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1
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Krishnan S, Kanthaje S, Rekha PD, Mujeeburahiman M, Ratnacaram CK. Expanding frontiers in liquid biopsy-discovery and validation of circulating biomarkers in renal cell carcinoma and bladder cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 391:135-197. [PMID: 39939075 DOI: 10.1016/bs.ircmb.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Renal cell carcinoma (RCC) and Bladder cancer (BC) are two lethal urological cancers that require diagnosis at their earliest stage causing decreasing survival rates in case of aggressive disease. However, there is no reliable circulating marker in blood or urine for their less or non-invasive diagnosis. Our objective was to review the potential circulating biomarkers, namely proteins, micro-RNA (miRNA), long non-coding RNA (lncRNA), and circulating tumour cells (CTCs) for which we performed a PubMed-based literature search of biomolecules (protein, miRNA, lncRNA and CTCs) found as circulating biomarkers in blood and urine for the early detection of RCC and BC. Among the numerous studies, certain biomolecules represent promising early-stage biomarkers such as proteins (NNMT, LCP1, and NM23A; KIM1), mi-RNAs (5-panel: miR-193a-3p, miR-362, miR-572, miR-378, and miR-28-5p; miR-200a) and lncRNAs (5-panel: LET, PVT1, PANDAR, PTENP1 and linc00963; GIHCG) for RCC. Similarly, proteins (APOA1), miRNAs (7-panel: miR-7-5p, miR-22-3p, miR-29a-3p, miR-126-5p, miR- 200a-3p, miR-375, and miR-423-5p; miRNA 181a, miRNA 30c, and miRNA 570) and lncRNAs (3-panel: MALAT1, MEG3, and SNHG16; exosomal derived 3-panel: PCAT-1, UBC1 and SNHG16; H19) were reported in BC subjects. Notably, the majority of the biomarkers presented for early detection in RCC cases were found in blood, while in urine for BC. Our results reveal that though a plethora of circulating biomarkers show early diagnostic ability, all of them are still bench-only biomarkers and require further validation. Adequate clinical trials/studies testing which of these potential markers individually or in combination, will become clinically applicable still remain elusive.
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Affiliation(s)
- Sabareeswaran Krishnan
- Division of Cancer Research and Therapeutics, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangaluru, Karnataka, India; Department of Urology, Yenepoya Medical College Hospital, Deralakatte, Mangaluru, Karnataka, India
| | - Shruthi Kanthaje
- Division of Cancer Research and Therapeutics, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangaluru, Karnataka, India
| | - Punchappady Devasya Rekha
- Division of Microbiology and Biotechnology, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangaluru, Karnataka, India
| | - M Mujeeburahiman
- Department of Urology, Yenepoya Medical College Hospital, Deralakatte, Mangaluru, Karnataka, India.
| | - Chandrahas Koumar Ratnacaram
- Division of Cancer Research and Therapeutics, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangaluru, Karnataka, India.
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Diagnostic performance of urine and blood microRNAs for bladder cancer: a meta-analysis. Expert Rev Anticancer Ther 2022; 22:1357-1369. [PMID: 36374119 DOI: 10.1080/14737140.2022.2147511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To compare and assess the diagnostic value of urine and blood microRNAs(miRNAs) in discriminating bladder cancer (BCa). METHODS A total of 45 articles were selected, which included 4050 BCa cases and 3490 controls. Summary receiver operating characteristic (SROC) curve analyses were performed, an area under curve (AUC) was calculated and pooled accuracy was analyzed using Stata 16.0 software. RESULTS The AUC, sensitivity, and specificity for urinary miRNAs were 0.88, 0.82, and 0.81, respectively, those for blood miRNAs were 0.91, 0.86, and 0.82. For miR-143, the AUC was 0.88, with 0.79 sensitivity and 0.87 specificity. The results of subgroup analyses and meta-regression suggested the publication year, ethnicity, sample size, miRNAs type, and specimen type were possible sources of heterogeneity. The Deeks funnel plot indicated there was no significant publication bias. CONCLUSION Urine and blood-based miRNAs may potentially be promising biomarkers for noninvasive early detection of bladder tumor. The diagnostic accuracy of blood-based miRNAs would be better than those of urine-based ones, and multiple miRNA panels yielded more accurate results than single-miRNA assay. Besides, miR-143 is a promising candidate biomarker for diagnosing BCa. More prospective and standardized studies are required to confirm the future findings.
