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Seres M, Spacayova K, Sulova Z, Spaldova J, Breier A, Pavlikova L. Dynamic Multilevel Regulation of EGFR, KRAS, and MYC Oncogenes: Driving Cancer Cell Proliferation Through (Epi)Genetic and Post-Transcriptional/Translational Pathways. Cancers (Basel) 2025; 17:248. [PMID: 39858030 PMCID: PMC11763799 DOI: 10.3390/cancers17020248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer.
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Affiliation(s)
- Mario Seres
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia; (M.S.); (K.S.); (Z.S.)
| | - Katarina Spacayova
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia; (M.S.); (K.S.); (Z.S.)
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Ilkovičova 6, 84215 Bratislava, Slovakia
| | - Zdena Sulova
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia; (M.S.); (K.S.); (Z.S.)
| | - Jana Spaldova
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia;
| | - Albert Breier
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia; (M.S.); (K.S.); (Z.S.)
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia;
| | - Lucia Pavlikova
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia; (M.S.); (K.S.); (Z.S.)
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Lang K, Köhler CU, Wichert K, Deix T, Bartsch G, Sommer G, Lübke C, Roghmann F, Reike MJ, Krentel H, Engellandt K, Schiermeier S, Menke V, Noldus J, Behrens T, Brüning T, Käfferlein HU. Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals. J Transl Med 2024; 22:1061. [PMID: 39587670 PMCID: PMC11590282 DOI: 10.1186/s12967-024-05844-x] [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: 05/29/2024] [Accepted: 10/31/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND For more than 80 years, cystoscopy has been the gold standard for identification of urothelial carcinoma (UCa). Because of many factors, such as pain of the patients during this procedure or the costs involved, non-invasive detection of UCa remains a challenge. Herein, we verify our previously identified urinary biomarkers C-X-C Motif Chemokine Ligand 16 (CXCL16) and transforming growth-factor beta induced protein (TGFBI) on the protein level as well as the CpG sites ALOX5, TRPS1 and an intergenic region on Chromosome 16 on DNA methylation level in an independent cross-sectional study. METHODS We collected N = 1119 urines from individuals coming to urological and gynecological check-ups, follow-up care or patients suspicious for UCa or already diagnosed for different urologic or gynecologic cancer entities. We performed methylation analysis of various CpG sites with DNA isolated from urine sediment and quantified the concentration of the protein markers CXCL16 and TGFBI in the corresponding urine supernatant using ELISA. We tested for patient-group differences with two-sided Wilcoxon rank sum tests and examined the performance with receiver operating characteristic curves. For verification, we analyzed the marker performance with previously set cutoff-values and marker combinations with established and experimental algorithms (with logical OR-conjunction, iterative threshold-based biomarker and score combining algorithm "PanelomiX"). RESULTS Evaluation confirmed that our previously identified protein and DNA methylation biomarkers can distinguish UCa from frequent urological and gynecological cancers. CXCL16 and TGFBI discriminated UCa cases with a sensitivity of 31% and 56% and a specificity of 94% and 85%, respectively. Combining methylation markers resulted in UCa detection in men with a sensitivity of 54% and a specificity of 94%. Extending analysis by combining all methylation and protein markers (up to five markers in total) yielded a convincingly high specificity of 97% at a sensitivity of 72% for the identification of UCa patients within a heterogeneous collective of cancer-free individuals and patients suffering from urological or gynecological cancers. CONCLUSION Combining various biomarkers at protein and DNA level demonstrates a new option of non-invasive UCa diagnosis in urine, and thus might help to reduce the number of unnecessary cystoscopies, especially in patients without a history of UCa.
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Affiliation(s)
- Kerstin Lang
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
| | - Christina U Köhler
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
| | - Katharina Wichert
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
| | - Thomas Deix
- URO DR, Clinic of Urology and Andrology, Mülheimer Str. 37, 40878, Ratingen, Germany
| | - Georg Bartsch
- URO DR, Clinic of Urology and Andrology, Mülheimer Str. 37, 40878, Ratingen, Germany
| | - Gudrun Sommer
- Surgery of Gynecology, Husemannplatz 6-7, 44787, Bochum, Germany
| | - Christiane Lübke
- Surgery of Gynecology, Husemannplatz 6-7, 44787, Bochum, Germany
| | - Florian Roghmann
- Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Hölkeskampring 40, 44625, Herne, Germany
| | - Moritz J Reike
- Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Hölkeskampring 40, 44625, Herne, Germany
| | - Harald Krentel
- Department of Obstetrics and Gynecology, Bethesda Hospital, Duisburg, Germany
| | - Katja Engellandt
- Department of Obstetrics and Gynecology, Bethesda Hospital, Duisburg, Germany
| | - Sven Schiermeier
- Department of Obstetrics and Gynecology, Marien-Hospital, University Witten-Herdecke, Witten, Germany
| | - Valentin Menke
- Department of Obstetrics and Gynecology, St. Anna Hospital, Herne, Germany
| | - Joachim Noldus
- Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Hölkeskampring 40, 44625, Herne, Germany
| | - Thomas Behrens
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
| | - Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
| | - Heiko U Käfferlein
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany.
