|
1
|
Feng CZ, Gou XY, Liu YQ, Xin YW, Zhang YL, Zhao HM, Wei SC, Hong N, Wang Y, Cheng J. Extramural venous invasion in gastric cancer: 9.4T magnetic resonance imaging assessment and circular RNA functional analysis. World J Gastroenterol 2025; 31:99897. [PMID: 40248379 PMCID: PMC12001196 DOI: 10.3748/wjg.v31.i14.99897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 02/19/2025] [Accepted: 03/17/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Extramural venous invasion (EMVI) is a critical prognostic factor in gastric cancer (GC); however, its detection and underlying molecular mechanisms remain underexplored. AIM To investigate the relationship between EMVI and expression of the circular RNA hsa_circ_0097977 in orthotopic GC mouse models. METHODS A retrospective analysis was conducted in addition to a preclinical animal study, involving 13 GC patients and 24 orthotopic GC mouse models, respectively. EMVI was assessed using axial T2-weighted fat suppression sequences on a 9.4T magnetic resonance imaging (MRI) with histopathological confirmation as the gold standard for EMVI. The impact of hsa_circ_0097977 on EMVI and GC cell function was evaluated. Statistical analyses comprised consistency, area under the curve analysis, correlation, χ 2/Fisher exact, and Mann-Whitney U/t-tests, with significance set at P < 0.05. RESULTS EMVI was accurately detected using 9.4T MRI in orthotopic mouse models with an area under the curve of 0.843 (sensitivity 78.6%, specificity 90.0%). MRI detected EMVI was the only imaging factor associated with distant metastasis (P = 0.04). Furthermore, knockdown of hsa_circ_0097977 was the only factor associated with EMVI (P = 0.043, 0.038) and led to reduced invasion and increased apoptosis in GC cells. CONCLUSION EMVI, a risk factor for distant metastasis in GC, is detectable by 9.4T MRI and regulated by hsa_circ_0097977, making it a potential therapeutic target.
Collapse
Affiliation(s)
- Cai-Zhen Feng
- Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
| | - Xin-Yi Gou
- Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
| | - Yi-Qun Liu
- Department of Ultrasound, Peking University People’s Hospital, Beijing 100044, China
| | - Yu-Wei Xin
- Department of Ultrasound, Peking University People’s Hospital, Beijing 100044, China
| | - Yin-Li Zhang
- Department of Pathology, Peking University People’s Hospital, Beijing 100044, China
| | - Hui-Min Zhao
- Department of Pathology, Peking University People’s Hospital, Beijing 100044, China
| | - Sheng-Cai Wei
- Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
| | - Nan Hong
- Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
| | - Yi Wang
- Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
| | - Jin Cheng
- Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
| |
Collapse
|
|
2
|
Ugalde-Morales E, Wilf R, Pluta J, Ploner A, Fan M, Damra M, Aben KK, Anson-Cartwright L, Chen C, Cortessis VK, Daneshmand S, Ferlin A, Gamulin M, Gietema JA, Gonzalez-Niera A, Grotmol T, Hamilton RJ, Harland M, Haugen TB, Hauser R, Hildebrandt MAT, Karlsson R, Kiemeney LA, Kim J, Lessel D, Lothe RA, Loveday C, Chanock SJ, McGlynn KA, Meijer C, Nead KT, Nsengimana J, Popovic M, Rafnar T, Richiardi L, Rocca MS, Schwartz SM, Skotheim RI, Stefansson K, Stewart DR, Turnbull C, Vaughn DJ, Winge SB, Zheng T, Monteiro AN, Almstrup K, Kanetsky PA, Nathanson KL, Wiklund F. Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study. Am J Hum Genet 2025; 112:630-643. [PMID: 39999848 PMCID: PMC11947167 DOI: 10.1016/j.ajhg.2025.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 01/20/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene-disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.
Collapse
Affiliation(s)
- Emilio Ugalde-Morales
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Rona Wilf
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - John Pluta
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alexander Ploner
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Mengyao Fan
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mohammad Damra
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Katja K Aben
- Netherlands Comprehensive Cancer Organization, Radboud University Medical Center, Utrecht, the Netherlands; Radboud University Medical Center, Nijmegen, the Netherlands
| | - Lynn Anson-Cartwright
- Department of Surgery (Urology), University of Toronto and The Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Chu Chen
- Epidemiology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Victoria K Cortessis
- Departments of Preventive Medicine and Obstetrics and Gynecology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA
| | - Siamak Daneshmand
- Departments of Urology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA
| | - Alberto Ferlin
- Department of Medicine, University of Padova, Padua, Italy
| | - Marija Gamulin
- Department of Oncology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Jourik A Gietema
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Anna Gonzalez-Niera
- Human Genotyping Core Unit, Spanish National Cancer Centre (CNIO), Madrid, Spain
| | - Tom Grotmol
- Cancer Registry of Norway, Oslo Metropolitan University, Oslo, Norway
| | | | - Mark Harland
- Department of Surgery (Urology), University of Toronto and The Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Trine B Haugen
- Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway
| | - Russ Hauser
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Michelle A T Hildebrandt
- Department of Lymphoma and Myeloma, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Robert Karlsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | | | - Jung Kim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Davor Lessel
- Institute of Human Genetics, University of Regensburg, Regensburg, Germany; Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
| | - Chey Loveday
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK; William Harvey Research Institute, Queen Mary University, London, UK
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Coby Meijer
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Kevin T Nead
- Department of Lymphoma and Myeloma, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jeremie Nsengimana
- Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | - Maja Popovic
- Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy
| | | | - Lorenzo Richiardi
- Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy
| | - Maria S Rocca
- Department of Medicine, University of Padova, Padua, Italy
| | - Stephen M Schwartz
- Epidemiology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Rolf I Skotheim
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
| | | | - Douglas R Stewart
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Clare Turnbull
- Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
| | - David J Vaughn
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sofia B Winge
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Tongzhang Zheng
- Department of Epidemiology, Brown School of Public Health, Brown University, Providence, RI, USA
| | - Alvaro N Monteiro
- Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Kristian Almstrup
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Peter A Kanetsky
- Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Katherine L Nathanson
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Fredrik Wiklund
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
| |
Collapse
|
|
3
|
Freedman AN, Clark J, Eaves LA, Roell K, Oran A, Koval L, Rager J, Santos HP, Kuban K, Joseph RM, Frazier J, Marsit CJ, Burt AA, O’Shea TM, Fry RC. A multi-omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm. Autism Res 2023; 16:918-934. [PMID: 36938998 PMCID: PMC10192070 DOI: 10.1002/aur.2915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 02/25/2023] [Indexed: 03/21/2023]
Abstract
Children born preterm are at heightened risk of neurodevelopmental impairments, including Autism Spectrum Disorder (ASD). The placenta is a key regulator of neurodevelopmental processes, though the precise underlying molecular mechanisms remain unclear. Here, we employed a multi-omic approach to identify placental transcriptomic and epigenetic modifications related to ASD diagnosis at age 10, among children born preterm. Working with the extremely low gestational age (ELGAN) cohort, we hypothesized that a pro-inflammatory placental environment would be predictive of ASD diagnosis at age 10. Placental messenger RNA (mRNA) expression, CpG methylation, and microRNA (miRNA) expression were compared among 368 ELGANs (28 children diagnosed with ASD and 340 children without ASD). A total of 111 genes displayed expression levels in the placenta that were associated with ASD. Within these ASD-associated genes is an ASD regulatory complex comprising key genes that predicted ASD case status. Genes with expression that predicted ASD case status included Ewing Sarcoma Breakpoint Region 1 (EWSR1) (OR: 6.57 (95% CI: 2.34, 23.58)) and Bromodomain Adjacent To Zinc Finger Domain 2A (BAZ2A) (OR: 0.12 (95% CI: 0.03, 0.35)). Moreover, of the 111 ASD-associated genes, nine (8.1%) displayed associations with CpG methylation levels, while 14 (12.6%) displayed associations with miRNA expression levels. Among these, LRR Binding FLII Interacting Protein 1 (LRRFIP1) was identified as being under the control of both CpG methylation and miRNAs, displaying an OR of 0.42 (95% CI: 0.17, 0.95). This gene, as well as others identified as having functional epimutations, plays a critical role in immune system regulation and inflammatory response. In summary, a multi-omic approach was used to identify functional epimutations in the placenta that are associated with the development of ASD in children born preterm, highlighting future avenues for intervention.
Collapse
Affiliation(s)
- Anastasia N. Freedman
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jeliyah Clark
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Lauren A. Eaves
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Kyle Roell
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Ali Oran
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Lauren Koval
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Julia Rager
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
- Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Hudson P Santos
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
- School of Nursing and Health Studies, University of Miami, Coral Gables, FL, USA
| | - Karl Kuban
- Department of Pediatrics, Division of Child Neurology, Boston Medical Center, Boston, Massachusetts, USA
| | - Robert M. Joseph
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Jean Frazier
- Eunice Kennedy Shriver Center, Department of Psychiatry, University of Massachusetts Medical School/University of Massachusetts Memorial Health Care, Worcester, MA, USA
| | - Carmen J. Marsit
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America
| | - Amber A. Burt
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America
| | - T. Michael O’Shea
- Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Rebecca C. Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, University of North Carolina, Chapel Hill, North Carolina, USA
- Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| |
Collapse
|
|
4
|
Haddadi M, Ataei R. wde, calpA, if, dap160, and poe genes knock down Drosophila models exhibit neurofunctional deficit. Gene 2022; 829:146499. [PMID: 35447243 DOI: 10.1016/j.gene.2022.146499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/14/2022] [Accepted: 04/14/2022] [Indexed: 11/27/2022]
Abstract
Intellectual disability (ID) is a heterogeneous disorder with high prevalence and remarkable social and cost burdens. Novel genetic variants of ATF7IP, CAPN9, ITGAV, ITSN1, and UBR4 genes are reported to be associated with the ID among Iranian families. However, in vivo validation is required to confirm the functional role of these variants in ID development. Drosophila melanogaster is a convenient model for such functional investigations as its genome bears ortholog of more than 75% of the disease-causing genes in human and represents numerous approaches to study defects in neuronal function. In this connection, RNAi gene silencing was applied to wde, calpA, if, dap160, and poe genes, the Drosophila ortholog of the selected human genes, and then consequent structural and functional changes in neurons were studied by means of immunohistochemistry and confocal microscopy of mushroom bodies (MBs) and validated behavioural assays including larvae and adult conditioning learning and memories, and ethanol sensitivity. Down-regulation of these genes led to neuronal loss which was evident by decline in total fluorescent signal intensity in micrographs of MBs structure. The gene silencing caused neuronal dysfunction and induction of ID-like symptoms manifested by deficits in larval preference learning, and short-term olfactory memory and courtship suppression learning in adults. Moreover, the RNAi flies showed higher sensitivity to ethanol vapour. Interestingly, the poe knock-down flies exhibited the most severe phenotypes among other genes. Altogether, we believe this study is first-of-its-kind and findings are highly applicable to confirm pathogenecity of the selected ID gene variants in Iranian population.
