD, Grunwald JT, Ramos SA, Propper CR, Selmin OI. Epigenetics of breast cancer: Modifying role of environmental and bioactive food compounds. Mol Nutr Food Res 2017; 60:1310-29. [PMID: 27144894 DOI: 10.1002/mnfr.201501063] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Revised: 04/24/2016] [Accepted: 04/26/2016] [Indexed: 12/12/2022]
Abstract
SCOPE Reduced expression of tumor suppressor genes (TSG) increases the susceptibility to breast cancer. However, only a small percentage of breast tumors is related to family history and mutational inactivation of TSG. Epigenetics refers to non-mutational events that alter gene expression. Endocrine disruptors found in foods and drinking water may disrupt epigenetically hormonal regulation and increase breast cancer risk. This review centers on the working hypothesis that agonists of the aromatic hydrocarbon receptor (AHR), bisphenol A (BPA), and arsenic compounds, induce in TSG epigenetic signatures that mirror those often seen in sporadic breast tumors. Conversely, it is hypothesized that bioactive food components that target epigenetic mechanisms protect against sporadic breast cancer induced by these disruptors. METHODS AND RESULTS This review highlights (i) overlaps between epigenetic signatures placed in TSG by AHR-ligands, BPA, and arsenic with epigenetic alterations associated with sporadic breast tumorigenesis; and (ii) potential opportunities for the prevention of sporadic breast cancer with food components that target the epigenetic machinery. CONCLUSIONS Characterizing the overlap between epigenetic signatures elicited in TSG by endocrine disruptors with those observed in sporadic breast tumors may afford new strategies for breast cancer prevention with specific bioactive food components or diet.
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Affiliation(s)
- Donato F Romagnolo
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA.,The University of Arizona Cancer Center, Tucson, AZ, USA
| | - Kevin D Daniels
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, USA
| | - Jonathan T Grunwald
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, USA
| | - Stephan A Ramos
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, USA
| | - Catherine R Propper
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, USA
| | - Ornella I Selmin
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA.,The University of Arizona Cancer Center, Tucson, AZ, USA
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16
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Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma. Int J Mol Sci 2016; 17:ijms17122003. [PMID: 27916892 PMCID: PMC5187803 DOI: 10.3390/ijms17122003] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 11/14/2016] [Accepted: 11/22/2016] [Indexed: 12/12/2022] Open
Abstract
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed.
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17
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Wu L, Shen Y, Peng X, Zhang S, Wang M, Xu G, Zheng X, Wang J, Lu C. Aberrant promoter methylation of cancer-related genes in human breast cancer. Oncol Lett 2016; 12:5145-5155. [PMID: 28105221 PMCID: PMC5228392 DOI: 10.3892/ol.2016.5351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 10/18/2016] [Indexed: 12/15/2022] Open
Abstract
The clinical relevance of aberrant DNA methylation is being increasingly recognized in breast cancer. The present study aimed to evaluate the promoter methylation status of seven candidate genes and to explore their potential use as a biomarker for the diagnosis of breast cancer. A total of 70 Chinese patients with breast cancer were recruited, and matched with 20 patients with benign breast disease (BBD). Methylation-specific polymerase chain reaction was performed to measure the methylation status of selected genes. The protein expression of candidate genes was determined by immunohistochemistry. Hypermethylation of Breast cancer 1, early onset; DNA repair associated (BRCA1), glutathione S-transferase pi 1 (GSTP1), cyclin dependent kinase inhibitor 2A, O-6-methylguanine-DNA methyltransferase, phosphatase and tensin homolog, retinoic acid receptor beta 2 and cyclin D2 was observed to be more common in cancerous tissues (24.3, 31.4, 40.0, 27.1, 48.6, 55.7 and 67.1%, respectively) as compared with BBD controls (0.0, 0.0, 20.0, 25.0, 40.0, 40.0 and 45.0%, respectively). Immunohistochemical analysis demonstrated a correlation between the methylation of the target gene and downregulation of protein expression. When BRCA1 and GSTP1 were combined as the biomarker, the area under the receiver operating characteristic curve reached 0.721 (95% confidence interval, 0.616–0.827). The present findings indicated that promoter methylation of cancer-related genes was frequently observed in patients with breast cancer and was associated with various clinical features. Hypermethylation of BRCA1 and GSTP1 may be used as promising biomarkers for breast cancer.