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Diagnostic Strategies for Urologic Cancer Using Expression Analysis of Various Oncogenic Surveillance Molecules—From Non-Coding Small RNAs to Cancer-Specific Proteins. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12157390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Urinary-tract-related tumors are prone to simultaneous or heterogeneous multiple tumor development within the primary organ. Urologic tumors have a very high risk of recurrence in the long and short term. This may be related to the disruption of homeostasis on the genetic level, such as the induction of genetic mutations due to exposure to various carcinogenic factors and the disruption of cancer suppressor gene functions. It is essential to detect the cancer progression signals caused by genetic abnormalities and find treatment therapies. In this review, we discuss the usefulness of tumor-expressing clinical biomarkers for predicting cancer progression. Furthermore, we discuss various factors associated with disturbed intracellular signals and those targeted by microRNAs, which are representative of non-coding small RNAs.
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4
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Abedi Z, MotieGhader H, Hosseini SS, Sheikh Beig Goharrizi MA, Masoudi-Nejad A. mRNA-miRNA bipartite networks reconstruction in different tissues of bladder cancer based on gene co-expression network analysis. Sci Rep 2022; 12:5885. [PMID: 35393513 PMCID: PMC8991185 DOI: 10.1038/s41598-022-09920-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 03/24/2022] [Indexed: 12/14/2022] Open
Abstract
Bladder cancer (BC) is one of the most important cancers worldwide, and if it is diagnosed early, its progression in humans can be prevented and long-term survival will be achieved accordingly. This study aimed to identify novel micro-RNA (miRNA) and gene-based biomarkers for diagnosing BC. The microarray dataset of BC tissues (GSE13507) listed in the GEO database was analyzed for this purpose. The gene expression data from three BC tissues including 165 primary bladder cancer (PBC), 58 normal looking-bladder mucosae surrounding cancer (NBMSC), and 23 recurrent non-muscle invasive tumor tissues (RNIT) were used to reconstruct gene co-expression networks. After preprocessing and normalization, deferentially expressed genes (DEGs) were obtained and used to construct the weighted gene co-expression network (WGCNA). Gene co-expression modules and low-preserved modules were extracted among BC tissues using network clustering. Next, the experimentally validated mRNA-miRNA interaction information were used to reconstruct three mRNA-miRNA bipartite networks. Reactome pathway database and Gene ontology (GO) was subsequently performed for the extracted genes of three bipartite networks and miRNAs, respectively. To further analyze the data, ten hub miRNAs (miRNAs with the highest degree) were selected in each bipartite network to reconstruct three bipartite subnetworks. Finally, the obtained biomarkers were comprehensively investigated and discussed in authentic studies. The obtained results from our study indicated a group of genes including PPARD, CST4, CSNK1E, PTPN14, ETV6, and ADRM1 as well as novel miRNAs (e.g., miR-16-5p, miR-335-5p, miR-124-3p, and let-7b-5p) which might be potentially associated with BC and could be a potential biomarker. Afterward, three drug-gene interaction networks were reconstructed to explore candidate drugs for the treatment of BC. The hub miRNAs in the mRNA-miRNA bipartite network played a fundamental role in BC progression; however, these findings need further investigation.
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Affiliation(s)
- Zahra Abedi
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Habib MotieGhader
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
| | - Sahar Sadat Hosseini
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | | | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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5
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Humayun-Zakaria N, Ward DG, Arnold R, Bryan RT. Trends in urine biomarker discovery for urothelial bladder cancer: DNA, RNA, or protein? Transl Androl Urol 2021; 10:2787-2808. [PMID: 34295762 PMCID: PMC8261432 DOI: 10.21037/tau-20-1327] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 04/23/2021] [Indexed: 02/01/2023] Open
Abstract
Urothelial bladder cancer is a complex disease displaying a landscape of heterogenous molecular subtypes, mutation profiles and clinical presentations. Diagnosis and surveillance rely on flexible cystoscopy which has high accuracy, albeit accompanied by a high-cost burden for healthcare providers and discomfort for patients. Advances in "omic" technologies and computational biology have provided insights into the molecular pathogenesis of bladder cancer and provided powerful tools to identify markers for disease detection, risk stratification, and predicting responses to therapy. To date, numerous attempts have been made to discover and validate diagnostic biomarkers that could be deployed as an adjunct to the cystoscopic diagnosis and long-term surveillance of bladder cancer. We report a comprehensive literature analysis using PubMed to assess the changing trends in investigating DNA, RNA, or proteins as diagnostic urinary biomarkers over a period of 5 decades: 1970-2020. A gradual shift has been observed in research away from protein biomarkers to nucleic acids including different classes of RNA, and DNA methylation and mutation markers. Until 2000, publications involving protein biomarker discovery constituted 87% of the total number of research articles with DNA comprising 6% and RNA 7%. Since 2000 the proportion of protein biomarker articles has fallen to 40%, and DNA and RNA studies increased to 32% and 28%, respectively. Clearly research focus, perhaps driven by technological innovation, has shifted from proteins to nucleic acids. We optimistically hypothesise that, following thorough validation, a clinically useful detection test for bladder cancer based on a panel of DNA or RNA markers could become reality within 5-10 years.