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Li K, Qi L, Tang G, Xu H, Li Z, Fan B, Li Z, Li Y. Epigenetic Regulation in Urothelial Carcinoma. Curr Mol Med 2024; 24:85-97. [PMID: 36545729 DOI: 10.2174/1566524023666221221094432] [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: 05/24/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 12/24/2022]
Abstract
Urothelial carcinoma (UC) is a common malignancy that remains a clinical challenge: Non-muscle-invasive urothelial carcinoma (NMIUC) has a high rate of recurrence and risk of progression, while muscle-invasive urothelial carcinoma (MIUC) has a high mortality. Although some new treatments, such as immunotherapies, have shown potential effects on some patients, most cases of advanced UC remain incurable. While treatments based on epigenetic mechanisms, whether combined with traditional platinum-based chemotherapy or emerging immunotherapy, show therapeutic advantages. With the advancement of sequencing and bioinformatics, the study of epigenomics, containing DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, is increasingly linked with the occurrence and progression of UC. Since the epigenetics of UC is a constantly developing field of medicine, this review aims to summarize the latest research on epigenetic regulation of UC, generalize the mechanism of epigenetics in UC, and reveal the potential epigenetic therapies in the clinical setting, in order to provide some new clues on the discovery of new drugs based on the epigenetics.
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Affiliation(s)
- Ke Li
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Lin Qi
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Guyu Tang
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Haozhe Xu
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhi Li
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Bo Fan
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhongbei Li
- College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Yuan Li
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, China
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Albulescu A, Plesa A, Fudulu A, Iancu IV, Anton G, Botezatu A. Epigenetic approaches for cervical neoplasia screening (Review). Exp Ther Med 2021; 22:1481. [PMID: 34765022 PMCID: PMC8576616 DOI: 10.3892/etm.2021.10916] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Human papillomavirus (HPV) infection is the leading cause of cervical cancer. The Papanicolaou cytology test is the usually employed type of screening for this infection; however, its sensibility is limited. Only a small percentage of women infected with high-risk HPV develop cervical cancer with an array of genetic and epigenetic modifications. Thus, it is necessary to develop rapid, reproducible and minimally invasive technologies for screening. DNA methylation has gained attention as an alternative method for molecular diagnosis and prognosis in HPV infection. The aim of the present review was to highlight the potential of DNA methylation in cervical neoplasia screening for clinical applications. It was observed that the methylation human and viral genes was correlated with high-grade lesions and cancer. Methylation biomarkers have shown a good capacity to discriminate between high-grade lesions with a transformative potential and cervical cancer, being able to detect these modifications at an early stage. With further research, the epigenetic profiles and subtypes of the tumors could be elaborated, which would aid in therapy selection by opening avenues in personalized precision medicine. Response to therapy could also be evaluated through such methods and the accessibility of liquid biopsies would allow a constant monitoring of the patient's status without invasive sampling techniques.
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Affiliation(s)
- Adrian Albulescu
- Department of Molecular Virology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania.,Pharmacology Department, National Institute for Chemical Pharmaceutical Research and Development, Bucharest 031299, Romania
| | - Adriana Plesa
- Department of Molecular Virology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Alina Fudulu
- Department of Molecular Virology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Iulia Virginia Iancu
- Department of Molecular Virology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Gabriela Anton
- Department of Molecular Virology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Anca Botezatu
- Department of Molecular Virology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Tripathi K, Goel A, Singhai A, Garg M. Promoter hypomethylation as potential confounder of Ras gene overexpression and their clinical significance in subsets of urothelial carcinoma of bladder. Mol Biol Rep 2021; 48:2183-2199. [PMID: 33620658 DOI: 10.1007/s11033-021-06227-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/10/2021] [Indexed: 12/31/2022]
Abstract
Overexpression of normal Ras and its aberrant CpG island methylation in the promoter regions have been shown to direct cells for uncontrolled abnormal growth and bladder tumor formation and therefore, fetched recent attention as a marker of diagnosis and prognosis to predict the biological behavior of urothelial carcinoma of bladder (UCB). Methylation pattern at CpG islands of the promoter regions of rat sarcoma (Ras) gene homologues namely Kristen-Ras (K-Ras), Harvey (H-Ras), and Neuroblastoma (N-Ras) were examined by methylation specific polymerase chain reaction (MSP). Real time-quantitative polymerase chain reaction (RT-qPCR) was done to determine transcriptomic expressions of these Ras isoforms in the prospective series of 42 NMIBC (non-muscle invasive bladder cancer) and 45 MIBC (muscle invasive bladder cancer) biopsies. CpG loci in H-Ras and K-Ras were observed to be more hypomethylated in MIBC, whereas more hypomethylation in N-Ras was noted in NMIBC. Strong association of hypomethylation index with tumor stage, grade, type and size validate them it as marker of diagnosis in UCB patients. Differential overexpression of H-Ras, N-Ras and K-Ras genes in NMIBC and MIBC and their association with patients' demographics identify them as important diagnostic markers in pathogenesis of UCB. Given the reported ability of promoter hypomethylation to activate Ras expression, correlation studies examined positive significant association between hypomethylation index and expression. Study concludes that promoter hypomethylation of N-Ras and K-Ras could be a potential confounder of their increased expression in NMIBC. Biological significance of simultaneous presence of higher expression and promoter hypomethylation of Ras gene isoforms in MIBC is difficult to resolve in a given cohort of patients.
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Affiliation(s)
- Kiran Tripathi
- Department of Biochemistry, University of Lucknow, Lucknow, 226007, India
| | - Apul Goel
- Department of Urology, King George Medical University, Lucknow, 226003, India
| | - Atin Singhai
- Department of Pathology, King George Medical University, Lucknow, 226003, India
| | - Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow, 226007, India.