Collapse
Affiliation(s)
- Mohammad Haddadi
- Department of Biology, Faculty of Science, University of Zabol, Zabol, Iran.
| | - Reza Ataei
- Department of Biology, Faculty of Science, University of Zabol, Zabol, Iran
| |
Collapse
|
|
5
|
Moon SW, Mo HY, Choi EJ, Yoo NJ, Lee SH. Mutational Alterations of DNA Methylation-related Genes CTCF, ZFP57, and ATF7IP Genes in Colon Cancers. Appl Immunohistochem Mol Morphol 2022; 30:e16-e20. [PMID: 35175239 PMCID: PMC8862777 DOI: 10.1097/pai.0000000000000989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/04/2021] [Indexed: 11/26/2022]
Abstract
Deregulations of DNA-methylation-related genes are common in cancers, but frameshift mutation status in colon cancer (CC) is unknown. Our study aims to assess whether CTCF, ZFP57, and ATF7IP genes in this category are mutated in CC. CTCF, ZFP57, and ATF7IP genes have repeat coding sequences, which are frequently deleted or duplicated in CC, harboring the phenotype of unstable or high microsatellite instability (MSI-H). We studied 140 CCs [95 MSI-H CCs and 45 stable MSI (MSS) CCs], and found 7 CCs with MSI-H (6/95: 6.3%) harbored frameshift mutations within the repeats, whereas those with MSS did not. Of note, the CTCF frameshift mutations showed the regional difference in the 2 (12.5%) of 16 MSI-H CCs, indicating there was intratumoral heterogeneity. In the immunohistochemistry for ATF7IP, the MSI-H CC showed low intensity compared to MSS CC. Together, CTCF, ZFP57, and ATF7IP genes, despite the low incidence of the mutations, are altered in several ways (mutation, expression, and intratumoral heterogeneity) and could contribute to MSI-H CC development.
Collapse
Affiliation(s)
| | - Ha Yoon Mo
- Departments of Pathology
- Biomedicine & Health Sciences
| | | | | | - Sug Hyung Lee
- Departments of Pathology
- Biomedicine & Health Sciences
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| |
Collapse
|
|
6
|
Rehman MYA, Briedé JJ, van Herwijnen M, Krauskopf J, Jennen DGJ, Malik RN, Kleinjans JCS. Integrating SNPs-based genetic risk factor with blood epigenomic response of differentially arsenic-exposed rural subjects reveals disease-associated signaling pathways. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 292:118279. [PMID: 34619179 DOI: 10.1016/j.envpol.2021.118279] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/13/2021] [Accepted: 09/30/2021] [Indexed: 06/13/2023]
Abstract
Arsenic (As) contamination in groundwater is responsible for numerous adverse health outcomes among millions of people. Epigenetic alterations are among the most widely studied mechanisms of As toxicity. To understand how As exposure alters gene expression through epigenetic modifications, a systematic genome-wide study was designed to address the impact of multiple important single nucleotide polymorphisms (SNPs) related to As exposure on the methylome of drinking water As-exposed rural subjects from Pakistan. Urinary As levels were used to stratify subjects into low, medium and high exposure groups. Genome-wide DNA methylation was investigated using MeDIP in combination with NimbleGen 2.1 M Deluxe Promotor arrays. Transcriptome levels were measured using Agilent 8 × 60 K expression arrays. Genotyping of selected SNPs (As3MT, DNMT1a, ERCC2, EGFR and MTHFR) was measured and an integrated genetic risk factor for each respondent was calculated by assigning a specific value to the measured genotypes based on known risk allele numbers. To select a representative model related to As exposure we compared 9 linear mixed models comprising of model 1 (including the genetic risk factor), model 2 (without the genetic risk factor) and models with individual SNPs incorporated into the methylome data. Pathway analysis was performed using ConsensusPathDB. Model 1 comprising the integrated genetic risk factor disclosed biochemical pathways including muscle contraction, cardio-vascular diseases, ATR signaling, GPCR signaling, methionine metabolism and chromatin modification in association with hypo- and hyper-methylated gene targets. A unique pathway (direct P53 effector) was found associated with the individual DNMT1a polymorphism due to hyper-methylation of CSE1L and TRRAP. Most importantly, we provide here the first evidence of As-associated DNA methylation in relation with gene expression of ATR, ATF7IP, TPM3, UBE2J2. We report the first evidence that integrating SNPs data with methylome data generates a more representative epigenome profile and discloses a better insight in disease risks of As-exposed individuals.
Collapse
Affiliation(s)
- Muhammad Yasir Abdur Rehman
- Environmental Health Laboratory, Department of Environmental Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Jacco Jan Briedé
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands.
| | - Marcel van Herwijnen
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands
| | - Julian Krauskopf
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands
| | - Danyel G J Jennen
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands
| | - Riffat Naseem Malik
- Environmental Health Laboratory, Department of Environmental Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Jos C S Kleinjans
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands
| |
Collapse
|
|
7
|
Li Q, Ma Q, Xu L, Gao C, Yao L, Wen J, Yang M, Cheng J, Zhou X, Zou J, Zhong X, Guo X. Human Telomerase Reverse Transcriptase as a Therapeutic Target of Dihydroartemisinin for Esophageal Squamous Cancer. Front Pharmacol 2021; 12:769787. [PMID: 34744749 PMCID: PMC8569230 DOI: 10.3389/fphar.2021.769787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/07/2021] [Indexed: 12/24/2022] Open
Abstract
Objective: To elucidate the oncogenic role of human telomerase reverse transcriptase (hTERT) in esophageal squamous cancer and unravel the therapeutic role and molecular mechanism of dihydroartemisinin (DHA) by targeting hTERT. Methods: The expression of hTERT in esophageal squamous cancer and the patients prognosis were analyzed by bioinformatic analysis from TCGA database, and further validated with esophageal squamous cancer tissues in our cohort. The Cell Counting Kit-8 (CCK8) and colony formation assay were used to evaluate the proliferation of esophageal squamous cancer cell lines (Eca109, KYSE150, and TE1) after hTERT overexpression or treated with indicated concentrations of DHA. Transwell migration assay and scratch assay were employed to determine the migration abilities of cancer cells. Fluorescence microscopy and flow cytometry were conducted to measure the intracellular reactive oxygen species (ROS) levels in cancer cells after treated with DHA. Moreover, RT-PCR and Western blot were performed to test the alteration of associated genes on mRNA and protein level in DHA treated esophageal squamous cancer cell lines, respectively. Furthermore, tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Results: We found that hTERT was significantly upregulated in esophageal squamous cancer both from TCGA database and our cohort also. Overexpression of hTERT evidently promoted the proliferation and migration of esophageal squamous cancer cells in vitro. Moreover, DHA could significantly inhibit the proliferation and migration of esophageal cancer cell lines Eca109, KYSE150, and TE1 in vitro, and significantly down-regulate the expression of hTERT on both mRNA and protein level in a time- and dose-dependent manner as well. Further studies showed that DHA could induce intracellular ROS production in esophageal cancer cells and down-regulate SP1 expression, a transcription factor that bound to the promoter region of hTERT gene. Moreover, overexpression of SP1 evidently promoted the proliferation and migration of Eca109 and TE1 cells. Intriguingly, rescue experiments showed that inhibiting ROS by NAC alleviated the downregulation of SP1 and hTERT in cells treated with DHA. Furthermore, overexpression of SP1 or hTERT could attenuate the inhibition effect of DHA on the proliferation and migration of Eca109 cells. In tumor-bearing nude mice model, DHA significantly inhibited the growth of esophageal squamous cancer xenografts, and downregulated the expression of SP1 and hTERT protein, while no side effects were observed from heart, kidney, liver, and lung tissues by HE stain. Conclusion: hTERT plays an oncogenic role in esophageal squamous cancer and might be a therapeutic target of DHA through regulating ROS/SP1 pathway.
Collapse
Affiliation(s)
- Qingrong Li
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Lei Xu
- Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China
| | - Chuanli Gao
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Lihua Yao
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Jilin Wen
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Miyuan Yang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Jibing Cheng
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Xi Zhou
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Jiang Zou
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Xiaowu Zhong
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, China
| |
Collapse
|
|
8
|
Takakura M, Takata E, Sasagawa T. A Novel Liquid Biopsy Strategy to Detect Small Amounts of Cancer Cells Using Cancer-Specific Replication Adenoviruses. J Clin Med 2020; 9:jcm9124044. [PMID: 33327605 PMCID: PMC7765046 DOI: 10.3390/jcm9124044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 11/26/2022] Open
Abstract
Circulating tumor cells (CTCs) are a promising source of clinical and biological cancer information and can be a material for liquid biopsy. However, detecting and capturing these cells remains a challenge. Various biological factors (e.g., cell surface proteins, cell size, deformability, or dielectrophoresis) have been applied to detect CTCs. Cancer cells dramatically change their characteristics during tumorigenesis and metastasis. Hence, defining a cell as malignant using such a parameter is difficult. Moreover, immortality is an essential characteristic of cancer cells. Telomerase elongates telomeres and plays a critical role in cellular immortality and is specifically activated in cancer cells. Thus, the activation of telomerase can be a good fingerprint for cancer cells. Telomerase cannot be recognized by antibodies in living cells because it is a nuclear enzyme. Therefore, telomerase-specific replication adenovirus, which expresses the green fluorescent protein, has been applied to detect CTCs. This review explores the overview of this novel technology and its application in gynecological cancers.