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Affiliation(s)
- Nada Humayun-Zakaria
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Douglas G Ward
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Roland Arnold
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Richard T Bryan
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
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6
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Kabekkodu SP, Shukla V, Varghese VK, Adiga D, Vethil Jishnu P, Chakrabarty S, Satyamoorthy K. Cluster miRNAs and cancer: Diagnostic, prognostic and therapeutic opportunities. WILEY INTERDISCIPLINARY REVIEWS. RNA 2020; 11:e1563. [PMID: 31436881 DOI: 10.1002/wrna.1563] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 07/05/2019] [Accepted: 07/25/2019] [Indexed: 02/06/2023]
Abstract
MiRNAs are class of noncoding RNA important for gene expression regulation in many plants, animals and viruses. MiRNA clusters contain a set of two or more miRNA encoding genes, transcribed together as polycistronic miRNAs. Currently, there are approximately 159 miRNA clusters reported in the human genome consisting of miRNAs ranging from two or more miRNA genes. A large proportion of clustered miRNAs resides in and around the fragile sites or cancer associated genomic hotspots and plays an important role in carcinogenesis. Altered expression of miRNA cluster can be pro-tumorigenic or anti-tumorigenic and can be targeted for clinical management of cancer. Over the past few years, manipulation of miRNA clusters expression is attempted for experimental purpose as well as for diagnostic, prognostic and therapeutic applications in cancer. Re-expression of miRNAs by epigenetic therapy, genome editing such as clustered regulatory interspaced short palindromic repeats (CRISPR) and miRNA mowers showed promising results in cancer therapy. In this review, we focused on the potential of miRNA clusters as a biomarker for diagnosis, prognosis, targeted therapy as well as strategies for modulating their expression in a therapeutic context. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Processing > Processing of Small RNAs RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.
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Affiliation(s)
- Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vaibhav Shukla
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vinay Koshy Varghese
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Padacherri Vethil Jishnu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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7
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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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8
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Abstract
Bladder cancer (BC) is the second highest morbid malignancy of the urinary tract and the fifth most common cancer worldwide. BC is highly malignant with significant morbidity and mortality, especially muscle-invasive BC (MIBC), which has a poor prognosis and frequently recurs after the first resection. Therefore, more sensitive diagnostic tools and effective therapeutic methods are urgently needed. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of protein-coding genes by repressing their translation or cleaving RNA transcripts in a sequence-specific manner. miRNAs play very important roles in regulating genes related to tumorigenesis, tumor development, progression, metastasis and angiogenesis. With the rapid development of high-throughput sequencing technology, an increasing number of miRNAs with aberrant expression between either BC patients and healthy volunteers or between BC tumor tissues and matched peripheral control tissues have been recently examined. The tumor etiopathogenesis must be determined to promote the development of new markers as diagnostic and prognostic tools and targets for bladder tumor therapy, it is therefore vital to elucidate the function of miRNAs with aberrant expression in BC. In the present study, we examined the published data of BC-related miRNAs by reviewing their expression levels, possible functions, potential target genes, related molecular regulatory networks, candidate markers for prognosis and diagnosis, and prospective therapeutic cases, and we summarized the status of research on BC-related miRNAs in recent years.