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Affiliation(s)
- Liang Wu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Ye Shen
- Department of Gastrointestinal Surgery, Aoyoung Hospital, Zhangjiagang, Jiangsu 215617, P.R. China
| | - Xianzhen Peng
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Simin Zhang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Ming Wang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Guisheng Xu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Xianzhi Zheng
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Jianming Wang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China; Department of Social Medicine and Health Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, P.R. China; The Innovation Center for Social Risk Governance in Health, Nanjing, Jiangsu, 211166, P.R. China
| | - Cheng Lu
- Department of Breast, Nanjing Maternity and Child Health Hospital of Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China
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18
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Kaya Z, Akkiprik M, Karabulut S, Peker I, Gullu Amuran G, Ozmen T, Gulluoglu BM, Kaya H, Ozer A. Comparison of telomere length and insulin-like growth factor-binding protein 7 promoter methylation between breast cancer tissues and adjacent normal tissues in Turkish women. J Clin Lab Anal 2016; 31. [PMID: 27775181 DOI: 10.1002/jcla.22083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/18/2016] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Both insulin-like growth factor-binding protein 7 (IGFBP7) and telomere length (TL) are associated with proliferation and senescence of human breast cancer. This study assessed the clinical significance of both TL and IGFBP7 methylation status in breast cancer tissues compared with adjacent normal tissues. We also investigated whether IGFBP7 methylation status could be affecting TL. METHODS Telomere length was measured by quantitative PCR to compare tumors with their adjacent normal tissues. The IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. RESULTS Telomeres were shorter in tumor tissues compared to controls (P<.0001). The mean TL was higher in breast cancer with invasive ductal carcinoma (IDC; n=72; P=.014) compared with other histological type (n=29), and TL in IDC with HER2 negative (n=53; P=.017) was higher than TL in IDC with HER2 positive (n=19). However, telomeres were shortened in advanced stages and growing tumors. IGFBP7 methylation was observed in 90% of tumor tissues and 59% of controls (P=.0002). Its frequency was significantly higher in IDC compared with invasive mixed carcinoma (IMC; P=.002) and it was not correlated either with protein expression or the other clinicopathological parameters. CONCLUSION These results suggest that IGFBP7 promoter methylation and shorter TL in tumor compared with adjacent tissues may be predictive biomarkers for breast cancer. Telomere maintenance may be indicative of IDC and IDC with HER2 (-) of breast cancer. Further studies with larger number of cases are necessary to verify this association.
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Affiliation(s)
- Zehra Kaya
- Medical Biology Department, School of Medicine, Marmara University, Istanbul, Turkey.,Medical Biology Department, School of Medicine, Yüzüncü Yıl University, Van, Turkey
| | - Mustafa Akkiprik
- Medical Biology Department, School of Medicine, Marmara University, Istanbul, Turkey
| | - Sevgi Karabulut
- Medical Biology Department, School of Medicine, Marmara University, Istanbul, Turkey.,Health Services Vocational School, Bayburt University, Bayburt, Turkey
| | - Irem Peker
- Medical Biology Department, School of Medicine, Marmara University, Istanbul, Turkey
| | - Gokce Gullu Amuran
- Medical Biology Department, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tolga Ozmen
- General Surgery, School of Medicine, Marmara University, Istanbul, Turkey
| | | | - Handan Kaya
- Pathology Department, School of Medicine, Marmara University, Istanbul, Turkey
| | - Ayse Ozer
- Medical Biology Department, School of Medicine, Marmara University, Istanbul, Turkey
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19
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Danforth DN. Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2016; 10:109-46. [PMID: 27559297 PMCID: PMC4990153 DOI: 10.4137/bcbcr.s39384] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 04/17/2016] [Accepted: 04/19/2016] [Indexed: 12/12/2022]
Abstract
Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women.
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Affiliation(s)
- David N Danforth
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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20
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Aghagolzadeh P, Radpour R. New trends in molecular and cellular biomarker discovery for colorectal cancer. World J Gastroenterol 2016; 22:5678-5693. [PMID: 27433083 PMCID: PMC4932205 DOI: 10.3748/wjg.v22.i25.5678] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/16/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, which is consequence of multistep tumorigenesis of several genetic and epigenetic events. Since CRC is mostly asymptomatic until it progresses to advanced stages, the early detection using effective screening approaches, selection of appropriate therapeutic strategies and efficient follow-up programs are essential to reduce CRC mortalities. Biomarker discovery for CRC based on the personalized genotype and clinical information could facilitate the classification of patients with certain types and stages of cancer to tailor preventive and therapeutic approaches. These cancer-related biomarkers should be highly sensitive and specific in a wide range of specimen(s) (including tumor tissues, patients’ fluids or stool). Reliable biomarkers which enable the early detection of CRC, can improve early diagnosis, prognosis, treatment response prediction, and recurrence risk. Advances in our understanding of the natural history of CRC have led to the development of different CRC associated molecular and cellular biomarkers. This review highlights the new trends and approaches in CRC biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches and follow-up of patients.
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21
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Khan S, Shukla S, Sinha S, Meeran SM. Epigenetic targets in cancer and aging: dietary and therapeutic interventions. Expert Opin Ther Targets 2016; 20:689-703. [PMID: 26667209 DOI: 10.1517/14728222.2016.1132702] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Epigenetic regulation plays a critical role in normal growth and embryonic development by controlling the transcriptional activities of several genes. A growing number of epigenetic changes have been reported in the regulation of key genes involved in cancer and aging. Drugs with epigenetic modulatory activities, mainly histone deacetylase and DNA methyltransferase inhibitors, have received wider attention in aging and cancer research. AREAS COVERED In this review, we summarize the major epigenetic alterations in cancer and aging, with special emphasis on possible therapeutic targets and interventions by dietary as well as bioactive phytochemicals. EXPERT OPINION Some epigenetic-targeting drugs have received FDA approval and many others are undergoing different phases of clinical trials for cancer therapy. In addition to the synthetic compounds, several bioactive phytochemicals and dietary interventions, such as caloric restriction, have been shown to possess epigenetic modulatory activities in multiple cancers. These epigenetic modulators have been shown to delay aging and minimize the risk of cancer both in preclinical as well as clinical models. Therefore, knowledge of bioactive phytochemicals along with dietary interventions can be utilized for cancer prevention and therapy both alone and with existing drugs to achieve optimum efficacy.