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Ahmed AA, Adam Essa ME. Epigenetic alterations in female urogenital organs cancer: Premise, properties, and perspectives. SCIENTIFIC AFRICAN 2020. [DOI: 10.1016/j.sciaf.2020.e00318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Martinez VG, Munera-Maravilla E, Bernardini A, Rubio C, Suarez-Cabrera C, Segovia C, Lodewijk I, Dueñas M, Martínez-Fernández M, Paramio JM. Epigenetics of Bladder Cancer: Where Biomarkers and Therapeutic Targets Meet. Front Genet 2019; 10:1125. [PMID: 31850055 PMCID: PMC6902278 DOI: 10.3389/fgene.2019.01125] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 10/17/2019] [Indexed: 12/12/2022] Open
Abstract
Bladder cancer (BC) is the most common neoplasia of the urothelial tract. Due to its high incidence, prevalence, recurrence and mortality, it remains an unsolved clinical and social problem. The treatment of BC is challenging and, although immunotherapies have revealed potential benefit in a percentage of patients, it remains mostly an incurable disease at its advanced state. Epigenetic alterations, including aberrant DNA methylation, altered chromatin remodeling and deregulated expression of non-coding RNAs are common events in BC and can be driver events in BC pathogenesis. Accordingly, these epigenetic alterations are now being used as potential biomarkers for these disorders and are being envisioned as potential therapeutic targets for the future management of BC. In this review, we summarize the recent findings in these emerging and exciting new aspects paving the way for future clinical treatment of this disease.
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Affiliation(s)
- Victor G. Martinez
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Ester Munera-Maravilla
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Alejandra Bernardini
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Carolina Rubio
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Cristian Suarez-Cabrera
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Cristina Segovia
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Iris Lodewijk
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Marta Dueñas
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Mónica Martínez-Fernández
- Genomes & Disease Lab, CiMUS (Center for Research in Molecular Medicine and Chronic Diseases), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Jesus Maria Paramio
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Zheng D, Williams C, Vold JA, Nguyen JH, Harnois DM, Bagaria SP, McLaughlin SA, Li Z. Regulation of sex hormone receptors in sexual dimorphism of human cancers. Cancer Lett 2018; 438:24-31. [PMID: 30223066 PMCID: PMC6287770 DOI: 10.1016/j.canlet.2018.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/24/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023]
Abstract
Gender differences in the incidences of cancers have been found in almost all human cancers. However, the mechanisms that underlie gender disparities in most human cancer types have been under-investigated. Here, we provide a comprehensive overview of potential mechanisms underlying sexual dimorphism of each cancer regarding sex hormone signaling. Fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of precision medicine. Our discussions of potential mechanisms underlying sexual dimorphism in each cancer will be instructive for future cancer research on gender disparities.
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Affiliation(s)
- Daoshan Zheng
- Department of Cancer Biology, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Cecilia Williams
- Department of Biosciences and Nutrition, KTH Royal Institute of Technology, Karolinska Institutet, Science for Life Laboratory, Stockholm, Sweden
| | - Jeremy A Vold
- Mayo Cancer Registry, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Justin H Nguyen
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Denise M Harnois
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Sanjay P Bagaria
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Sarah A McLaughlin
- Department of Surgery, and Mayo Clinic Cancer Center, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Zhaoyu Li
- Department of Cancer Biology, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
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Yousef PG, Gabril MY. An update on the molecular pathology of urinary bladder tumors. Pathol Res Pract 2017; 214:1-6. [PMID: 29254798 DOI: 10.1016/j.prp.2017.11.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 10/27/2017] [Accepted: 11/03/2017] [Indexed: 01/21/2023]
Abstract
Urothelial carcinoma is the fourth most common tumors after prostate cancer, lung, and colorectal carcinoma but the second most common urologic malignancy. Urothelial carcinoma composed more than 90% of bladder tumors while squamous cell carcinoma and adenocarcinomas composed 5% and 2% respectively. The intense research involving the different molecular aspects of bladder cancer has provided a great insight into identifying more about molecular profiling and pathways of bladder cancer. In this review, we will highlight the general concepts of the molecular features; profiling and classification as well as the molecular pathways for bladder carcinomas, especially urothelial carcinoma. Also, we will discuss the advances of molecular biomarkers for screening, early diagnosis, surveillance and potential prognosis of urothelial carcinoma of the bladder. Studies showed that accumulation of genetic alterations involving the clonal expansion of altered cells with growth advantages through sequential multi-step pathways results in progression of bladder tumors. The accumulated research data from literature has revealed that the genomic signatures of urothelial carcinoma are required to subclassify bladder cancer into genetically distinct subgroups. These findings could improve the understating of pathogenesis as well as will provide new therapeutic modules e.g. targeted therapy.
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Affiliation(s)
- Peter G Yousef
- Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Manal Y Gabril
- Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada.