Collapse
|
|
9
|
Wiechmann S, Saupp E, Schilling D, Heinzlmeir S, Schneider G, Schmid RM, Combs SE, Kuster B, Dobiasch S. Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells. Mol Cell Proteomics 2020; 19:1649-1663. [PMID: 32651227 PMCID: PMC8014995 DOI: 10.1074/mcp.ra120.002046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 06/22/2020] [Indexed: 01/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.
Collapse
Affiliation(s)
- Svenja Wiechmann
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany; German Cancer Consortium, Munich, Germany; German Cancer Center, Heidelberg, Germany
| | - Elena Saupp
- Department of Radiation Oncology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Daniela Schilling
- Department of Radiation Oncology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany; Institute of Radiation Medicine, Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany
| | - Stephanie Heinzlmeir
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Günter Schneider
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Roland M Schmid
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Stephanie E Combs
- German Cancer Consortium, Munich, Germany; German Cancer Center, Heidelberg, Germany; Department of Radiation Oncology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany; Institute of Radiation Medicine, Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany
| | - Bernhard Kuster
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany; German Cancer Consortium, Munich, Germany; German Cancer Center, Heidelberg, Germany; Bavarian Center for Biomolecular Mass Spectrometry, Technical University of Munich, Freising, Germany
| | - Sophie Dobiasch
- German Cancer Consortium, Munich, Germany; German Cancer Center, Heidelberg, Germany; Department of Radiation Oncology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany; Institute of Radiation Medicine, Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany.
| |
Collapse
|
|
10
|
Yasuda Y, Tokunaga K, Koga T, Sakamoto C, Goldberg IG, Saitoh N, Nakao M. Computational analysis of morphological and molecular features in gastric cancer tissues. Cancer Med 2020; 9:2223-2234. [PMID: 32012497 PMCID: PMC7064096 DOI: 10.1002/cam4.2885] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/13/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
Biological morphologies of cells and tissues represent their physiological and pathological conditions. The importance of quantitative assessment of morphological information has been highly recognized in clinical diagnosis and therapeutic strategies. In this study, we used a supervised machine learning algorithm wndchrm to classify hematoxylin and eosin (H&E)‐stained images of human gastric cancer tissues. This analysis distinguished between noncancer and cancer tissues with different histological grades. We then classified the H&E‐stained images by expression levels of cancer‐associated nuclear ATF7IP/MCAF1 and membranous PD‐L1 proteins using immunohistochemistry of serial sections. Interestingly, classes with low and high expressions of each protein exhibited significant morphological dissimilarity in H&E images. These results indicated that morphological features in cancer tissues are correlated with expression of specific cancer‐associated proteins, suggesting the usefulness of biomolecular‐based morphological classification.
Collapse
Affiliation(s)
- Yoko Yasuda
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.,Department of Health Science, Faculty of Medical Science, Kyushu University, Fukuoka, Japan
| | - Kazuaki Tokunaga
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Tomoaki Koga
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Chiyomi Sakamoto
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Ilya G Goldberg
- Image Informatics and Computational Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | | | - Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
11
|
Abstract
Human germ cell tumours (GCTs) are derived from stem cells of the early embryo and the germ line. They occur in the gonads (ovaries and testes) and also in extragonadal sites, where migrating primordial germ cells are located during embryogenesis. This group of heterogeneous neoplasms is unique in that their developmental potential is in effect determined by the latent potency state of their cells of origin, which are reprogrammed to omnipotent, totipotent or pluripotent stem cells. Seven GCT types, defined according to their developmental potential, have been identified, each with distinct epidemiological and (epi)genomic features. Heritable predisposition factors affecting the cells of origin and their niches likely explain bilateral, multiple and familial occurrences of the different types of GCTs. Unlike most other tumour types, GCTs are rarely caused by somatic driver mutations, but arise through failure to control the latent developmental potential of their cells of origin, resulting in their reprogramming. Consistent with their non-mutational origin, even the malignant tumours of the group are characterized by wild-type TP53 and high sensitivity for DNA damage. However, tumour progression and the rare occurrence of treatment resistance are driven by embryonic epigenetic state, specific (sub)chromosomal imbalances and somatic mutations. Thus, recent progress in understanding GCT biology supports a comprehensive developmental pathogenetic model for the origin of all GCTs, and provides new biomarkers, as well as potential targets for treatment of resistant disease.
Collapse
Affiliation(s)
- J Wolter Oosterhuis
- Laboratory for Experimental Patho-Oncology, Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
| | - Leendert H J Looijenga
- Laboratory for Experimental Patho-Oncology, Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| |
Collapse
|
|
12
|
Jie MM, Chang X, Zeng S, Liu C, Liao GB, Wu YR, Liu CH, Hu CJ, Yang SM, Li XZ. Diverse regulatory manners of human telomerase reverse transcriptase. Cell Commun Signal 2019; 17:63. [PMID: 31186051 PMCID: PMC6560729 DOI: 10.1186/s12964-019-0372-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 05/17/2019] [Indexed: 12/22/2022] Open
Abstract
Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.
Collapse
Affiliation(s)
- Meng-Meng Jie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Xing Chang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Shuo Zeng
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Cheng Liu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Guo-Bin Liao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Ya-Ran Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Chun-Hua Liu
- Teaching evaluation center of Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Chang-Jiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
| | - Xin-Zhe Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
| |
Collapse
|
|
13
|
Timms RT, Tchasovnikarova IA, Antrobus R, Dougan G, Lehner PJ. ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex. Cell Rep 2017; 17:653-659. [PMID: 27732843 PMCID: PMC5081395 DOI: 10.1016/j.celrep.2016.09.050] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 08/19/2016] [Accepted: 09/15/2016] [Indexed: 12/27/2022] Open
Abstract
The histone methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays. ATF7IP and SETDB1 knockout cells exhibit near-identical defects in the global deposition of H3K9me3, which results in similar dysregulation of the transcriptome. Overall, these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus.
The SETDB1-interacting partner ATF7IP is critical for HUSH-mediated silencing ATF7IP shields SETDB1 from proteasomal degradation in the nucleus Loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays
Collapse
Affiliation(s)
- Richard T Timms
- Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Iva A Tchasovnikarova
- Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Robin Antrobus
- Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Gordon Dougan
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK
| | - Paul J Lehner
- Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
| |
Collapse
|
|
14
|
Rajagopalan D, Pandey AK, Xiuzhen MC, Lee KK, Hora S, Zhang Y, Chua BH, Kwok HS, Bhatia SS, Deng LW, Tenen DG, Kappei D, Jha S. TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. PLoS Pathog 2017; 13:e1006681. [PMID: 29045464 PMCID: PMC5662243 DOI: 10.1371/journal.ppat.1006681] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/30/2017] [Accepted: 10/04/2017] [Indexed: 12/13/2022] Open
Abstract
HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.
Collapse
Affiliation(s)
- Deepa Rajagopalan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Amit Kumar Pandey
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Magdalene Claire Xiuzhen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kwok Kin Lee
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Shainan Hora
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yanzhou Zhang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Boon Haow Chua
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Hui Si Kwok
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Lih Wen Deng
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Daniel G. Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, United States of America
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Sudhakar Jha
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| |
Collapse
|
|
15
|
Appiah-Kubi K, Lan T, Wang Y, Qian H, Wu M, Yao X, Wu Y, Chen Y. Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies. Crit Rev Oncol Hematol 2016; 109:20-34. [PMID: 28010895 DOI: 10.1016/j.critrevonc.2016.11.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 10/21/2016] [Accepted: 11/15/2016] [Indexed: 12/31/2022] Open
Abstract
PURPOSE To investigate oncogenic platelet-derived growth factor receptor(PDGFR) fusion genes involvement in hematological malignancies, the advances in the PDGFR fusion genes diagnosis and development of PDGFR fusions inhibitors. METHODS Literature search was done using terms "PDGFR and Fusion" or "PDGFR and Myeloid neoplasm" or 'PDGFR and Lymphoid neoplasm' or "PDGFR Fusion Diagnosis" or "PDGFR Fusion Targets" in databases including PubMed, ASCO.org, and Medscape. RESULTS Out of the 36 fusions detected, ETV6(TEL)-PDGFRB and FIP1L1-PDGFRA fusions were frequently detected, 33 are as a result of chromosomal translocation, FIP1L1-PDGFRA and EBF1-PDGFRB are the result of chromosomal deletion and CDK5RAP2- PDGFRΑ is the result of chromosomal insertion. Seven of the 34 rare fusions have detectable reciprocals. CONCLUSION RNA aptamers are promising therapeutic target of PDGFRs and diagnostic tools of PDGFRs fusion genes. Also, PDGFRs have variable prospective therapeutic strategies including small molecules, RNA aptamers, and interference therapeutics as well as development of adaptor protein Lnk mimetic drugs.