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Affiliation(s)
- Sajid Khan
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
| | - Samriddhi Shukla
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
| | - Sonam Sinha
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
| | - Syed Musthapa Meeran
- a Division of Endocrinology , CSIR-Central Drug Research Institute , Lucknow , India
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22
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Nikolic N, Anicic B, Carkic J, Simonovic J, Toljic B, Tanic N, Tepavcevic Z, Vukadinovic M, Konstantinovic VS, Milasin J. High frequency of p16 and p14 promoter hypermethylation and marked telomere instability in salivary gland tumors. Arch Oral Biol 2015; 60:1662-6. [DOI: 10.1016/j.archoralbio.2015.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 06/18/2015] [Accepted: 08/18/2015] [Indexed: 12/22/2022]
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23
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Hu CW, Hsu CL, Wang YC, Ishihama Y, Ku WC, Huang HC, Juan HF. Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin. Mol Cell Proteomics 2015; 14:3284-98. [PMID: 26503892 DOI: 10.1074/mcp.m115.051383] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Indexed: 12/19/2022] Open
Abstract
Citreoviridin, one of toxic mycotoxins derived from fungal species, can suppress lung cancer cell growth by inhibiting the activity of ectopic ATP synthase, but has limited effect on normal cells. However, the mechanism of citreoviridin triggering dynamic molecular responses in cancer cells remains unclear. Here, we performed temporal phosphoproteomics to elucidate the dynamic changes after citreoviridin treatment in cells and xenograft model. We identified a total of 829 phosphoproteins and demonstrated that citreoviridin treatment affects protein folding, cell cycle, and cytoskeleton function. Furthermore, response network constructed by mathematical modeling shows the relationship between the phosphorylated heat shock protein 90 β and mitogen-activated protein kinase signaling pathway. This work describes that citreoviridin suppresses cancer cell growth and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 and provides perspectives in cancer therapeutic strategies.
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Affiliation(s)
- Chia-Wei Hu
- From the ‡Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan
| | - Chia-Lang Hsu
- §Department of Life Science, National Taiwan University, Taipei 106, Taiwan
| | - Yu-Chao Wang
- ¶Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 112, Taiwan
| | - Yasushi Ishihama
- ‖Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
| | - Wei-Chi Ku
- **School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Hsuan-Cheng Huang
- ¶Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 112, Taiwan;
| | - Hsueh-Fen Juan
- From the ‡Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan; §Department of Life Science, National Taiwan University, Taipei 106, Taiwan; ‡‡Genome and Systems Biology Degree Program, National Taiwan University, Taipei 106, Taiwan; §§Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan
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24
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Telomere length alterations unique to invasive lobular carcinoma. Hum Pathol 2015; 46:1197-203. [DOI: 10.1016/j.humpath.2015.05.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 04/30/2015] [Accepted: 05/07/2015] [Indexed: 12/17/2022]
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25
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Delmonico L, Moreira ADS, Franco MF, Esteves EB, Scherrer L, Gallo CVDM, do Nascimento CM, Ornellas MHF, de Azevedo CM, Alves G. CDKN2A (p14(ARF)/p16(INK4a)) and ATM promoter methylation in patients with impalpable breast lesions. Hum Pathol 2015; 46:1540-7. [PMID: 26255234 DOI: 10.1016/j.humpath.2015.06.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 06/05/2015] [Accepted: 06/10/2015] [Indexed: 12/16/2022]
Abstract
Early detection of breast cancer increases the chances of cure, but the reliable identification of impalpable lesions is still a challenge. In spite of the advances in breast cancer detection, the molecular basis of impalpable lesions and the corresponding circulating biomarkers are not well understood. Impalpable lesions, classified by radiologists according to the Breast Imaging Reporting and Data System in the categories 3 and 4, can be either benign or malignant (slow growing or aggressive). In this article, we report the DNA methylation pattern in CDKN2A (p14(ARF)/p16(INK4a)) and in ATM gene promoters from 62 impalpable lesions, 39 peripheral blood samples, and 39 saliva samples, assessed by methylation-specific polymerase chain reaction method. ATM showed the greatest percentage of methylation in DNA from lesions (benign and malignant), blood (even with p16(INK4a)), and saliva, followed by p16(INK4a) and p14(ARF). Among the malignant cases, ATM promoter was the most hypermethylated in lesion DNA and in blood and saliva DNAs, and p14(ARF), the least. The highest percentage of p16(INK4a) methylation was found in the blood. Finally, our data are relevant because they were obtained using impalpable breast lesions from patients who were carefully recruited in 2 public hospitals of Rio de Janeiro.