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Promoter hypermethylation of LGALS4 correlates with poor prognosis in patients with urothelial carcinoma. Oncotarget 2017; 8:23787-23802. [PMID: 28423602 PMCID: PMC5410344 DOI: 10.18632/oncotarget.15865] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 02/13/2017] [Indexed: 01/09/2023] Open
Abstract
Galectine-4 (gal-4), encoded by the LGALS4 gene, was recently shown to exhibit a tumor suppressive effect in colorectal carcinoma and pancreatic adenocarcinoma, although how the expression of this gene is regulated remains unknown. No reports describe the significance of gal-4 in the malignant potential of urothelial tumors. Thus, we analyzed LGALS4 methylation and gene expression and their clinical relevance and biological function in urothelial carcinoma (UC). LGALS4 methylation was initially identified as a progression biomarker for UC patients through genome-wide DNA methylation profiling of 16 tumor samples. Bisulfite sequencing PCR and immunohistochemistry were performed to validate the promoter methylation and expression of LGALS4. We used quantitative methylation-specific PCR to determine the methylation levels of LGALS4 normalized to ACTB in the tumor samples of 79 UC patients and compared the levels between patients with different clinicopathological characteristics. The association with survival probability was analyzed with the Kaplan-Meier method and Cox regression analysis. The ectopic expression of gal-4 in cancer cell lines was used to address its biological function in UC in vitro. The promoter hypermethylation of LGALS4 (>2.51, log10 scale) revealed a positive correlation with high levels of both histological grade and tumor T category and with lymph node metastasis (all P≤0.001). In addition, LGALS4 hypermethylation was an independent predictor of inferior survival in UC patients (P<0.05). The ectopic expression studies demonstrated that gal-4 suppressed urothelial cancer cell growth, migration, and invasion. Thus, LGALS4 may function as a tumor suppressor gene in UC progression. Our findings provide evidence that methylation-mediated LGALS4 gene repression may be involved in urothelial tumor progression.
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Kojima T, Kawai K, Miyazaki J, Nishiyama H. Biomarkers for precision medicine in bladder cancer. Int J Clin Oncol 2016; 22:207-213. [PMID: 27896485 DOI: 10.1007/s10147-016-1068-8] [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: 11/11/2016] [Accepted: 11/15/2016] [Indexed: 01/12/2023]
Abstract
Bladder cancer (BC) is classified as non-muscle-invasive BC (NMIBC) or muscle-invasive BC (MIBC). Because the recurrence and mortality rates of BC are high, suitable biomarkers for early detection, evaluation of prognosis, and surveillance of drug responses are needed. Urinary markers simplify surveillance schedules and improve early detection of tumors, especially in NMIBC. Various markers have been identified at DNA, RNA, and protein levels with different sensitivities and specificities. Several biomarkers show a higher sensitivity than urinary cytology, but they are not accurate enough to replace it. In terms of prediction of clinical outcome and treatment response of BC, conventional clinical and pathological parameters are widely used, but the predictive ability of these parameters is limited; therefore, molecular biomarkers in this field are strongly desired. Molecular profiling using fluid and tissue is becoming more feasible with recent developments in next-generation sequencing technologies. Currently, these profiling methods are beginning to be used for early detection, prediction of prognosis, and drug sensitivity. Furthermore, several groups used transcriptome profiling to classify MIBC into various distinct subtypes, showing distinct clinical behaviors and responses to chemotherapy and immune checkpoint inhibitors. The aim of this review is to provide a summary of the most relevant biomarkers that have been investigated as diagnostic and prognostic indicators of BC.
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Affiliation(s)
- Takahiro Kojima
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Koji Kawai
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Jun Miyazaki
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Hiroyuki Nishiyama
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
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Genetic and Epigenetic Alterations in Bladder Cancer. Int Neurourol J 2016; 20:S84-94. [PMID: 27915480 PMCID: PMC5169086 DOI: 10.5213/inj.1632752.376] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 10/27/2016] [Indexed: 12/11/2022] Open
Abstract
Bladder cancer is one of the most common cancers worldwide, with a high rate of recurrence and poor outcomes as a result of relapse. Bladder cancer patients require lifelong invasive monitoring and treatment, making bladder cancer one of the most expensive malignancies. Lines of evidence increasingly point to distinct genetic and epigenetic alteration patterns in bladder cancer, even between the different stages and grades of disease. In addition, genetic and epigenetic alterations have been demonstrated to play important roles during bladder tumorigenesis. This review will focus on bladder cancer-associated genomic and epigenomic alterations, which are common in bladder cancer and provide potential diagnostic markers and therapeutic targets for bladder cancer treatment.
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13
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Rodrigues MFSD, Esteves CM, Xavier FCA, Nunes FD. Methylation status of homeobox genes in common human cancers. Genomics 2016; 108:185-193. [PMID: 27826049 DOI: 10.1016/j.ygeno.2016.11.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 09/27/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023]
Abstract
Approximately 300 homeobox loci were identified in the euchromatic regions of the human genome, of which 235 are probable functional genes and 65 are likely pseudogenes. Many of these genes play important roles in embryonic development and cell differentiation. Dysregulation of homeobox gene expression is a frequent occurrence in cancer. Accumulating evidence suggests that as genetics disorders, epigenetic modifications alter the expression of oncogenes and tumor suppressor genes driving tumorigenesis and perhaps play a more central role in the evolution and progression of this disease. Here, we described the current knowledge regarding homeobox gene DNA methylation in human cancer and describe its relevance in the diagnosis, therapeutic response and prognosis of different types of human cancers.
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Affiliation(s)
| | | | | | - Fabio Daumas Nunes
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil.