Collapse
Affiliation(s)
- Kwaku Appiah-Kubi
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China; Department of Applied Biology, University for Development Studies, Navrongo, Ghana.
| | - Ting Lan
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Ying Wang
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Hai Qian
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Min Wu
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Xiaoyuan Yao
- Basic medical department, Changchun medical college, Changchun, Jilin 130013, People's Republic of China
| | - Yan Wu
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China
| | - Yongchang Chen
- Department of Physiology, School of Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, People's Republic of China.
| |
Collapse
|
|
16
|
Wong HSC, Chang WC. Correlation of clinical features and genetic profiles of stromal interaction molecule 1 (STIM1) in colorectal cancers. Oncotarget 2016; 6:42169-82. [PMID: 26543234 PMCID: PMC4747217 DOI: 10.18632/oncotarget.5888] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/22/2015] [Indexed: 01/06/2023] Open
Abstract
STIM1 overexpression has been observed in a portion of colorectal cancer (CRC) patients and associated with cancer cell invasion and migration. To characterize the distinctive expression profiles associated with stromal interaction molecule 1 (STIM1) overexpression/low-expression between CRC subtypes, and further assess the divergence transcription regulation impact of STIM1 between colon (COADs) and rectum (READs) adenocarcinomas in order to depict the role of SOCE pathway in CRCs, we have conducted a comprehensive phenome-transcriptome-interactome analysis to clarify underlying molecular differences of COADs/READs contributed by STIM1. Results demonstrated that a number of novel STIM1-associated signatures have been identified in COADs but not READs. Specifically, the presence of STIM1 overexpression in COADs, which represented a disturbance of the SOCE pathway, was associated with cell migration and cell motility properties. We identified 11 prognostic mRNA/miRNA predictors associated with the overall survival of COAD patients, suggesting the correlation of STIM1-associated features to clinicopathological outcomes. These findings enhance our understanding on differences between CRC subtypes in panoramic view, and suggested STIM1 as a promising therapeutic biomarker in COADs.
Collapse
Affiliation(s)
- Henry Sung-Ching Wong
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.,Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chiao Chang
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.,Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.,Department of Pharmacy, Taipei Medical University Wan Fang Hospital, Taipei, Taiwan.,Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Pharmacy, Taipei Medical University Wan Fang Hospital, Taipei, Taiwan
| |
Collapse
|
|
17
|
Transcription Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene. Genes (Basel) 2016; 7:genes7080050. [PMID: 27548225 PMCID: PMC4999838 DOI: 10.3390/genes7080050] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 07/23/2016] [Accepted: 08/01/2016] [Indexed: 12/11/2022] Open
Abstract
Embryonic stem cells and induced pluripotent stem cells have the ability to maintain their telomere length via expression of an enzymatic complex called telomerase. Similarly, more than 85%–90% of cancer cells are found to upregulate the expression of telomerase, conferring them with the potential to proliferate indefinitely. Telomerase Reverse Transcriptase (TERT), the catalytic subunit of telomerase holoenzyme, is the rate-limiting factor in reconstituting telomerase activity in vivo. To date, the expression and function of the human Telomerase Reverse Transcriptase (hTERT) gene are known to be regulated at various molecular levels (including genetic, mRNA, protein and subcellular localization) by a number of diverse factors. Among these means of regulation, transcription modulation is the most important, as evident in its tight regulation in cancer cell survival as well as pluripotent stem cell maintenance and differentiation. Here, we discuss how hTERT gene transcription is regulated, mainly focusing on the contribution of trans-acting factors such as transcription factors and epigenetic modifiers, as well as genetic alterations in hTERT proximal promoter.
Collapse
|
|
18
|
Lewis KA, Tollefsbol TO. Regulation of the Telomerase Reverse Transcriptase Subunit through Epigenetic Mechanisms. Front Genet 2016; 7:83. [PMID: 27242892 PMCID: PMC4860561 DOI: 10.3389/fgene.2016.00083] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 04/22/2016] [Indexed: 12/21/2022] Open
Abstract
Chromosome-shortening is characteristic of normal cells, and is known as the end replication problem. Telomerase is the enzyme responsible for extending the ends of the chromosomes in de novo synthesis, and occurs in germ cells as well as most malignant cancers. There are three subunits of telomerase: human telomerase RNA (hTERC), human telomerase associated protein (hTEP1), or dyskerin, and human telomerase reverse transcriptase (hTERT). hTERC and hTEP1 are constitutively expressed, so the enzymatic activity of telomerase is dependent on the transcription of hTERT. DNA methylation, histone methylation, and histone acetylation are basic epigenetic regulations involved in the expression of hTERT. Non-coding RNA can also serve as a form of epigenetic control of hTERT. This epigenetic-based regulation of hTERT is important in providing a mechanism for reversibility of hTERT control in various biological states. These include embryonic down-regulation of hTERT contributing to aging and the upregulation of hTERT playing a critical role in over 90% of cancers. Normal human somatic cells have a non-methylated/hypomethylated CpG island within the hTERT promoter region, while telomerase-positive cells paradoxically have at least a partially methylated promoter region that is opposite to the normal roles of DNA methylation. Histone acetylation of H3K9 within the promoter region is associated with an open chromatin state such that transcription machinery has the space to form. Histone methylation of hTERT has varied control of the gene, however. Mono- and dimethylation of H3K9 within the promoter region indicate silent euchromatin, while a trimethylated H3K9 enhances gene transcription. Non-coding RNAs can target epigenetic-modifying enzymes, as well as transcription factors involved in the control of hTERT. An epigenetics diet that can affect the epigenome of cancer cells is a recent fascination that has received much attention. By combining portions of this diet with epigenome-altering treatments, it is possible to selectively regulate the epigenetic control of hTERT and its expression.
Collapse
Affiliation(s)
- Kayla A Lewis
- Department of Biology, University of Alabama at Birmingham, Birmingham AL, USA
| | - Trygve O Tollefsbol
- Department of Biology, University of Alabama at Birmingham, BirminghamAL, USA; Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, BirminghamAL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, BirminghamAL, USA; Nutrition Obesity Research Center, University of Alabama at Birmingham, BirminghamAL, USA; Comprehensive Diabetes Center, University of Alabama at Birmingham, BirminghamAL, USA
| |
Collapse
|
|
19
|
Elzinga-Tinke JE, Dohle GR, Looijenga LH. Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis. Asian J Androl 2016; 17:381-93. [PMID: 25791729 PMCID: PMC4430936 DOI: 10.4103/1008-682x.148079] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20-40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. It is expected that TGCT have carcinoma in situ(CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. The overall cure rate of TGCT is more than 90%, however, men surviving TGCT can present long-term side effects of systemic cancer treatment. In contrast, men diagnosed and treated for CIS only continue to live without these long-term side effects. Therefore, early detection of CIS has great health benefits, which will require an informative screening method. This review described the etiology and early pathogenesis of TGCT, as well as the possibilities of early detection and future potential of screening men at risk for TGCT. For screening, a well-defined risk profile based on both genetic and environmental risk factors is needed. Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. Prenatal, perinatal, and postnatal environmental factors also influence the onset of CIS. A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. Further research is needed to develop a well-defined TGCT risk profile, based on gene-environment interactions, combined with noninvasive detection method for CIS.
Collapse
Affiliation(s)
| | | | - Leendert Hj Looijenga
- Department of Pathology, Laboratory of Experimental Patho-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| |
Collapse
|
|
20
|
Ishibashi T, Yaguchi A, Terada K, Ueno-Yokohata H, Tomita O, Iijima K, Kobayashi K, Okita H, Fujimura J, Ohki K, Shimizu T, Kiyokawa N. Ph-like ALL-related novel fusion kinase ATF7IP-PDGFRB exhibits high sensitivity to tyrosine kinase inhibitors in murine cells. Exp Hematol 2015; 44:177-88.e5. [PMID: 26703895 DOI: 10.1016/j.exphem.2015.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 11/24/2015] [Accepted: 11/26/2015] [Indexed: 11/27/2022]
Abstract
ATF7IP-PDGFRB is a novel PDGFRB-related fusion gene identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with a signature similar to that of Ph1 ALL, so-called Ph-like ALL. When we introduced ATF7IP-PDGFRB, murine Ba/F3 cells acquired the ability to proliferate in an interleukin (IL)-3-independent manner. On the contrary, the expression of wild-type PDGFRB is not sufficient to acquire the ability for IL-3-independent proliferation in Ba/F3 cells. The introduction of ATF7IP-PDGFRB also induces a typical gene expression profile for Ph1-ALL in Ba/F3 cells. A series of biochemical and cell biological experiments revealed the constitutive activation of ATF7IP-PDGFRB as well as downstream signaling molecules, including AKT and MAPK. Although the phosphoinositide 3-kinase inhibitor led to cell death in both cells into which ATF7IP-PDGFRB had been introduced and IL-3-maintained Mock cells, MEK inhibitor selectively led to cell death into which ATF7IP-PDGFRB had been introduced. The introduction of tyrosine to phenylalanine mutations at binding sites of adaptor molecules important in the MAPK pathway located in the PDGFRB portion abolished ATF7IP-PDGFRB-mediated cell transformation, suggesting that MAPK-mediated signals are critical in ATF7IP-PDGFRB-mediated cell transformation. On treatment with tyrosine kinase inhibitors, ATF7IP-PDGFRB-expressing, but not Mock, Ba/F3 cells underwent rapid apoptosis accompanied by reduced phosphorylation of MAPK. Importantly, the sensitivity of ATF7IP-PDGFRB-expressing Ba/F3 cells to imatinib is significantly higher than that of BCR-ABL1-transformed Ba/F3 cells, as assessed by the IC50. Taken together, ATF7IP-PDGFRB has transforming potential via the constitutive activation of MAPK and participates in the pathogenesis of Ph-like ALL. Our observations suggest the therapeutic importance of tyrosine kinase inhibitors and possibly MEK inhibitor for a subset of BCP-ALL harboring PDGFRB-related fusion kinases.