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Affiliation(s)
- Lucas Delmonico
- Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil; Pós-Graduação em Ciências Médicas, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-170, Brazil; Laboratório de Marcadores Circulantes, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-170, Brazil
| | - Aline dos Santos Moreira
- Laboratório de Genômica Funcional de Bioinformática, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil
| | - Marco Felipe Franco
- Serviço de Radiologia, Hospital Universitário Gaffrée-Guinle, Rio de Janeiro 20270-004, Brazil
| | | | - Luciano Scherrer
- Sociedade Brasileira Oncologia Clínica, Belo Horizonte, Minas Gerais 30120-010, Brazil
| | - Claúdia Vitória de Moura Gallo
- Departamento de Genética, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro 20550-900, Brazil
| | | | - Maria Helena Faria Ornellas
- Pós-Graduação em Ciências Médicas, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-170, Brazil; Laboratório de Marcadores Circulantes, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-170, Brazil
| | | | - Gilda Alves
- Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil; Pós-Graduação em Ciências Médicas, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-170, Brazil; Laboratório de Marcadores Circulantes, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-170, Brazil.
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KAMMORI MAKOTO, SUGISHITA YOSHIYUKI, OKAMOTO TAKAHIRO, KOBAYASHI MAKIO, YAMAZAKI KAZUKO, YAMADA EMIKO, YAMADA TETSU. Telomere shortening in breast cancer correlates with the pathological features of tumor progression. Oncol Rep 2015; 34:627-32. [DOI: 10.3892/or.2015.4063] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 06/02/2015] [Indexed: 11/06/2022] Open
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DNA methylation analysis of cancer-related genes in oral epithelial cells of healthy smokers. Arch Oral Biol 2015; 60:825-33. [PMID: 25791328 DOI: 10.1016/j.archoralbio.2015.02.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 11/18/2014] [Accepted: 02/24/2015] [Indexed: 12/22/2022]
Abstract
AIM The aim of this study was to investigate the smoking habit influence on DNA methylation status in the promoters of the cancer related-genes MLH1, hTERT and TP53 in oral epithelial cells of healthy subjects. MATERIALS AND METHODS DNA methylation analysis was performed using methylation-sensitive restriction enzymes (MSRE) in oral epithelial cells from non-smokers, smokers and ex-smokers. RESULTS The investigated CpG dinucleotides located at HhaI and HpaII sites in the MLH1 gene promoter were observed to be fully methylated in the majority of DNA samples from the smoker group and statistical differences were found between non-smokers and smokers and between smokers and ex-smokers (p<0.05). The same was observed in the hTERT gene promoter at HhaI sites (p<0.05) and for HpaII sites the unmethylated condition was more frequent in smokers in comparison to non-smokers (p<0.05). For TP53, no differences were found among groups (p>0.05), with the fully methylated condition found to be a common event in healthy oral epithelial cells. CONCLUSION We conclude that smoking may induce changes in DNA methylation status in cancer-related genes of oral epithelial cells and that the cessation of smoking is capable of reversing this process. Based on our data, we suggest that DNA methylation status of the hTERT and MLH1 gene promoters are promising markers for screening a set of smoking-related alterations in oral cells.
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Llanos AA, Dumitrescu RG, Brasky TM, Liu Z, Mason JB, Marian C, Makambi KH, Spear SL, Kallakury BVS, Freudenheim JL, Shields PG. Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues. Carcinogenesis 2014; 36:60-7. [PMID: 25344837 DOI: 10.1093/carcin/bgu219] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
p16(INK4a) is a tumor suppressor gene, frequently hypermethylated in breast cancer; this epigenetic silencing of p16(INK4a) occurs early in carcinogenesis. The risk factors and functional consequences of p16(INK4a) methylation are unknown. Alcohol consumption, a breast cancer risk factor, impedes folate metabolism and may thereby alter gene methylation since folate plays a pivotal role in DNA methylation. In a cross-sectional study of 138 women with no history of breast cancer who underwent reduction mammoplasty, we studied breast cancer risk factors, plasma and breast folate concentrations, variation in one-carbon metabolism genes, p16(INK4a) promoter methylation and P16 protein expression. Logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). p16(INK4a) methylation was negatively correlated with P16 expression (r = -0.28; P = 0.002). Alcohol consumption was associated with lower breast folate (P = 0.03), higher p16(INK4a) promoter methylation (P = 0.007) and less P16 expression (P = 0.002). Higher breast folate concentrations were associated with lower p16(INK4a) promoter methylation (P = 0.06). Genetic variation in MTRR (rs1801394) and MTHFD1 (rs1950902) was associated with higher p16 (INK4a) promoter methylation (OR = 2.66, 95% CI: 1.11-6.42 and OR = 2.72, 95% CI: 1.12-6.66, respectively), whereas variation in TYMS (rs502396) was associated with less P16 protein expression (OR = 0.22, 95% CI: 0.05-0.99). Given that this is the first study to indicate that alcohol consumption, breast folate and variation in one-carbon metabolism genes are associated with p16(INK4a) promoter methylation and P16 protein expression in healthy tissues; these findings require replication.