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14
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Abstract
DNA methylation alterations are common in urothelial carcinoma, a prevalent cancer worldwide caused predominantly by chemical carcinogens. Recent studies have proposed sets of hypermethylated genes as promising diagnostic and prognostic biomarkers from urine or tissue samples, which require validation. Other studies have revealed intriguing links between specific carcinogens and DNA methylation alterations in cancer tissues or blood that might clarify carcinogenesis mechanisms and aid prevention. Like DNA methylation alterations, mutations in chromatin regulators are frequent, underlining the importance of epigenetic changes. However, the relations between the two changes and their functions in urothelial carcinogenesis remain unclear. Transcription factor genes with altered methylation deserve particular interest. Elucidating the functional impact of methylation changes is a prerequisite for their therapeutic targeting.
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Affiliation(s)
- Wolfgang A Schulz
- Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Wolfgang Goering
- Department of Pathology, Medical Faculty, Heinrich Heine University Duesseldorf, Germany
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15
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Niegisch G, Hoffmann MJ, Koutsogiannouli EA, Schulz WA. [Epigenetics in urothelial cancer: Pathogenesis, improving diagnostics and developing novel treatment options]. Urologe A 2016; 54:526-32. [PMID: 25784269 DOI: 10.1007/s00120-014-3756-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Urothelial carcinoma of the bladder is a common tumor for which improvements in diagnostic markers and new therapy approaches, in addition to or combined with standard chemotherapy, are urgently required. Epigenetic alterations could provide both novel diagnostic markers and therapeutic targets as they are emerging as crucial factors in the development and progression of this tumor type, likely contributing to altered differentiation and metastatic potential. These alterations affect DNA methylation, histone modifications, chromatin remodeling, long noncoding RNAs, and microRNAs. Factors involved in histone modifications and chromatin remodeling appear to be particularly frequently inactivated by mutations. Thus, histone-modifying enzymes may represent good targets for rational new therapeutic approaches, although thorough investigation of their complex functions is a prerequisite. DNA methylation changes and altered miRNA expression provide promising biomarkers for diagnosis and prognosis that need further validation in comprehensive and well-standardized studies.
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Affiliation(s)
- G Niegisch
- Medizinische Fakultät, Urologische Klinik, Heinrich-Heine-Universität Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland,
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16
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Khan SA, Reddy D, Gupta S. Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment? World J Biol Chem 2015; 6:333-345. [PMID: 26629316 PMCID: PMC4657128 DOI: 10.4331/wjbc.v6.i4.333] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/10/2015] [Accepted: 10/08/2015] [Indexed: 02/05/2023] Open
Abstract
Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanisms such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular, covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further, histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review, we will explore and discuss how histone modifications are involved in cancer diagnosis, prognosis and treatment.
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17
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Darwiche F, Parekh DJ, Gonzalgo ML. Biomarkers for non-muscle invasive bladder cancer: Current tests and future promise. Indian J Urol 2015; 31:273-82. [PMID: 26604437 PMCID: PMC4626910 DOI: 10.4103/0970-1591.166448] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The search continues for optimal markers that can be utilized to improve bladder cancer detection and to predict disease recurrence. Although no single marker has yet replaced the need to perform cystoscopy and urine cytology, many tests have been evaluated and are being developed. In the future, these promising markers may be incorporated into standard practice to address the challenge of screening in addition to long-term surveillance of patients who have or are at risk for developing bladder cancer.
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Affiliation(s)
- Fadi Darwiche
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Dipen J Parekh
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Mark L Gonzalgo
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA
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18
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Woo YM, Shin Y, Hwang JA, Hwang YH, Lee S, Park EY, Kong HK, Park HC, Lee YS, Park JH. Epigenetic silencing of the MUPCDH gene as a possible prognostic biomarker for cyst growth in ADPKD. Sci Rep 2015; 5:15238. [PMID: 26463459 PMCID: PMC4604459 DOI: 10.1038/srep15238] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 08/28/2015] [Indexed: 11/09/2022] Open
Abstract
Although autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease, and is characterized by the formation of multiple fluid-filled cysts, which results in renal failure, early diagnosis and treatment of ADPKD have yet to be defined. Herein, we observed that the promoter region of the gene encoding mucin-like protocadherin (MUPCDH) was hypermethylated in the renal tissue of patients with ADPKD compared to non-ADPKD controls. Inversely, MUPCDH was significantly repressed in ADPKD, especially in cyst-lining cells. Our results indicate that aberrant methylation of MUPCDH promoter CpG islands may be negatively correlated with reduced expression level of MUPCDH and that this contributes to abnormal cell proliferation in ADPKD. It suggests that methylation status of MUPCDH promoter can be used as a novel epigenetic biomarker and a therapeutic target in ADPKD.