Collapse
Affiliation(s)
- Takeshi Ishibashi
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Akinori Yaguchi
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kazuki Terada
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Hitomi Ueno-Yokohata
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Osamu Tomita
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kazutoshi Iijima
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Shinjuku-ku, Tokyo, Japan
| | - Kenichiro Kobayashi
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Hajime Okita
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Junya Fujimura
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kentaro Ohki
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Nobutaka Kiyokawa
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
| |
Collapse
|
|
21
|
Litchfield K, Shipley J, Turnbull C. Common variants identified in genome-wide association studies of testicular germ cell tumour: an update, biological insights and clinical application. Andrology 2015; 3:34-46. [DOI: 10.1111/andr.304] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 10/03/2014] [Accepted: 10/06/2014] [Indexed: 01/13/2023]
Affiliation(s)
- K. Litchfield
- Division of Genetics and Epidemiology; The Institute of Cancer Research; London UK
| | - J. Shipley
- Divisions of Molecular Pathology and Cancer Therapeutics; The Institute of Cancer Research; London UK
| | - C. Turnbull
- Division of Genetics and Epidemiology; The Institute of Cancer Research; London UK
- Royal Marsden NHS Foundation Trust; London UK
| |
Collapse
|
|
22
|
Beishline K, Azizkhan-Clifford J. Sp1 and the 'hallmarks of cancer'. FEBS J 2015; 282:224-58. [PMID: 25393971 DOI: 10.1111/febs.13148] [Citation(s) in RCA: 396] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 09/26/2014] [Accepted: 11/10/2014] [Indexed: 12/19/2022]
Abstract
For many years, transcription factor Sp1 was viewed as a basal transcription factor and relegated to a role in the regulation of so-called housekeeping genes. Identification of Sp1's role in recruiting the general transcription machinery in the absence of a TATA box increased its importance in gene regulation, particularly in light of recent estimates that the majority of mammalian genes lack a TATA box. In this review, we briefly consider the history of Sp1, the founding member of the Sp family of transcription factors. We review the evidence suggesting that Sp1 is highly regulated by post-translational modifications that positively and negatively affect the activity of Sp1 on a wide array of genes. Sp1 is over-expressed in many cancers and is associated with poor prognosis. Targeting Sp1 in cancer treatment has been suggested; however, our review of the literature on the role of Sp1 in the regulation of genes that contribute to the 'hallmarks of cancer' illustrates the extreme complexity of Sp1 functions. Sp1 both activates and suppresses the expression of a number of essential oncogenes and tumor suppressors, as well as genes involved in essential cellular functions, including proliferation, differentiation, the DNA damage response, apoptosis, senescence and angiogenesis. Sp1 is also implicated in inflammation and genomic instability, as well as epigenetic silencing. Given the apparently opposing effects of Sp1, a more complete understanding of the function of Sp1 in cancer is required to validate its potential as a therapeutic target.
Collapse
Affiliation(s)
- Kate Beishline
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
| | | |
Collapse
|
|
23
|
Rijlaarsdam MA, Looijenga LHJ. An oncofetal and developmental perspective on testicular germ cell cancer. Semin Cancer Biol 2014; 29:59-74. [PMID: 25066859 DOI: 10.1016/j.semcancer.2014.07.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 07/17/2014] [Indexed: 12/19/2022]
Abstract
Germ cell tumors (GCTs) represent a diverse group of tumors presumably originating from (early fetal) developing germ cells. Most frequent are the testicular germ cell cancers (TGCC). Overall, TGCC is the most frequent malignancy in Caucasian males (20-40 years) and remains an important cause of (treatment related) mortality in these young men. The strong association between the phenotype of TGCC stem cell components and their totipotent ancestor (fetal primordial germ cell or gonocyte) makes these tumors highly relevant from an onco-fetal point of view. This review subsequently discusses the evidence for the early embryonic origin of TGCCs, followed by an overview of the crucial association between TGCC pathogenesis, genetics, environmental exposure and the (fetal) testicular micro-environment (genvironment). This culminates in an evaluation of three genvironmentally modulated hallmarks of TGCC directly related to the oncofetal pathogenesis of TGCC: (1) maintenance of pluripotency, (2) cell cycle control/cisplatin sensitivity and (3) regulation of proliferation/migration/apoptosis by KIT-KITL mediated receptor tyrosine kinase signaling. Briefly, TGCC exhibit identifiable stem cell components (seminoma and embryonal carcinoma) and progenitors that show large and consistent similarities to primordial/embryonic germ cells, their presumed totipotent cells of origin. TGCC pathogenesis depends crucially on a complex interaction of genetic and (micro-)environmental, i.e. genvironmental risk factors that have only been partly elucidated despite significant effort. TGCC stem cell components also show a high degree of similarity with embryonic stem/germ cells (ES) in the regulation of pluripotency and cell cycle control, directly related to their exquisite sensitivity to DNA damaging agents (e.g. cisplatin). Of note, (ES specific) micro-RNAs play a pivotal role in the crossover between cell cycle control, pluripotency and chemosensitivity. Moreover, multiple consistent observations reported TGCC to be associated with KIT-KITL mediated receptor tyrosine kinase signaling, a pathway crucially implicated in proliferation, migration and survival during embryogenesis including germ cell development. In conclusion, TGCCs are a fascinating model for onco-fetal developmental processes especially with regard to studying cell cycle control, pluripotency maintenance and KIT-KITL signaling. The knowledge presented here contributes to better understanding of the molecular characteristics of TGCC pathogenesis, translating to identification of at risk individuals and enhanced quality of care for TGCC patients (diagnosis, treatment and follow-up).
Collapse
Affiliation(s)
- Martin A Rijlaarsdam
- Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Leendert H J Looijenga
- Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
| |
Collapse
|
|
24
|
Minkovsky A, Sahakyan A, Rankin-Gee E, Bonora G, Patel S, Plath K. The Mbd1-Atf7ip-Setdb1 pathway contributes to the maintenance of X chromosome inactivation. Epigenetics Chromatin 2014; 7:12. [PMID: 25028596 PMCID: PMC4099106 DOI: 10.1186/1756-8935-7-12] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 06/05/2014] [Indexed: 01/08/2023] Open
Abstract
Background X chromosome inactivation (XCI) is a developmental program of heterochromatin formation that initiates during early female mammalian embryonic development and is maintained through a lifetime of cell divisions in somatic cells. Despite identification of the crucial long non-coding RNA Xist and involvement of specific chromatin modifiers in the establishment and maintenance of the heterochromatin of the inactive X chromosome (Xi), interference with known pathways only partially reactivates the Xi once silencing has been established. Here, we studied ATF7IP (MCAF1), a protein previously characterized to coordinate DNA methylation and histone H3K9 methylation through interactions with the methyl-DNA binding protein MBD1 and the histone H3K9 methyltransferase SETDB1, as a candidate maintenance factor of the Xi. Results We found that siRNA-mediated knockdown of Atf7ip in mouse embryonic fibroblasts (MEFs) induces the activation of silenced reporter genes on the Xi in a low number of cells. Additional inhibition of two pathways known to contribute to Xi maintenance, DNA methylation and Xist RNA coating of the X chromosome, strongly increased the number of cells expressing Xi-linked genes upon Atf7ip knockdown. Despite its functional importance in Xi maintenance, ATF7IP does not accumulate on the Xi in MEFs or differentiating mouse embryonic stem cells. However, we found that depletion of two known repressive biochemical interactors of ATF7IP, MBD1 and SETDB1, but not of other unrelated H3K9 methyltransferases, also induces the activation of an Xi-linked reporter in MEFs. Conclusions Together, these data indicate that Atf7ip acts in a synergistic fashion with DNA methylation and Xist RNA to maintain the silent state of the Xi in somatic cells, and that Mbd1 and Setdb1, similar to Atf7ip, play a functional role in Xi silencing. We therefore propose that ATF7IP links DNA methylation on the Xi to SETDB1-mediated H3K9 trimethylation via its interaction with MBD1, and that this function is a crucial feature of the stable silencing of the Xi in female mammalian cells.
Collapse
Affiliation(s)
- Alissa Minkovsky
- David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA
| | - Anna Sahakyan
- David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA
| | - Elyse Rankin-Gee
- David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA
| | - Giancarlo Bonora
- David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA
| | - Sanjeet Patel
- David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA
| | - Kathrin Plath
- David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA
| |
Collapse
|
|
25
|
Huang D, Li Y, Liu N, Zhang Z, Peng Z, Duan C, Tang X, Tan G, Yan G, Tang F. Identification of novel signaling components in N,N'-dinitrosopiperazine-mediated metastasis of nasopharyngeal carcinoma by quantitative phosphoproteomics. BMC Cancer 2014; 14:243. [PMID: 24708550 PMCID: PMC4101831 DOI: 10.1186/1471-2407-14-243] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 03/25/2014] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer. N,N'-dinitrosopiperazine (DNP), a carcinogen with specificity for nasopharyngeal epithelium, facilitates NPC metastasis. However, the underlying mechanism is not known. METHODS Quantitative phosphoproteomics, using stable isotope labeling of amino acids in cell cultures, was employed to identify phosphoproteins associated with NPC metastasis mediated by DNP. NPC cell line 6-10B, which is relatively less metastatic, was used to investigate DNP-mediated metastasis. Boyden chamber invasion assay was used to measure DNP-induced motility and invasion, and nude mice were used to verify DNP-mediated metastasis in vivo. Several different phosphoproteins detected by proteomics analysis were verified by immunoblotting. DNP-mediated metastasis facilitated by lysine-rich CEACAM1 co-isolated protein (LYRIC) phosphorylation at serine 568 was confirmed using mutations targeting the phosphorylation site of LYRIC. DNP-mediated metastasis through LYRIC phosphorylation was confirmed in the NPC cell line CNE1. DNP-mediated LYRIC phosphorylation at serine 568 was also verified in metastatic tumors of BABL/c nude mice. RESULTS Boyden chamber invasion assay indicated that DNP mediated cell motility and invasion of NPC cell 6-10B in vitro, and experiments with nude mice indicated that DNP increased 6-10B metastasis in vivo. In the phosphoproteomics analysis, we detected 216 phosphorylation sites on 130 proteins; among these, 48 phosphorylation sites on 30 unique phosphopeptides were modulated by DNP by at least 1.5-fold. DNP mediated the expression of phosphorylated GTPase, ferritin, LYRIC, and RNA polymerase, and it decreased the expression of phosphorylated torsin-1A protein 1. Furthermore, DNP induced LYRIC phosphorylation at serine 568 to facilitate cell motility and invasion, whereas DNP-mediated motility and invasion was decreased when serine 568 in LYRIC was mutated. In another NPC cell line, CNE1, DNP also mediated cell motility and invasion followed by enhanced phosphorylation of LYRIC at serine 568. Finally, phosphorylated-LYRIC expression at serine 568 was significantly increased in metastatic tumors induced by DNP. CONCLUSION DNP regulates multiple signaling pathways through protein phosphorylation, including the phosphorylation of LYRIC at serine 568, and mediates NPC metastasis. These findings provide insights on the complexity and dynamics of DNP-facilitated metastasis, and may help to gain a better understanding of the mechanisms by clarifying NPC-induced metastasis.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | - Faqing Tang