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Affiliation(s)
- Adana A Llanos
- Division of Population Sciences, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43201, USA, Department of Epidemiology, RBHS-School of Public Health and Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Ramona G Dumitrescu
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA, Department of Medical Genetics and Epidemiology, Basic Sciences Program, Saba University School of Medicine, Saba, Dutch Caribbean, The Netherlands
| | - Theodore M Brasky
- Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Zhenhua Liu
- Human Nutrition Research Center, Tufts University, Boston, MA 02111, USA, Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Joel B Mason
- Human Nutrition Research Center, Tufts University, Boston, MA 02111, USA
| | - Catalin Marian
- Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH 43210, USA, Department of Biochemistry and Pharmacology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Kepher H Makambi
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC 20057, USA
| | - Scott L Spear
- Department of Plastic Surgery, Georgetown University, Washington, DC 20057, USA
| | | | - Jo L Freudenheim
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214, USA
| | - Peter G Shields
- Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, OH 43210, USA,
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Comparative analyses of individual and multiple alterations of p53, PTEN and p16 in non-small cell lung carcinoma, glioma and breast carcinoma samples. Biomed Pharmacother 2014; 68:521-6. [DOI: 10.1016/j.biopha.2014.03.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 03/13/2014] [Indexed: 02/08/2023] Open
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Haghighi MM, Aghagolzadeh P, Zadeh SM, Molaei M, Zali MR, Radpour R. Telomere shortening: a biological marker of sporadic colorectal cancer with normal expression of p53 and mismatch repair proteins. Genet Test Mol Biomarkers 2014; 18:236-44. [PMID: 24495131 DOI: 10.1089/gtmb.2013.0436] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Uncontrolled growth of cells, a main criterion of cancer, is merged with pathologic telomere length alteration. Thereby, measurement of telomere length could provide important information on cell proliferation and senescence in cancer tissues. Telomere shortening and its potential correlation with clinicopathological predictive markers in sporadic colorectal cancer (CRC) with normal expression of mismatch repair (MMR) proteins (including Mlh1, Msh2, Pms2, and Msh6) and normal p53 expression was completely explored. Relative telomere length (RTL) was quantitatively measured in a cohort of 164 samples (68 patients with sporadic CRC and 96 healthy unrelated controls). Our results demonstrated a significant shortening of RTL in the tumor-derived tissue of patients compared with the control group (p<0.001). Interestingly, significant telomere shortening was observed in tumors from an ascending and sigmoid colon in comparison with tumors located in a descending colon. Additionally, the telomere length was significantly shorter in those with lymph node metastasis (p<0.05). The results suggest that pathological telomere shortening, leading to genome instability and lymphatic transformation, could serve as a potential sensitive detection and also as a classification marker for facilitating diagnosis and management of CRC.
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Affiliation(s)
- Mahdi Montazer Haghighi
- 1 Department of Biology, Science Faculty, Islamic Azad University , East Tehran Branch, Tehran, Iran
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Zhang JC, Gao B, Yu ZT, Liu XB, Lu J, Xie F, Luo HJ, Li HP. Promoter hypermethylation of p14 (ARF) , RB, and INK4 gene family in hepatocellular carcinoma with hepatitis B virus infection. Tumour Biol 2013; 35:2795-802. [PMID: 24254306 DOI: 10.1007/s13277-013-1372-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 10/28/2013] [Indexed: 01/14/2023] Open
Abstract
Both hepatitis B virus (HBV) and gene methylation play important roles in hepatocarcinogenesis. However, their association between HBV infection and gene methylation is not fully understood. Cell cycle control involving RB1 gene-related cell inhibitors is one of the main regulatory pathways were reported to be altered in hepatocellular carcinoma (HCC). The purpose of this research is to assess the methylation status of p14 (ARF) and INK4 gene family (p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and p18 (INK4C) ) in HCC with HBV infection and HCC without it, and discuss possible role of HBV-induced hypermethylation in the mechanism of hepatocarcinogenesis. Methylation status of RB, p14 (ARF) , and INK4 gene family in 64 case of HCC with HBV infection and 24 cases without it were detected by methylation-specific polymerase chain reaction, and HBV-DNA of the plasma were detected by quantitative real-time polymerase chain reaction. p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and RB hypermethylation were observed in 30 (34.1%), 50 (56.8%), 62 (70.5%), and 24(27.3%) of 88 hepatocellular carcinomas, respectively. Methylation frequencies of them between HCC with HBV infection and HCC without it were 43.8% versus 8.3 % (p14 (ARF) ), 68.9% versus 25% (p15 (INK4B) ), 90.6% versus 16.7% ( p16 (INK4A) ), and 28.1 % versus 25% (RB), respectively. In HBV-associated HCC, the numbers of methylated genes were also more than HCC without virus infection, more than two methylated genes were seen in 48 of 64 (75 %) cases; more than three methylated genes were found in 32 of 64 (50%); correspondently, no one case has more than two genes methylated. p18 (INK4C) methylation product was not found in cancerous or non-cancerous tissues of 88 HCC. HBV infection is associated with p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and RB gene methylation (P = 0.048, 0.035, 0.02); HBV-DNA replication is associated with p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and RB gene methylation (P = 0.048, 0.035, 0.02); high rate of p14 (ARF) , p15 (INK4B) , and p16 (INK4A) in HCC with HBV infection suggests that HBV-induced hypermethylation may be one of the mechanisms of HBV involved in hepatocellular carcinogenesis.
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Affiliation(s)
- Ji-Cai Zhang
- Department of Laboratory Medicine, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan, 442000, People's Republic of China
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Shan M, Zhang X, Liu X, Qin Y, Liu T, Liu Y, Wang J, Zhong Z, Zhang Y, Geng J, Pang D. P16 and p53 play distinct roles in different subtypes of breast cancer. PLoS One 2013; 8:e76408. [PMID: 24146864 PMCID: PMC3795768 DOI: 10.1371/journal.pone.0076408] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 08/26/2013] [Indexed: 11/18/2022] Open
Abstract
Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16INK4a and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple-negative breast cancers in DCIS and IDC.