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Affiliation(s)
- Yu Mi Woo
- Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea
| | - Yubin Shin
- Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea
| | - Jung-Ah Hwang
- Branch of Cancer Genomics, Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Korea
| | - Young-Hwan Hwang
- Department of Internal Medicine, Eulji General Hospital, Seoul, 139-892, Korea
| | - Sunyoung Lee
- Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea
| | - Eun Young Park
- Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea
| | - Hyun Kyung Kong
- Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea
| | - Hayne Cho Park
- Division of Nephrology, Armed Forces Capital Hospital, Seongnam, Korea
| | - Yeon-Su Lee
- Branch of Cancer Genomics, Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Korea
| | - Jong Hoon Park
- Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea
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19
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Bryzgunova OE, Laktionov PP. Extracellular Nucleic Acids in Urine: Sources, Structure, Diagnostic Potential. Acta Naturae 2015; 7:48-54. [PMID: 26483959 PMCID: PMC4610164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Cell-free nucleic acids (cfNA) may reach the urine through cell necrosis or apoptosis, active secretion of nucleic acids by healthy and tumor cells of the urinary tract, and transport of circulating nucleic acids (cir- NA) from the blood into primary urine. Even though urinary DNA and RNA are fragmented, they can be used to detect marker sequences. MicroRNAs are also of interest as diagnostic probes. The stability of cfNA in the urine is determined by their structure and packaging into supramolecular complexes and by nuclease activity in the urine. This review summarizes current data on the sources of urinary cfNA, their structural features, diagnostic potential and factors affecting their stability.
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Affiliation(s)
- O. E. Bryzgunova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia
| | - P. P. Laktionov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Lavrentiev Avenue, 630090, Novosibirsk, Russia
- E.N. Meshalkin Novosibirsk Research Institute of Circulation Pathology, st. Rechkunovskaya 15, 630055, Novosibirsk, Russia
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20
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Su SF, de Castro Abreu AL, Chihara Y, Tsai Y, Andreu-Vieyra C, Daneshmand S, Skinner EC, Jones PA, Siegmund KD, Liang G. A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence. Clin Cancer Res 2014; 20:1978-89. [PMID: 24691641 DOI: 10.1158/1078-0432.ccr-13-2637] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The high risk of recurrence after transurethral resection of bladder tumor of nonmuscle invasive disease requires lifelong treatment and surveillance. Changes in DNA methylation are chemically stable, occur early during tumorigenesis, and can be quantified in bladder tumors and in cells shed into the urine. Some urine markers have been used to help detect bladder tumors; however, their use in longitudinal tumor recurrence surveillance has yet to be established. EXPERIMENTAL DESIGN We analyzed the DNA methylation levels of six markers in 368 urine sediment samples serially collected from 90 patients with noninvasive urothelial carcinoma (Tis, Ta, T1; grade low-high). The optimum marker combination was identified using logistic regression with 5-fold cross-validation, and validated in separate samples. RESULTS A panel of three markers discriminated between patients with and without recurrence with the area under the curve of 0.90 [95% confidence interval (CI), 0.86-0.92] and 0.95 (95% CI, 0.90-1.00), sensitivity and specificity of 86%/89% (95% CI, 74%-99% and 81%-97%) and 80%/97% (95% CI, 60%-96% and 91%-100%) in the testing and validation sets, respectively. The three-marker DNA methylation test reliably predicted tumor recurrence in 80% of patients superior to cytology (35%) and cystoscopy (15%) while accurately forecasting no recurrence in 74% of patients that scored negative in the test. CONCLUSIONS Given their superior sensitivity and specificity in urine sediments, a combination of hyper- and hypomethylated markers may help avoid unnecessary invasive exams and reveal the importance of DNA methylation in bladder tumorigenesis.
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Affiliation(s)
- Sheng-Fang Su
- Authors' Affiliations: Departments of Urology and Preventive Medicine; Program in Genetic, Molecular, and Cellular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles; and Department of Urology, School of Medicine, University of Stanford, Stanford, California
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21
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Ralla B, Stephan C, Meller S, Dietrich D, Kristiansen G, Jung K. Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies. Crit Rev Clin Lab Sci 2014; 51:200-31. [PMID: 24878357 DOI: 10.3109/10408363.2014.914888] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This review focuses on the promising potential of nucleic acids in body fluids such as blood and urine as diagnostic, prognostic, predictive and monitoring biomarkers in urologic malignancies. The tremendous progress in the basic knowledge of molecular processes in cancer, as shown in the companion review on nucleic acid-based biomarkers in tissue of urologic tumors, provides a strong rationale for using these molecular changes as non-invasive markers in body fluids. The changes observed in body fluids are an integrative result, reflecting both tissue changes and processes occurring in the body fluids. The availability of sensitive methods has only recently made possible detailed studies of DNA- and RNA-based markers in body fluids. In addition to these biological aspects, methodological aspects of the determination of nucleic acids in body fluids, i.e. pre-analytical, analytical and post-analytical issues, are particularly emphasized. The characteristic changes of RNA (differential mRNA and miRNA expression) and DNA (concentrations, integrity index, mutations, microsatellite and methylation alterations) in serum/plasma and urine samples of patients suffering from the essential urologic cancers of the prostate, bladder, kidney and testis are summarized and critically discussed below. To translate the promising results into clinical practice, laboratory scientists and clinicians have to collaborate to resolve the challenges of harmonized and feasible pre-analytical and analytical conditions for the selected markers and to validate these markers in well-designed and sufficiently powered multi-center studies.