- Medical Research Center and Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| |
Collapse
|
|
26
|
Kobayashi K, Mitsui K, Ichikawa H, Nakabayashi K, Matsuoka M, Kojima Y, Takahashi H, Iijima K, Ootsubo K, Oboki K, Okita H, Yasuda K, Sakamoto H, Hata K, Yoshida T, Matsumoto K, Kiyokawa N, Ohara A. ATF7IPas a novelPDGFRBfusion partner in acute lymphoblastic leukaemia in children. Br J Haematol 2014; 165:836-41. [DOI: 10.1111/bjh.12834] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 01/29/2014] [Indexed: 01/28/2023]
Affiliation(s)
- Kenichiro Kobayashi
- Department of Paediatric Haematology and Oncology Research; National Research Institute for Child Health and Development; Tokyo Japan
| | - Kazumasa Mitsui
- Department of Paediatrics; Toho Omori Medical Centre; Tokyo Japan
| | - Hitoshi Ichikawa
- Division of Genetics; National Cancer Centre Research Institute; Tokyo Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology; National Research Institute for Child Health and Development; Tokyo Japan
| | - Masaki Matsuoka
- Department of Paediatrics; Toho Omori Medical Centre; Tokyo Japan
| | - Yasuko Kojima
- Department of Paediatrics; Toho Omori Medical Centre; Tokyo Japan
| | | | - Kazutoshi Iijima
- Department of Paediatric Haematology and Oncology Research; National Research Institute for Child Health and Development; Tokyo Japan
| | - Kaori Ootsubo
- SRL Inc.; Centre for Molecular Biology and Cytogenetics; Tokyo Japan
| | - Keisuke Oboki
- Department of Molecular Medical Research; Tokyo Metropolitan Institute of Medical Science; Tokyo Japan
| | - Hajime Okita
- Department of Paediatric Haematology and Oncology Research; National Research Institute for Child Health and Development; Tokyo Japan
| | - Kazuki Yasuda
- Department of Metabolic Disorder; Diabetes Research Centre; National Centre for Global Health and Medicine; Tokyo Japan
| | - Hiromi Sakamoto
- Division of Genetics; National Cancer Centre Research Institute; Tokyo Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology; National Research Institute for Child Health and Development; Tokyo Japan
| | - Teruhiko Yoshida
- Division of Genetics; National Cancer Centre Research Institute; Tokyo Japan
| | - Kenji Matsumoto
- Department of Allergy and Immunology; National Research Institute for Child Health and Development; Tokyo Japan
| | - Nobutaka Kiyokawa
- Department of Paediatric Haematology and Oncology Research; National Research Institute for Child Health and Development; Tokyo Japan
| | - Akira Ohara
- Department of Paediatrics; Toho Omori Medical Centre; Tokyo Japan
| |
Collapse
|
|
27
|
Stathopoulos S, Neafsey DE, Lawniczak MKN, Muskavitch MAT, Christophides GK. Genetic dissection of Anopheles gambiae gut epithelial responses to Serratia marcescens. PLoS Pathog 2014; 10:e1003897. [PMID: 24603764 PMCID: PMC3946313 DOI: 10.1371/journal.ppat.1003897] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 12/09/2013] [Indexed: 12/29/2022] Open
Abstract
Genetic variation in the mosquito Anopheles gambiae profoundly influences its ability to transmit malaria. Mosquito gut bacteria are shown to influence the outcome of infections with Plasmodium parasites and are also thought to exert a strong drive on genetic variation through natural selection; however, a link between antibacterial effects and genetic variation is yet to emerge. Here, we combined SNP genotyping and expression profiling with phenotypic analyses of candidate genes by RNAi-mediated silencing and 454 pyrosequencing to investigate this intricate biological system. We identified 138 An. gambiae genes to be genetically associated with the outcome of Serratia marcescens infection, including the peptidoglycan recognition receptor PGRPLC that triggers activation of the antibacterial IMD/REL2 pathway and the epidermal growth factor receptor EGFR. Silencing of three genes encoding type III fibronectin domain proteins (FN3Ds) increased the Serratia load and altered the gut microbiota composition in favor of Enterobacteriaceae. These data suggest that natural genetic variation in immune-related genes can shape the bacterial population structure of the mosquito gut with high specificity. Importantly, FN3D2 encodes a homolog of the hypervariable pattern recognition receptor Dscam, suggesting that pathogen-specific recognition may involve a broader family of immune factors. Additionally, we showed that silencing the gene encoding the gustatory receptor Gr9 that is also associated with the Serratia infection phenotype drastically increased Serratia levels. The Gr9 antibacterial activity appears to be related to mosquito feeding behavior and to mostly rely on changes of neuropeptide F expression, together suggesting a behavioral immune response following Serratia infection. Our findings reveal that the mosquito response to oral Serratia infection comprises both an epithelial and a behavioral immune component. In malaria vector mosquitoes, the presence of bacteria and malaria parasites is tightly linked. Bacteria that are part of the mosquito gut ecosystem are critical modulators of the immune response elicited during infection with malaria parasites. Furthermore, responses against oral bacterial infections can affect malaria parasites. Here, we combined mosquito gut infections with the enterobacterium Serratia marcescens with genome-wide discovery and phenotypic analysis of genes involved in antibacterial responses to characterize molecular processes that control gut bacterial infections thus possibly affecting the mosquito susceptibility to infection by malaria parasites. Our data reveal complex genetic networks controlling the gut bacterial infection load and ecosystem homeostasis. These networks appear to exhibit much higher specificity toward specific classes of bacteria than previously thought and include behavioral response circuits involved in antibacterial immunity.
Collapse
Affiliation(s)
| | | | | | | | - George K. Christophides
- Department of Life Sciences, Imperial College London, London, United Kingdom
- The Cyprus Institute, Nicosia, Cyprus
- * E-mail:
| |
Collapse
|
|
28
|
Chorion formation in panoistic ovaries requires windei and trimethylation of histone 3 lysine 9. Exp Cell Res 2014; 320:46-53. [DOI: 10.1016/j.yexcr.2013.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 07/09/2013] [Accepted: 07/10/2013] [Indexed: 02/05/2023]
|
|
29
|
Genome-wide association study identifies loci at ATF7IP and KLK2 associated with percentage of circulating free PSA. Neoplasia 2013; 15:95-101. [PMID: 23359319 DOI: 10.1593/neo.121620] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 11/15/2012] [Accepted: 11/15/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. MATERIALS/METHODS To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. RESULTS We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness. CONCLUSIONS These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.
Collapse
|
|
30
|
Dimassi S, Andrieux J, Labalme A, Lesca G, Cordier MP, Boute O, Neut D, Edery P, Sanlaville D, Schluth-Bolard C. Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability. Am J Med Genet A 2013; 161A:2564-9. [PMID: 23918416 DOI: 10.1002/ajmg.a.36079] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 05/13/2013] [Indexed: 11/07/2022]
Abstract
We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia. Array-CGH studies revealed overlapping interstitial 12p13.1 microdeletions encompassing all or part of GRIN2B. GRIN2B encodes the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. This receptor is a heteromeric glutamate-activated ion channel, present throughout the central nervous system. It plays a critical role in corticogenesis, neuronal migration, and synaptogenesis during brain development. GRIN2B alterations, including mutation and gene disruption by apparently balanced chromosomal rearrangements, have been described in patients with intellectual disability and autism spectrum disorder. We report here on the first cases of GRIN2B deletion, enlarging the spectrum of GRIN2B abnormalities. Our findings confirm the involvement of this gene in neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Sarra Dimassi
- Service de Génétique, Laboratoire de Cytogénétique Constitutionnelle, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Sasai N, Saitoh N, Saitoh H, Nakao M. The transcriptional cofactor MCAF1/ATF7IP is involved in histone gene expression and cellular senescence. PLoS One 2013; 8:e68478. [PMID: 23935871 PMCID: PMC3728336 DOI: 10.1371/journal.pone.0068478] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 05/31/2013] [Indexed: 12/27/2022] Open
Abstract
Cellular senescence is post-mitotic or oncogene-induced events combined with nuclear remodeling. MCAF1 (also known as hAM or ATF7IP), a transcriptional cofactor that is overexpressed in various cancers, functions in gene activation or repression, depending on interacting partners. In this study, we found that MCAF1 localizes to PML nuclear bodies in human fibroblasts and non-cancerous cells. Interestingly, depletion of MCAF1 in fibroblasts induced premature senescence that was characterized by cell cycle arrest, SA-β-gal activity, and senescence-associated heterochromatic foci (SAHF) formation. Under this condition, core histones and the linker histone H1 significantly decreased at both mRNA and protein levels, resulting in reduced nucleosome formation. Consistently, in activated Ras-induced senescent fibroblasts, the accumulation of MCAF1 in PML bodies was enhanced via the binding of this protein to SUMO molecules, suggesting that sequestration of MCAF1 to PML bodies promotes cellular senescence. Collectively, these results reveal that MCAF1 is an essential regulator of cellular senescence.