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Affiliation(s)
- Ming Shan
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Xianyu Zhang
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Xiaolong Liu
- Department of Pathology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Yu Qin
- Department of Pathology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Tong Liu
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Yang Liu
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ji Wang
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Zhenbin Zhong
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Youxue Zhang
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Jingshu Geng
- Department of Pathology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Da Pang
- Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
- * E-mail:
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Burke LS, Hyland PL, Pfeiffer RM, Prescott J, Wheeler W, Mirabello L, Savage SA, Burdette L, Yeager M, Chanock S, De Vivo I, Tucker MA, Goldstein AM, Yang XR. Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. PLoS One 2013; 8:e71121. [PMID: 23990928 PMCID: PMC3747185 DOI: 10.1371/journal.pone.0071121] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 06/25/2013] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. DISCUSSION Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.
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Affiliation(s)
- Laura S. Burke
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Paula L. Hyland
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
- Cancer Prevention Fellowship Program, Office of Directors, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Ruth M. Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Jennifer Prescott
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
- Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - William Wheeler
- Information Management Services, Inc., Rockville, Maryland, United States of America
| | - Lisa Mirabello
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Sharon A. Savage
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Laurie Burdette
- Core Genotyping Facility, SAIC-Frederick, Inc., National Cancer Institute -Frederick, Frederick, Maryland, United States of America
| | - Meredith Yeager
- Core Genotyping Facility, SAIC-Frederick, Inc., National Cancer Institute -Frederick, Frederick, Maryland, United States of America
| | - Stephen Chanock
- Core Genotyping Facility, SAIC-Frederick, Inc., National Cancer Institute -Frederick, Frederick, Maryland, United States of America
| | - Immaculata De Vivo
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
- Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Margaret A. Tucker
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Alisa M. Goldstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
| | - Xiaohong R. Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America
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Hao XD, Yang Y, Song X, Zhao XK, Wang LD, He JD, Kong QP, Tang NLS, Zhang YP. Correlation of telomere length shortening with TP53 somatic mutations, polymorphisms and allelic loss in breast tumors and esophageal cancer. Oncol Rep 2012; 29:226-36. [PMID: 23124483 DOI: 10.3892/or.2012.2098] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Accepted: 09/07/2012] [Indexed: 11/05/2022] Open
Abstract
Genomic instability caused by telomere erosion is an important mechanism of tumorigenesis. p53 plays a key role in cellular senescence and/or apoptosis associated with telomere erosion which positions p53 as a guard against tumorigenesis. The present study was undertaken to investigate the potential interactions between p53 functional mutations, polymorphisms, allelic loss and telomere erosion in 126 breast tumor patients and 68 esophageal cancer patients. Telomere length (TL) was measured by real-time quantitative PCR. Somatic mutations, polymorphisms and allelic loss in the TP53 gene were detected by direct sequencing of both tumor and normal tissue samples. Our results showed that telomeres were significantly shorter in tumors with somatic p53 mutations compared with tumors with wild-type p53 in both breast tumors (P=0.007) and esophageal cancer (P=0.001). Telomeres of patients with minor genotype CC of rs12951053 and GG of rs1042522 were significantly shorter compared to patients with other genotypes of this single nucleotide polymorphism in esophageal cancer tissue. Furthermore, TP53 allelic loss was detected and significantly associated with somatic mutations in both types of tumor tissues. These findings suggest that somatic p53 mutations, rs12951053 genotype CC and rs1042522 genotype GG contribute to erosion of telomeres, and TP53 allelic loss may be one of the representations of chromosomal instability caused by telomere erosion combined with somatic p53 mutations. These results support that the TP53 gene has a strong interaction with TL erosion in tumorigenesis.
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Affiliation(s)
- Xiao-Dan Hao
- State Key Laboratory of Genetic Resources and Evolution, and Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, PR China
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Butler KS, Hines WC, Heaphy CM, Griffith JK. Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas. Cancer Med 2012; 1:165-75. [PMID: 23342266 PMCID: PMC3544452 DOI: 10.1002/cam4.14] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 05/15/2012] [Accepted: 06/01/2012] [Indexed: 02/02/2023] Open
Abstract
Telomere dysregulation occurs in both the in situ and invasive stages of many carcinomas, including breast. Knockout experiments have identified several telomere-associated proteins required for proper telomere function and maintenance, including telomere repeat-binding factor 1 and 2 (TRF1 and TRF2), protection of telomeres (POT1), and TRF1-interacting nuclear factor 2 (TIN2). Using telomere content assays and quantitative reverse transcription-polymerase chain reaction (RT-PCR), we examined the relationship between telomere length and the mRNA levels of telomere-associated proteins in breast tumors. The levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Significant associations were identified between the mRNA levels of TRF1, TIN2, and POT1; however, there were no significant associations with the mRNA levels of TRF2 or TERT. These associations suggest that a complex transcriptional program coordinately regulates the expression of these mRNAs. We examined the promoter regions of the telomere-associated proteins to identify transcription factors consistent with the observed patterns of presumed coordinate expression. We demonstrated in human breast cancer cell lines that expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by tumor necrosis factor-α (TNF-α), suggesting activation of the nuclear factor kappa B transcription factor. These findings link telomere content in breast tumors to the coordinate expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines. The results further suggest a possible link between the expressions of the telomere-associated proteins and mediators of stress and inflammation. Telomere content assays and quantitative RT-PCR demonstrate that the levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Within human breast cancer cell lines, expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by TNF-α, suggesting activation of the NFκB transcription factor. These findings link telomere content in breast tumors to the expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines and suggest a link between the expressions of the telomere-associated proteins and mediators of stress and inflammation.