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9
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Allione A, Pardini B, Viberti C, Giribaldi G, Turini S, Di Gaetano C, Guarrera S, Cordero F, Oderda M, Allasia M, Gontero P, Sacerdote C, Vineis P, Matullo G. MMP23B expression and protein levels in blood and urine are associated with bladder cancer. Carcinogenesis 2019; 39:1254-1263. [PMID: 30052775 DOI: 10.1093/carcin/bgy098] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/19/2018] [Indexed: 02/07/2023] Open
Abstract
Urothelial bladder cancer (UBC) represents a public health problem because of its high incidence/relapse rates. At present, there are no suitable biomarkers for early diagnosis or relapse/progression prognosis. To improve diagnostic accuracy and overcome the disadvantages of current diagnostic strategies, the detection of UBC biomarkers in easily accessible biofluids, such as urine, represents a promising approach compared with painful biopsies. We investigated the levels of MMP23 genes (microarray and qPCR) and protein (western blot and enzyme-linked immunosorbent assay) in a set of samples (blood, plasma and urine) from patients with UBC and controls as biomarkers for this cancer. MMP23B and its pseudogene MMP23A resulted downregulated in blood cells from UBC compared with controls (66 cases, 70 controls; adjusted P-value = 0.02 and 0.03, respectively). In contrast, MMP23B protein levels in plasma (53 UBC, 49 controls) and urine (59 UBC, 57 controls) increased in cases, being statistically significant in urine. MMP23B dosage observed in urine samples was related to both tumor risk classification and grading. As the lack of correlation between mRNA and protein levels could be due to a posttranscriptional regulation mediated by microRNAs (miRNAs), we investigated the expression of urinary miRNAs targeting MMP23B. Five miRNAs resulted differentially expressed between cases and controls. We reported the first evidence of MMP23B secretion in plasma and urine, suggesting a role of this poorly characterized metalloproteinase in UBC as a potential non-invasive biomarker for this cancer. Further analyses are needed to elucidate the mechanism of regulation of MMP23B expression by miRNAs.
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Affiliation(s)
- Alessandra Allione
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | - Barbara Pardini
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | - Clara Viberti
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Stefano Turini
- Department of Oncology, University of Turin, Turin, Italy
| | - Cornelia Di Gaetano
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | - Simonetta Guarrera
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Marco Oderda
- Department of Urology, Città della Salute e della Scienza, Turin, Italy
| | - Marco Allasia
- Department of Urology, Città della Salute e della Scienza, Turin, Italy
| | - Paolo Gontero
- Department of Urology, Città della Salute e della Scienza, Turin, Italy
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy
| | - Paolo Vineis
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
| | - Giuseppe Matullo
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
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10
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Piao XM, Jeong P, Kim YH, Byun YJ, Xu Y, Kang HW, Ha YS, Kim WT, Lee JY, Woo SH, Kwon TG, Kim IY, Moon SK, Choi YH, Cha EJ, Yun SJ, Kim WJ. Urinary cell-free microRNA biomarker could discriminate bladder cancer from benign hematuria. Int J Cancer 2018; 144:380-388. [PMID: 30183088 DOI: 10.1002/ijc.31849] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/06/2018] [Accepted: 08/27/2018] [Indexed: 12/24/2022]
Abstract
The most common symptom of bladder cancer (BC) is hematuria. However, not all patients with hematuria are diagnosed with BC. Here, we explored a novel method to discriminate BC from hematuria under nonmalignant conditions by measuring differences in urinary cell-free microRNA (miRNA) expression between patients with BC and those with hematuria. A multicenter study was performed using 543 urine samples obtained from the National Biobank of Korea, including 326 BC, 174 hematuria and 43 pyuria without cancer. The urinary miR-6124 to miR-4511 ratio was considerably higher in BC than in hematuria or pyuria, and enabled the discrimination of BC from patients with hematuria at a sensitivity of >90% (p < 0.001). Conclusively, the proposed noninvasive diagnostic tool based on the expression ratio of urinary cell-free miR-6124 to miR-4511 can reduce unnecessary cystoscopies in patients with hematuria undergoing evaluation for BC, with a minimal loss in sensitivity for detecting cancer.