Collapse
Affiliation(s)
- Nobuhiro Sasai
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Noriko Saitoh
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Hisato Saitoh
- Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Kumamoto, Japan
| | - Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan
- * E-mail:
| |
Collapse
|
|
32
|
Genome-Wide Pathway Analysis in Major Depressive Disorder. J Mol Neurosci 2013; 51:428-36. [DOI: 10.1007/s12031-013-0047-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 06/06/2013] [Indexed: 01/23/2023]
|
|
33
|
McIver SC, Roman SD, Nixon B, Loveland KL, McLaughlin EA. The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets. F1000Res 2013; 2:55. [PMID: 24555040 PMCID: PMC3901536 DOI: 10.12688/f1000research.2-55.v1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/15/2013] [Indexed: 12/11/2022] Open
Abstract
Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including hypospadias, undescended testes and type II testicular germ cell tumours (TGCTs). The increase in TGCTs cannot be accounted for by genetic changes in the population. Therefore exposure to environmental toxicants appears to be a major contributor to the aetiology of TGCTs and men with a genetic predisposition are particularly vulnerable. In particular, Type II TGCTs have been identified to arise from a precursor lesion Carcinoma
in situ (CIS), identified as a dysfunctional gonocyte; however, the exact triggers for CIS development are currently unknown. Therefore the transition from gonocytes into spermatogonia is key to those studying TGCTs. Recently we have identified seven miRNA molecules (including members of the miR-290 family and miR-136, 463* and 743a) to be significantly changed over this transition period. These miRNA molecules are predicted to have targets within the CXCR4, PTEN, DHH, RAC and PDGF pathways, all of which have important roles in germ cell migration, proliferation and homing to the spermatogonial stem cell niche. Given the plethora of potential targets affected by each miRNA molecule, subtle changes in miRNA expression could have significant consequences e.g. tumourigenesis. The role of non-traditional oncogenes and tumour suppressors such as miRNA in TGCT is highlighted by the fact that the majority of these tumours express wild type p53, a pivotal tumour suppressor usually inactivated in cancer. While treatment of TGCTs is highly successful, the impact of these treatments on fertility means that identification of exact triggers, earlier diagnosis and alternate treatments are essential. This review examines the genetic factors and possible triggers of type II TGCT to highlight target areas for potential new treatments.
Collapse
Affiliation(s)
- Skye C McIver
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| | - Shaun D Roman
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| | - Brett Nixon
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| | - Kate L Loveland
- Department of Biochemistry & Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, 3800, Australia ; Department of Anatomy & Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, 3800, Australia
| | - Eileen A McLaughlin
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| |
Collapse
|
|
34
|
Shen J, Terry MB, Liao Y, Gurvich I, Wang Q, Senie RT, Santella RM. Genetic variation in telomere maintenance genes, telomere length and breast cancer risk. PLoS One 2012; 7:e44308. [PMID: 22970196 PMCID: PMC3435409 DOI: 10.1371/journal.pone.0044308] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Accepted: 08/01/2012] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses. METHODS We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model. RESULTS We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity. CONCLUSIONS We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.
Collapse
Affiliation(s)
- Jing Shen
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Lessel D, Gamulin M, Kulis T, Toliat MR, Grgic M, Friedrich K, Žunec R, Balija M, Nürnberg P, Kastelan Z, Högel J, Kubisch C. Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population. Carcinogenesis 2012; 33:1548-52. [DOI: 10.1093/carcin/bgs218] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
|
|
36
|
Buijs A, Poot M, van der Crabben S, van der Zwaag B, van Binsbergen E, van Roosmalen MJ, Tavakoli-Yaraki M, de Weerdt O, Nieuwenhuis HK, van Gijn M, Kloosterman WP. Elucidation of a novel pathogenomic mechanism using genome-wide long mate-pair sequencing of a congenital t(16;21) in a series of three RUNX1-mutated FPD/AML pedigrees. Leukemia 2012; 26:2151-4. [DOI: 10.1038/leu.2012.79] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|
|
37
|
Regulation of the human catalytic subunit of telomerase (hTERT). Gene 2012; 498:135-46. [PMID: 22381618 DOI: 10.1016/j.gene.2012.01.095] [Citation(s) in RCA: 205] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2011] [Revised: 01/29/2012] [Accepted: 01/30/2012] [Indexed: 12/12/2022]
Abstract
Over the past decade, there has been much interest in the regulation of telomerase, the enzyme responsible for maintaining the integrity of chromosomal ends, and its crucial role in cellular immortalization, tumorigenesis, and the progression of cancer. Telomerase activity is characterized by the expression of the telomerase reverse transcriptase (TERT) gene, suggesting that TERT serves as the major limiting agent for telomerase activity. Recent discoveries have led to characterization of various interactants that aid in the regulation of human TERT (hTERT), including numerous transcription factors; further supporting the pivotal role that transcription plays in both the expression and repression of telomerase. Several studies have suggested that epigenetic modulation of the hTERT core promoter region may provide an additional level of regulation. Although these studies have provided essential information on the regulation of hTERT, there has been ambiguity of the role of methylation within the core promoter region and the subsequent binding of various activating and repressive agents. As a result, we found it necessary to consolidate and summarize these recent developments and elucidate these discrepancies. In this review, we focus on the co-regulation of hTERT via transcriptional regulation, the presence or absence of various activators and repressors, as well as the epigenetic pathways of DNA methylation and histone modifications.
Collapse
|
|
38
|
Abstract
The methyl-CpG binding proteins (MBPs) interpret the methylation of DNA and its components. The number of MBPs in the human body currently stands at 15, which are split into 3 branches, a reflection of the intricate mechanisms of gene regulation. Each branch utilizes a different mechanism for interacting with methylated DNA or its components. These interactions function to direct gene expression and maintain or alter DNA architecture. It is these functions that are commonly exploited in human disease. For this review, we will focus on each protein and any roles it may have in initiating, promoting, progressing, or inhibiting cancer. This will highlight common threads in the roles of these proteins, which will allow us to speculate on potentially productive directions for future research.
Collapse
Affiliation(s)
- Lee Parry
- School of Biosciences, Cardiff University, Cardiff, UK
| | | |
Collapse
|
|
39
|
Kojima KK, Jurka J. Crypton transposons: identification of new diverse families and ancient domestication events. Mob DNA 2011; 2:12. [PMID: 22011512 PMCID: PMC3212892 DOI: 10.1186/1759-8753-2-12] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Accepted: 10/19/2011] [Indexed: 01/27/2023] Open
Abstract
Background "Domestication" of transposable elements (TEs) led to evolutionary breakthroughs such as the origin of telomerase and the vertebrate adaptive immune system. These breakthroughs were accomplished by the adaptation of molecular functions essential for TEs, such as reverse transcription, DNA cutting and ligation or DNA binding. Cryptons represent a unique class of DNA transposons using tyrosine recombinase (YR) to cut and rejoin the recombining DNA molecules. Cryptons were originally identified in fungi and later in the sea anemone, sea urchin and insects. Results Herein we report new Cryptons from animals, fungi, oomycetes and diatom, as well as widely conserved genes derived from ancient Crypton domestication events. Phylogenetic analysis based on the YR sequences supports four deep divisions of Crypton elements. We found that the domain of unknown function 3504 (DUF3504) in eukaryotes is derived from Crypton YR. DUF3504 is similar to YR but lacks most of the residues of the catalytic tetrad (R-H-R-Y). Genes containing the DUF3504 domain are potassium channel tetramerization domain containing 1 (KCTD1), KIAA1958, zinc finger MYM type 2 (ZMYM2), ZMYM3, ZMYM4, glutamine-rich protein 1 (QRICH1) and "without children" (WOC). The DUF3504 genes are highly conserved and are found in almost all jawed vertebrates. The sequence, domain structure, intron positions and synteny blocks support the view that ZMYM2, ZMYM3, ZMYM4, and possibly QRICH1, were derived from WOC through two rounds of genome duplication in early vertebrate evolution. WOC is observed widely among bilaterians. There could be four independent events of Crypton domestication, and one of them, generating WOC/ZMYM, predated the birth of bilaterian animals. This is the third-oldest domestication event known to date, following the domestication generating telomerase reverse transcriptase (TERT) and Prp8. Many Crypton-derived genes are transcriptional regulators with additional DNA-binding domains, and the acquisition of the DUF3504 domain could have added new regulatory pathways via protein-DNA or protein-protein interactions. Conclusions Cryptons have contributed to animal evolution through domestication of their YR sequences. The DUF3504 domains are domesticated YRs of animal Crypton elements.
Collapse
Affiliation(s)
- Kenji K Kojima
- Genetic Information Research Institute, 1925 Landings Drive, Mountain View, CA 94043, USA.
| | | |
Collapse
|
|
40
|
NF-kappaB p65 modulates the telomerase reverse transcriptase in the HepG₂ hepatoma cell line. Eur J Pharmacol 2011; 672:113-20. [PMID: 22008847 DOI: 10.1016/j.ejphar.2011.09.187] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Revised: 09/19/2011] [Accepted: 09/24/2011] [Indexed: 01/11/2023]
Abstract
Nuclear factor-kappa B (NF-kappaB) regulates the expression of various genes, several genes involved in inflammation and tumorigenesis, including those of the liver. A role for NF-kappaB has been implicated in the pathogenesis of hepatocellular carcinoma. This transcription factor can regulate hTERT gene transcription. Expression of hTERT was found to be at high levels in hepatocellular carcinoma. However, positive effects of NF-kappaB on hTERT protein synthesis in HepG(2) cells are unknown. In this study, we show that LPS (specific binding to TLR4 to activate NF-kappaB) was positive for NF-kappaB p65 mRNA expression and activation, and also up-regulated hTERT mRNA and protein expressions at 36h in a dose-dependent manner. In contrast, MG-132 (blocking the activity of 26S proteasome and thereby preventing nuclear translocation of NF-kappaB) significantly inhibited activation of NF-kappaB and mRNA expression. And also reduced the expression of hTERT at both mRNA and protein levels at 36h in a dose-dependent manner. Furthermore, dexamethasone inhibited LPS-induced activation of NF-kappaB and expression of the hTERT in HepG(2) cells. These findings suggest that NF-kappaB may modulate hTERT mRNA level, importantly, in protein level in HepG(2) cells and dexamethasone inhibits LPS-induced hTERT via blocking NF-kappaB.