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Affiliation(s)
- Kimberly S Butler
- Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine Albuquerque, New Mexico, 87131, USA
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Hou L, Zhang X, Wang D, Baccarelli A. Environmental chemical exposures and human epigenetics. Int J Epidemiol 2012; 41:79-105. [PMID: 22253299 PMCID: PMC3304523 DOI: 10.1093/ije/dyr154] [Citation(s) in RCA: 291] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2011] [Indexed: 02/06/2023] Open
Abstract
Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes.
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Affiliation(s)
- Lifang Hou
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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Moelans CB, Verschuur-Maes AHJ, van Diest PJ. Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. J Pathol 2011; 225:222-31. [DOI: 10.1002/path.2930] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 04/08/2011] [Accepted: 04/25/2011] [Indexed: 12/25/2022]
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Wentzensen IM, Mirabello L, Pfeiffer RM, Savage SA. The association of telomere length and cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2011; 20:1238-50. [PMID: 21467229 PMCID: PMC3111877 DOI: 10.1158/1055-9965.epi-11-0005] [Citation(s) in RCA: 370] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Telomeres shorten with each cell division and are essential for chromosomal stability. Short telomeres in surrogate tissues (e.g., blood cells) are associated with increased cancer risk in several case-control studies, but findings are inconsistent in prospective studies. METHODS We systematically reviewed studies published prior to August 30, 2010, on the association between telomere length (TL) in surrogate tissues and cancer. There were 27 reports on 13 cancers and/or incident cancer investigating this association. The majority, 16, were retrospective case--control studies, 11 were prospective studies. Meta-analyses were conducted to determine ORs and 95% CIs for these studies. RESULTS Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found associations between short telomeres and these cancers. Non-Hodgkin lymphoma, breast, lung, and colorectal cancer reports were inconsistent. Single studies on endometrial, prostate, and skin cancers were null. In a random-effects meta-analysis, short TL was significantly associated with cancer in retrospective studies (pooled OR for the shortest TL quartile compared with the longest: 2.9, 95% CI: 1.75-4.8, P < 0.0001). The pooled OR for prospective studies was 1.16 (95% CI: 0.87-1.54, P = 0.32). All studies combined yielded a pooled OR of 1.96 (95% CI: 1.37-2.81, P = 0.0001) for the association of short TL and cancer. CONCLUSION AND IMPACT There is suggestive evidence that short surrogate tissue TL is associated with cancer; the strongest evidence exists for bladder, esophageal, gastric, and renal cancers. Additional prospective studies with consistent methodology are needed to confirm this hypothesis.
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Affiliation(s)
- Ingrid M. Wentzensen
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Rockville, MD 20852
| | - Lisa Mirabello
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Rockville, MD 20852
| | - Ruth M. Pfeiffer
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Rockville, MD 20852
| | - Sharon A. Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Rockville, MD 20852
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Heaphy CM, Subhawong AP, Gross AL, Konishi Y, Kouprina N, Argani P, Visvanathan K, Meeker AK. Shorter telomeres in luminal B, HER-2 and triple-negative breast cancer subtypes. Mod Pathol 2011; 24:194-200. [PMID: 21057458 PMCID: PMC4416483 DOI: 10.1038/modpathol.2010.198] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Telomeres are nucleoprotein structures that protect chromosome ends from degradation and recombination. Cancers often have critically shortened telomeres, contributing to genomic instability. Many of these tumors activate telomerase to stabilize telomeric ends and achieve a capacity for unlimited replication. Telomere shortening has been reported in in situ and invasive carcinomas, including breast, and has been associated with disease recurrence after surgical resection. However, previous studies have not evaluated breast cancer subtypes. The objective of this study was to evaluate telomere lengths in different subtypes of breast cancer. Breast carcinomas (n=103) identified between 2001 and 2010 from patients seen at the Johns Hopkins Hospital were categorized into luminal A (n=18), luminal B (n=28), HER-2-positive (n=20) and triple-negative carcinomas (n=37) based on tumor characteristics. Telomere lengths were assessed directly at the single cell level by fluorescence in situ hybridization, and patient groups were compared using Fisher's exact tests. ER-negative status (P=0.022), PR-negative status (P=0.008), HER-2-positive status (P=0.023) and p53-positive status (P=0.022) were associated with shorter telomere length. A larger proportion of luminal A cancers had normal or long telomere lengths as compared with luminal B cases (P=0.002), HER-2-positive cases (P=0.011) or triple-negative cases (P=0.0003). Luminal B, HER-2-positive and triple-negative cases did not differ significantly. Telomere length was shorter in more aggressive subtypes, such as luminal B, HER-2-positive and triple-negative tumors, suggesting that tumor telomere length may have utility as a prognostic and/or risk marker for breast cancer.