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Affiliation(s)
- Xuan-Mei Piao
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Pildu Jeong
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Ye-Hwan Kim
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Young Joon Byun
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Yanjie Xu
- Department of Surgery, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Ho Won Kang
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Yun-Sok Ha
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, South Korea.,Department of Urology, Kyungpook National University Hospital, Daegu, South Korea
| | - Won Tae Kim
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Jong-Young Lee
- Department of Business Data Convergence, Chungbuk National University, Cheongju, South Korea.,Theragen Etex Bio Institute, Suwon, 443-270, South Korea
| | - Seung Hwo Woo
- Department of Urology, Eulji University Hospital, Daejeon, South Korea
| | - Tae Gyun Kwon
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, South Korea.,Department of Urology, Kyungpook National University Hospital, Daegu, South Korea
| | - Isaac Y Kim
- Section of Urologic Oncology and Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
| | - Sung-Kwon Moon
- Department of Food Science and Technology, Chung-Ang University, Ansung, 456-756, South Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, South Korea
| | - Eun-Jong Cha
- Department of Biomedical Engineering, Chungbuk National University College of Medicine, Cheongju, South Korea
| | - Seok Joong Yun
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
| | - Wun-Jae Kim
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, South Korea
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11
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Lodewijk I, Dueñas M, Rubio C, Munera-Maravilla E, Segovia C, Bernardini A, Teijeira A, Paramio JM, Suárez-Cabrera C. Liquid Biopsy Biomarkers in Bladder Cancer: A Current Need for Patient Diagnosis and Monitoring. Int J Mol Sci 2018; 19:E2514. [PMID: 30149597 PMCID: PMC6163729 DOI: 10.3390/ijms19092514] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 08/16/2018] [Accepted: 08/21/2018] [Indexed: 02/08/2023] Open
Abstract
Bladder Cancer (BC) represents a clinical and social challenge due to its high incidence and recurrence rates, as well as the limited advances in effective disease management. Currently, a combination of cytology and cystoscopy is the routinely used methodology for diagnosis, prognosis and disease surveillance. However, both the poor sensitivity of cytology tests as well as the high invasiveness and big variation in tumour stage and grade interpretation using cystoscopy, emphasizes the urgent need for improvements in BC clinical guidance. Liquid biopsy represents a new non-invasive approach that has been extensively studied over the last decade and holds great promise. Even though its clinical use is still compromised, multiple studies have recently focused on the potential application of biomarkers in liquid biopsies for BC, including circulating tumour cells and DNA, RNAs, proteins and peptides, metabolites and extracellular vesicles. In this review, we summarize the present knowledge on the different types of biomarkers, their potential use in liquid biopsy and clinical applications in BC.
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Affiliation(s)
- Iris Lodewijk
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
| | - Marta Dueñas
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Carolina Rubio
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Ester Munera-Maravilla
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
| | - Cristina Segovia
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Alejandra Bernardini
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Alicia Teijeira
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
| | - Jesús M Paramio
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
| | - Cristian Suárez-Cabrera
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº 40, 28040 Madrid, Spain.
- Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n, 28041 Madrid, Spain.
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12
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Tölle A, Blobel CC, Jung K. Circulating miRNAs in blood and urine as diagnostic and prognostic biomarkers for bladder cancer: an update in 2017. Biomark Med 2018; 12:667-676. [PMID: 29896971 DOI: 10.2217/bmm-2017-0392] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This study presents a critical appraisal of previously published study data of miRNAs in blood, urine and exosomes as biomarkers of bladder cancer (BC). The evaluation included 39 articles published from the beginning of 2010 until September 2017 and searched in PubMed. The heterogeneity of studies, due to their clinicopathological variability, including insufficient consideration of diagnostic and prognostic biomarker guidelines and missing internal and external validation of data, do not currently allow the recommending of a useful miRNA marker as diagnostic or prognostic tool in BC. Future multi-institutional studies are necessary to overcome the deficiencies in these studies in order to prove the usefulness of circulating miRNAs as robust biomarkers for BC.