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Affiliation(s)
- Bernhard Ralla
- Department of Urology, Charité - Universitätsmedizin Berlin , Berlin , Germany
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22
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Luo H, Zhao X, Wan X, Huang S, Wu D. Gene microarray analysis of the lncRNA expression profile in human urothelial carcinoma of the bladder. Int J Clin Exp Med 2014; 7:1244-54. [PMID: 24995079 PMCID: PMC4073740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 05/11/2014] [Indexed: 06/03/2023]
Abstract
OBJECTIVE To analyze the expression profile variation of lncRNAs in normal urinary bladder tissue and urothelial carcinoma of the urinary bladder through microarray technology. The differentially expressed lncRNAs were identified and classified, and their biological information was analyzed. The data obtained in the study will prove helpful for the diagnosis, treatment, and prevention of urothelial carcinoma of the bladder. MATERIALS AND METHODS Three specimens of urothelial carcinoma of the bladder and three specimens of normal bladder tissue were identified by histology. The total RNA was isolated from the bladder urothelial carcinomas and normal tissue and purified. The targets were mixed and hybridized with the genes on the microarray, which contained thirty thousand lncRNAs. The bladder urothelial carcinomas were then compared with the normal bladder tissue. The lncRNAs that were differentially expressed between the two groups were identified based on the signal-to-noise ratios using the Agilent Feature Extraction software and were analyzed with the Agilent Genespring GX software (Agilent). The outcome was obtained, and the biological information of these genes was deposited in GenBank. RESULTS The expression profile of lncRNAs was significantly different between normal bladder tissue and urothelial carcinoma of the bladder. Compared with normal bladder tissue, 1,122 lncRNAs exhibited at least a twofold, significant difference (P < 0.05) and are thus regarded as differentially expressed lncRNAs. Of these, 734 and 388 lncRNAs were upregulated and down regulated. The differentially expressed lncRNAs in the urothelial carcinoma of the bladder are distributed on every chromosome, and most of these lncRNAs are distributed on chromosomes 1, 2, 3, 4, 6, and X. CONCLUSIONS Urothelial carcinoma of the bladder is a complicated disease that involves the regulation of multiple genes and the participation of multiple chromosomes. Some of the differentially expressed lncRNAs that were upregulated, such as AK124776, lincRNA-RAB12-1, KRT8P25, RP11-474J18.4, AC000110.1, KRT8P13, KRT8P10, BC072678, and downregulated, such as nc-HOXB9-206, RP11-160A10.2, nc-HOXA11-86, nc-HOXD10-7, nc-HOXB9-205, CES4, nc-HOXD12-3, systematic research on these lncRNAs will help clarify the mechanisms of urothelial carcinoma of the bladder and guide the early diagnosis and treatment of this cancer in the future.
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Affiliation(s)
- Huarong Luo
- Department of Urology, Tongji Hospital of Tongji University Shanghai 200065, China
| | - Xin Zhao
- Department of Urology, Tongji Hospital of Tongji University Shanghai 200065, China
| | - Xiaodong Wan
- Department of Urology, Tongji Hospital of Tongji University Shanghai 200065, China
| | - Shengsong Huang
- Department of Urology, Tongji Hospital of Tongji University Shanghai 200065, China
| | - Denglong Wu
- Department of Urology, Tongji Hospital of Tongji University Shanghai 200065, China
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23
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Cavallo D, Casadio V, Bravaccini S, Iavicoli S, Pira E, Romano C, Fresegna AM, Maiello R, Ciervo A, Buresti G, Zoli W, Calistri D. Assessment of DNA damage and telomerase activity in exfoliated urinary cells as sensitive and noninvasive biomarkers for early diagnosis of bladder cancer in ex-workers of a rubber tyres industry. BIOMED RESEARCH INTERNATIONAL 2014; 2014:370907. [PMID: 24877087 PMCID: PMC4022006 DOI: 10.1155/2014/370907] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 03/22/2014] [Indexed: 01/22/2023]
Abstract
The aim of the present study was to identify sensitive and noninvasive biomarkers of early carcinogenic effect at target organ to use in biomonitoring studies of workers at risk for previous occupational exposure to potential carcinogens. Standard urine cytology (Papanicolaou staining test), comet assay, and quantitative telomerase repeat amplification protocol (TRAP) assay were performed in 159 ex-rubber workers employed in tyres production and 97 unexposed subjects. In TRAP positive cases, a second level analysis using FISH (Urovysion) was done. Cystoscopy results were available for 11 individuals whose 6 FISH/TRAP/comet positive showed in 3 cases a dysplastic condition confirmed by biopsy, 1 comet positive resulted in infiltrating UBC to the biopsy and with hyperplasia and slight dysplasia to the urinary cytology, 1 comet positive resulted in papillary superficial UBC to the biopsy, 1 FISH/TRAP positive showed a normal condition, and 2 TRAP positive showed in one case a phlogosis condition. The results evidenced good concordance of TRAP, comet, and FISH assays as early biomarkers of procarcinogenic effect confirmed by the dysplastic condition and UBC found by cystoscopy-biopsy analysis. The analysis of these markers in urine cells could be potentially more accurate than conventional cytology in monitoring workers exposed to mixture of bladder potential carcinogens.