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Radpour R, Barekati Z, Kohler C, Lv Q, Bürki N, Diesch C, Bitzer J, Zheng H, Schmid S, Zhong XY. Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a blood-based test in breast cancer. PLoS One 2011; 6:e16080. [PMID: 21283676 PMCID: PMC3025923 DOI: 10.1371/journal.pone.0016080] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2010] [Accepted: 12/06/2010] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Aberrant DNA methylation patterns might be used as a biomarker for diagnosis and management of cancer patients. METHODS AND FINDINGS To achieve a gene panel for developing a breast cancer blood-based test we quantitatively assessed the DNA methylation proportion of 248 CpG sites per sample (total of 31,248 sites in all analyzed samples) on 10 candidate genes (APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P16, P21 and TIMP3). The number of 126 samples consisting of two different cohorts was used (first cohort: plasma samples from breast cancer patients and normal controls; second cohort: triple matched samples including cancerous tissue, matched normal tissue and serum samples). In the first cohort, circulating cell free methylated DNA of the 8 tumor suppressor genes (TSGs) was significantly higher in patients with breast cancer compared to normal controls (P<0.01). In the second cohort containing triple matched samples, seven genes showed concordant hypermethylated profile in tumor tissue and serum samples compared to normal tissue (P<0.05). Using eight genes as a panel to develop a blood-based test for breast cancer, a sensitivity and specificity of more than 90% could be achieved in distinguishing between tumor and normal samples. CONCLUSIONS Our study suggests that the selected TSG panel combined with the high-throughput technology might be a useful tool to develop epigenetic based predictive and prognostic biomarker for breast cancer relying on pathologic methylation changes in tumor tissue, as well as in circulation.
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Affiliation(s)
- Ramin Radpour
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women's Hospital, University of Basel, Basel, Switzerland
| | - Zeinab Barekati
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women's Hospital, University of Basel, Basel, Switzerland
| | - Corina Kohler
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women's Hospital, University of Basel, Basel, Switzerland
| | - Qing Lv
- Department of Breast Surgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Nicole Bürki
- Department of Obstetrics and Gynecology, Kantonsspital, Liestal, Switzerland
| | - Claude Diesch
- Department of Obstetrics and Gynecology, Kantonsspital, Liestal, Switzerland
| | - Johannes Bitzer
- Department of Obstetrics and Gynecology, Women's Hospital, University of Basel, Basel, Switzerland
| | - Hong Zheng
- Laboratory of Molecular Diagnosis of Cancer, Department of Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Seraina Schmid
- Department of Obstetrics and Gynecology, Women's Hospital, University of Basel, Basel, Switzerland
- * E-mail: (XYZ); (SS)
| | - Xiao Yan Zhong
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women's Hospital, University of Basel, Basel, Switzerland
- * E-mail: (XYZ); (SS)
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Specificity of methylation assays in cancer research: a guideline for designing primers and probes. Obstet Gynecol Int 2010; 2010. [PMID: 20798774 PMCID: PMC2926695 DOI: 10.1155/2010/870865] [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: 02/20/2010] [Accepted: 06/21/2010] [Indexed: 12/12/2022] Open
Abstract
DNA methylation is an epigenetic regulation mechanism of genomic function, and aberrant methylation pattern has been found to be a common event in many diseases and human cancers. A large number of cancer studies have been focused on identification of methylation changes as biomarkers (i.e., breast cancer). However, still clinical use of them is very limited because of lack of specificity and sensitivity for diagnostic test. This highlights the critical need for specific primer and probe design to avoid false-positive detection of methylation profiling. The guideline and online web tools that are introduced in this paper might help to perform a successful experiment and to develop specific diagnosis biomarkers by designing right primer pair and probe prior to experimental step.
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Barekati Z, Radpour R, Kohler C, Zhang B, Toniolo P, Lenner P, Lv Q, Zheng H, Zhong XY. Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations. Hum Mol Genet 2010; 19:2936-46. [PMID: 20466735 DOI: 10.1093/hmg/ddq199] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.
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Affiliation(s)
- Zeinab Barekati
- Laboratory for Gynecological Oncology, Women's Hospital/Department of Biomedicine, University of Basel, Switzerland
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Dellon AL, Mackinnon SE, Lu Q, Bitzer J, Zheng H, Toniolo P, Lenner P, Zhong XY. Musculoaponeurotic variations along the course of the median nerve in the proximal forearm. BMC Cancer 1988; 12:244. [PMID: 22695536 PMCID: PMC3437205 DOI: 10.1186/1471-2407-12-244] [Citation(s) in RCA: 51] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Accepted: 05/31/2012] [Indexed: 12/29/2022] Open
Abstract
31 cadaver arms have been dissected to study the variations in the anatomy of the muscles and fibrous arches which might cause compression of the median nerve in the forearm. Pronator teres always had a superficial head and usually a deep head. Flexor digitorum superficialis varied greatly in its site of origin. The median nerve might be crossed by two, one or no fibro-aponeurotic arches. Gantzer's muscle, an accessory head of flexor pollicis longus, was present in 45% of cadavers. No ligament of Struthers was found. Possible sites and causes of nerve compression are discussed.
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Affiliation(s)
- A L Dellon
- Department of Plastic Surgery, Johns Hopkins Hospital, Baltimore, Maryland
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