Collapse
|
|
41
|
Impaired odontogenic differentiation of senescent dental mesenchymal stem cells is associated with loss of Bmi-1 expression. J Endod 2011; 37:662-6. [PMID: 21496667 DOI: 10.1016/j.joen.2011.02.009] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Revised: 01/24/2011] [Accepted: 02/03/2011] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Dental mesenchymal stem cells (dMSCs) might differentiate into odontoblast-like cells and form mineralized nodules. In the current study, we investigated the effects of senescence on odontogenic differentiation of dMSCs. METHODS dMSCs were serially subcultured until senescence. Telomere lengths and telomerase activities were determined by quantitative polymerase chain reaction. Expression of genes involved in cell proliferation and differentiation, eg, Bmi-1, p16(INK4A), osteocalcin (OC), dentin sialoprotein (DSP), bone sialoprotein (BSP), and dentin matrix protein-1 (DMP-1) were assayed by Western blotting and quantitative reverse transcription polymerase chain reaction. Exogenous Bmi-1 was expressed in dMSCs by using retroviral vectors. Odontogenic differentiation was assayed by alkaline phosphatase activity. RESULTS Subculture-induced replicative senescence of dMSCs led to reduced expression of Bmi-1, OC, DSP, and BSP compared with rapidly proliferating cells, whereas p16(INK4A) level increased. The cells exhibited progressive loss of telomeric DNA during subculture, presumably as a result of lack of telomerase activity. Bmi-1 transduction did not affect proliferation of cells but enhanced the expression of OC and DSP in the late passage cultures. Bmi-1-transduced cells also demonstrated enhanced alkaline phosphatase activity and mineralized nodule formation. CONCLUSIONS These results indicate that dMSCs lose their odontogenic differentiation potential during senescence, in part by reduced Bmi-1 expression.
Collapse
|
|
42
|
Oh JE, Kim RH, Shin KH, Park NH, Kang MK. DeltaNp63α protein triggers epithelial-mesenchymal transition and confers stem cell properties in normal human keratinocytes. J Biol Chem 2011; 286:38757-38767. [PMID: 21880709 DOI: 10.1074/jbc.m111.244939] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
p63 is a p53 family protein required for morphogenesis and postnatal regeneration of epithelial tissues. Here we demonstrate that ΔNp63α, a p63 isoform lacking the N-terminal transactivation domain, induces epithelial-mesenchymal transition (EMT) in primary human keratinocytes in a TGF-β-dependent manner. Rapidly proliferating normal human epidermal keratinocytes (NHEK) were infected with retroviral vector expressing ΔNp63α or empty vector and serially subcultured until replicative senescence. No phenotypic changes were observed until the culture reached senescence. Then the ΔNp63α-transduced cells underwent morphological changes resembling mesenchymal cells and acquired the EMT phenotype. Treatment with exogenous TGF-β accelerated EMT in presenescent ΔNp63α-transduced cells, whereas the inhibition of TGF-β signaling reversed the EMT phenotype. TGF-β treatment alone led to growth arrest in control NHEK with no evidence of EMT, indicating that ΔNp63α altered the cellular response to TGF-β treatment. ΔNp63α-transduced cells acquiring EMT gained the ability to be differentiated to osteo-/odontogenic and adipogenic pathways, resembling mesenchymal stem cells. Furthermore, these cells expressed enhanced levels of Nanog and Lin28, which are transcription factors associated with pluripotency. These data indicate that EMT required ΔNp63α transduction and intact TGF-β signaling in NHEK.
Collapse
Affiliation(s)
- Ju-Eun Oh
- School of Dentistry, UCLA, Los Angeles, California 90095
| | - Reuben H Kim
- School of Dentistry, UCLA, Los Angeles, California 90095; Dental Research Institute, UCLA, Los Angeles, California 90095; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095
| | - Ki-Hyuk Shin
- School of Dentistry, UCLA, Los Angeles, California 90095; Dental Research Institute, UCLA, Los Angeles, California 90095; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095
| | - No-Hee Park
- School of Dentistry, UCLA, Los Angeles, California 90095; Dental Research Institute, UCLA, Los Angeles, California 90095; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095; David Geffen School of Medicine, UCLA, Los Angeles, California 90095
| | - Mo K Kang
- School of Dentistry, UCLA, Los Angeles, California 90095; Dental Research Institute, UCLA, Los Angeles, California 90095; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095.
| |
Collapse
|
|
43
|
Turnbull C, Rahman N. Genome-wide association studies provide new insights into the genetic basis of testicular germ-cell tumour. ACTA ACUST UNITED AC 2011; 34:e86-96; discussion e96-7. [PMID: 21623831 DOI: 10.1111/j.1365-2605.2011.01162.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Testicular germ-cell tumour (TGCT) is the most common cancer in young men, and genetic epidemiological studies suggest that the disease has a strong genetic basis. Until 2009, very little of this genetic component had been explained. Genome-wide association studies have since identified eight SNPs at six loci which together account for approximately 15% of the genetic risk of TGCT and offer novel biological insights into testicular germ-cell oncogenesis. In this review, we summarize the genetic epidemiology of TGCT, detail the contribution genome-wide association studies have made to our understanding of the genetic basis of TGCT and reflect on how future technological advances may assist in revealing the remaining genetic factors underlying TGCT susceptibility.
Collapse
Affiliation(s)
- C Turnbull
- Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.
| | | |
Collapse
|
|
44
|
Gilbert D, Rapley E, Shipley J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nat Rev Cancer 2011; 11:278-88. [PMID: 21412254 DOI: 10.1038/nrc3021] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs. Furthermore, this improved understanding of the mechanisms underlying TGCT development and dissemination has clinical relevance for the management of patients with these tumours.
Collapse
Affiliation(s)
- Duncan Gilbert
- Sussex Cancer Centre, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, East Sussex, UK
| | | | | |
Collapse
|
|
45
|
Yawata T, Maeda Y, Okiku M, Ishida E, Ikenaka K, Shimizu K. Identification and functional characterization of glioma-specific promoters and their application in suicide gene therapy. J Neurooncol 2011; 104:497-507. [PMID: 21347689 DOI: 10.1007/s11060-010-0522-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2010] [Accepted: 12/22/2010] [Indexed: 11/26/2022]
Abstract
Suicide gene therapy has been shown to be effective in inducing tumor regression. In this study, a human brain tumor-specific promoter was identified and used to develop transcriptionally targeted gene therapy. We searched for genes with brain tumor-specific expression. By in silico and reverse-transcription polymerase chain reaction screening, MAGE-A3 and SSX4 were found to be expressed in a tumor-specific manner. SSX4 gene promoter activity was high in human brain tumor cells but not in normal human astrocyte cells, whereas the MAGE-A3 promoter showed activity in both tumor and normal cells. A retrovirus vector carrying a suicide gene, the herpes simplex virus thymidine kinase gene controlled by the SSX4 promoter, was constructed to evaluate the efficacy of the promoter in tumor-specific gene therapy. Glioma and human telomerase catalytic subunit-immortalized fibroblast BJ-5ta cell lines transduced with retrovirus vectors were assayed for killing activity by ganciclovir. Glioma cell lines were effectively killed by ganciclovir in a concentration-dependent manner, whereas BJ-5ta cells were not. By contrast, MAGE-A3 promoter failed to induce cytotoxicity in a brain tumor-specific manner. In addition, mouse glioma RSV-M cells transduced with retrovirus vector also showed suppressed tumor formation activity in syngeneic mice in response to ganciclovir administration. Therefore, the SSX4 promoter is a candidate for brain tumor-specific gene therapy and supports the efficacy and safety of suicide gene therapy for malignant brain tumors.
Collapse
Affiliation(s)
- Toshio Yawata
- Department of Neurosurgery, Kochi Medical School, Nankoku, Kochi, Japan
| | | | | | | | | | | |
Collapse
|
|
46
|
Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, Ricketts M, Linger R, Nsengimana J, Deloukas P, Huddart RA, Bishop DT, Easton DF, Stratton MR, Rahman N. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet 2010; 42:604-7. [PMID: 20543847 PMCID: PMC3773909 DOI: 10.1038/ng.607] [Citation(s) in RCA: 270] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Accepted: 05/17/2010] [Indexed: 12/13/2022]
Abstract
We conducted a genome-wide association study for testicular germ cell tumor, genotyping 298,782 SNPs in 979 affected individuals and 4,947 controls from the UK and replicating associations in a further 664 cases and 3,456 controls. We identified three new susceptibility loci, two of which include genes that are involved in telomere regulation. We identified two independent signals within the TERT-CLPTM1L locus on chromosome 5, which has previously been associated with multiple other cancers (rs4635969, OR=1.54, P=1.14x10(-23); rs2736100, OR=1.33, P=7.55x10(-15)). We also identified a locus on chromosome 12 (rs2900333, OR=1.27, P=6.16x10(-10)) that contains ATF7IP, a regulator of TERT expression. Finally, we identified a locus on chromosome 9 (rs755383, OR=1.37, P=1.12x10(-23)), containing the sex determination gene DMRT1, which has been linked to teratoma susceptibility in mice.
Collapse
Affiliation(s)
- Clare Turnbull
- Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Chang LK, Chuang JY, Nakao M, Liu ST. MCAF1 and synergistic activation of the transcription of Epstein-Barr virus lytic genes by Rta and Zta. Nucleic Acids Res 2010; 38:4687-700. [PMID: 20385599 PMCID: PMC2919728 DOI: 10.1093/nar/gkq243] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Epstein–Barr virus (EBV) expresses two transcription factors, Rta and Zta, during the immediate-early stage of the lytic cycle. The two proteins often collaborate to activate the transcription of EBV lytic genes synergistically. This study demonstrates that Rta and Zta form a complex via an intermediary protein, MCAF1, on Zta response element (ZRE) in vitro. The interaction among these three proteins in P3HR1 cells is also verified via coimmunoprecipitation, CHIP analysis and confocal microscopy. The interaction between Rta and Zta in vitro depends on the region between amino acid 562 and 816 in MCAF1. In addition, overexpressing MCAF1 enhances and introducing MCAF1 siRNA into the cells markedly reduces the level of the synergistic activation in 293T cells. Moreover, the fact that the synergistic activation depends on ZRE but not on Rta response element (RRE) originates from the fact that Rta and Zta are capable of activating the BMRF1 promoter synergistically after an RRE but not ZREs in the promoter are mutated. The binding of Rta–MCAF1–Zta complex to ZRE but not RRE also explains why Rta and Zta do not use RRE to activate transcription synergistically. Importantly, this study elucidates the mechanism underlying synergistic activation, which is important to the lytic development of EBV.
Collapse
Affiliation(s)
- Li-Kwan Chang
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan
| | | | | | | |
Collapse
|