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Affiliation(s)
- Delia Cavallo
- Department of Occupational Medicine, INAIL-Italian Workers' Compensation Authority, Research Area, Monteporzio Catone, 00040 Rome, Italy
| | - Valentina Casadio
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, 47014 Forlì-Cesena, Italy
| | - Sara Bravaccini
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, 47014 Forlì-Cesena, Italy
| | - Sergio Iavicoli
- Department of Occupational Medicine, INAIL-Italian Workers' Compensation Authority, Research Area, Monteporzio Catone, 00040 Rome, Italy
| | - Enrico Pira
- Department of Traumatology, Orthopaedics and Occupational Medicine, University of Turin, 10126 Turin, Italy
| | - Canzio Romano
- Department of Traumatology, Orthopaedics and Occupational Medicine, University of Turin, 10126 Turin, Italy
| | - Anna Maria Fresegna
- Department of Occupational Medicine, INAIL-Italian Workers' Compensation Authority, Research Area, Monteporzio Catone, 00040 Rome, Italy
| | - Raffaele Maiello
- Department of Occupational Medicine, INAIL-Italian Workers' Compensation Authority, Research Area, Monteporzio Catone, 00040 Rome, Italy
| | - Aureliano Ciervo
- Department of Occupational Medicine, INAIL-Italian Workers' Compensation Authority, Research Area, Monteporzio Catone, 00040 Rome, Italy
| | - Giuliana Buresti
- Department of Occupational Medicine, INAIL-Italian Workers' Compensation Authority, Research Area, Monteporzio Catone, 00040 Rome, Italy
| | - Wainer Zoli
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, 47014 Forlì-Cesena, Italy
| | - Daniele Calistri
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, 47014 Forlì-Cesena, Italy
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24
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Bladder cancer detection and monitoring: assessment of urine- and blood-based marker tests. Mol Diagn Ther 2013; 17:71-84. [PMID: 23479428 PMCID: PMC3627848 DOI: 10.1007/s40291-013-0023-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Bladder cancer is one of the most prevalent cancers worldwide, but the treatment and management of this disease can be very successful if the disease is detected early. The development of molecular assays that could diagnose bladder cancer accurately, and at an early stage, would be a significant advance. Ideally, such molecular assays would be applicable to non-invasively obtained body fluids, and be designed not only for diagnosis but also for monitoring disease recurrence and response to treatment. In this article, we assess the performance of current diagnostic assays for bladder cancer and discuss some of the emerging biomarkers that could be developed to augment current bladder cancer detection strategies.
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25
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Larkin S, Kyprianou N. Molecular signatures in urologic tumors. Int J Mol Sci 2013; 14:18421-36. [PMID: 24018887 PMCID: PMC3794787 DOI: 10.3390/ijms140918421] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 08/05/2013] [Accepted: 08/15/2013] [Indexed: 12/26/2022] Open
Abstract
Urologic tumors continue to represent a huge fraction of cancer cases in the United States, with over 376,310 estimated new diagnoses in 2013. As with many types of tumors, urologic tumors vary greatly in their phenotype, ranging from minimally invasive to malignancies possessing great metastatic potential. The increasing need for more efficient and less invasive methods of cancer detection, as well as the ability to predict severity of the disease phenotype is readily evident--yet reliable methods remain elusive in a clinical setting today. Comprehensive panels of gene clusters are being developed toward the generation of molecular signatures in order to better diagnose urologic malignancies, and identify effective treatment strategies in the emerging era of personalized medicine. In this review, we discuss the current literature on the credibility and biomarker value of such molecular signatures in the context of clinical significance relating to the pathological aggressiveness of urologic tumors (prostate, bladder and renal cancer)--also exploiting their predictive potential in the response to treatment.
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Affiliation(s)
- Spencer Larkin
- Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA; E-Mail:
| | - Natasha Kyprianou
- Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA; E-Mail:
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA
- Department of Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA
- Department of Pathology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-859-323-9812; Fax: +1-859-323-1944
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26
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Salama RHM, Selem TH, El-Gammal M, Elhagagy AEA, Bakar SM. Urinary tumor markers could predict survival in bladder carcinoma. Indian J Clin Biochem 2012; 28:265-71. [PMID: 24426222 DOI: 10.1007/s12291-012-0266-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 09/24/2012] [Indexed: 11/29/2022]
Abstract
The early diagnosis of bladder cancer is important for effective treatment of the disease. This study aimed to evaluate the nuclear matrix protein 22 (NMP 22), soluble epithelial cadherin (E-cadherin), cathepthin-D and total protein with clinico-pathological features of bladder cancer, and to determine the relation between each marker and tumor progression after treatment. The study includes 65 patients with bladder cancer, 14 benign urinary diseases and 11 healthy volunteers. Patients were categorized according to bilharzial infestation, T stage, tumor grade, size and the presence of lymph node metastasis. Forty patients were followed for disease progression after surgery. There was a significant increase of NMP22, E-cadherin, cathepthin-D and total protein detected in cancer group compared to healthy and benign groups. It was found that NMP 22 and E-cadherin had highest sensitivity (84.4, 76.9 %, respectively) while, total ddedprotein showed highest specificity (77.4 %). Tumor size correlated with urinary NMP22 (r = 0.3, p = 0.02), although, E-cadherin, cathepsin-D and total protein correlated with tumor size (r = 0.3, 0.28, 0.2; p = 0.01, p = 0.01, 0.04, respectively) and lymph node metastasis (r = 0.32, 0.34, 0.2; p = 0.003, 0.005, 0.04, respectively). Elevated pretreatment urinary NMP22, E-cadherin and total protein levels was associated significantly with bladder cancer recurrence (p = 0.02, 0.001, 0.005, respectively). In conclusion, determination of urinary NMP22, E-cadherin and total protein in bladder cancer patients or persons at risk of developing bladder cancer will help in early detection of the disease and prediction of recurrence. The use of a combination of tumor markers is markedly useful than the assessment of single one.
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Affiliation(s)
- Ragaa H M Salama
- Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt ; Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Tahia H Selem
- Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohammed El-Gammal
- Urology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Sally M Bakar
- Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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