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Affiliation(s)
- Angelika Tölle
- Department of Urology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.,CONGEN Biotechnology GmbH, 13125 Berlin, Germany
| | - Conrad C Blobel
- Department of Urology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Klaus Jung
- Berlin Institute for Urologic Research, 10117 Berlin, Germany
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13
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Cell-free microRNA expression signatures in urine serve as novel noninvasive biomarkers for diagnosis and recurrence prediction of bladder cancer. Oncotarget 2018; 8:40832-40842. [PMID: 28388561 PMCID: PMC5522322 DOI: 10.18632/oncotarget.16586] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Accepted: 03/14/2017] [Indexed: 12/11/2022] Open
Abstract
Urinary microRNAs (miRNAs) are potential biomarkers for the noninvasive diagnosis of bladder cancer (BC). In this study, we aimed to develop a urinary miRNAs panel for diagnosing and predicting recurrence of BC. Genome-wide miRNAs analysis by deep sequencing followed by two phases of quantitative real-time PCR assays were performed on urine supernatant of 276 BC patients and 276 controls. We identified a seven-miRNA panel (miR-7-5p, miR-22-3p, miR-29a-3p, miR-126-5p, miR-200a-3p, miR-375, and miR-423-5p) that provided high diagnostic accuracy of BC with an AUC of 0.923 and 0.916 in training and validation set, respectively. The corresponding AUCs of this panel for Ta, T1 and T2-T4 were 0.864, 0.930 and 0.978, significantly higher than those of urine cytology, which were 0.531, 0.628 and 0.724, respectively (all p < 0.05). Moreover, Kaplan–Meier analysis showed that nonmuscle-invasive BC (NMIBC) patients with high miR-22-3p and low miR-200a-3p level had worse recurrence-free survival (RFS) (p = 0.002 and 0.040, respectively). Multivariate Cox regression analysis revealed that miR-22-3p and miR-200a-3p were independently associated with RFS of NMIBC (p = 0.024 and 0.008, respectively). In conclusion, our results suggested that urinary miRNAs may have considerable clinical value in diagnosis and recurrence prediction of BC.
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14
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Kutwin P, Konecki T, Borkowska EM, Traczyk-Borszyńska M, Jabłonowski Z. Urine miRNA as a potential biomarker for bladder cancer detection - a meta-analysis. Cent European J Urol 2018; 71:177-185. [PMID: 30038807 PMCID: PMC6051360 DOI: 10.5173/ceju.2018.1605] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 01/02/2018] [Accepted: 03/23/2018] [Indexed: 12/14/2022] Open
Abstract
Introduction White light cystoscopy (WLC), often supported by urine cytology, is considered the ‘goldstandard’ in the diagnosis and follow-up of bladder cancer (BCa). In recent years, urine microRNA (miRNA) tests have been performed for the detection of bladder cancer. Material and methods A systematic review of the PubMed platform was performed by searching for articles in which miRNA in the urine was used for the detection of BCa. Results The greatest sensitivity (86.6%) in BCa detection was achieved for multi-miRNA in urine sediment. The greatest specificity (85.3%) was achieved for multi-miRNA from voided urine. There were significant differences (p <0.01) between single-miRNA (OR 8.96; CI 6.37–12.59) and the multi-miRNA group (OR 19.95; CI 13.35–29.81). There were no differences among the specimens (voided urine, supernatant, sediment) used for the test. Conclusions Urine miRNAs have the potential to be a valid marker for bladder cancer detection. They can successfully compete with other non-invasive diagnostic tests.
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Affiliation(s)
- Piotr Kutwin
- Medical University of Łódź, 1 Department of Urology, Łódź, Poland
| | - Tomasz Konecki
- Medical University of Łódź, 1 Department of Urology, Łódź, Poland
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15
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Dysregulation of miRNAs in bladder cancer: altered expression with aberrant biogenesis procedure. Oncotarget 2018; 8:27547-27568. [PMID: 28187437 PMCID: PMC5432357 DOI: 10.18632/oncotarget.15173] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 01/24/2017] [Indexed: 12/31/2022] Open
Abstract
Aberrant expression profiles of miRNAs are widely observed in the clinical tissue specimens and urine samples as well as the blood samples of bladder cancer patients. These profiles are closely related to the pathological features of bladder cancer, such as the tumour stage/grade, metastasis, recurrence and chemo-sensitivity. MiRNA biogenesis forms the basis of miRNA expression and function, and its dysregulation has been shown to be essential for variations in miRNA expression profiles as well as tumourigenesis and cancer progression. In this review, we summarize the up-to-date and widely reported miRNAs in bladder cancer that display significantly altered expression. We then compare the miRNA expression profiles among three different sample types (tissue, urine and blood) from patients with bladder cancer. Moreover, for the first time, we outline the dysregulated miRNA biogenesis network in bladder cancer from different levels and analyse its possible relationship with aberrant miRNA expression and the pathological characteristics of the disease.
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16
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Shi HB, Yu JX, Yu JX, Feng Z, Zhang C, Li GY, Zhao RN, Yang XB. Diagnostic significance of microRNAs as novel biomarkers for bladder cancer: a meta-analysis of ten articles. World J Surg Oncol 2017; 15:147. [PMID: 28774300 PMCID: PMC5543742 DOI: 10.1186/s12957-017-1201-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 07/08/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Previous studies have revealed the importance of microRNAs' (miRNAs) function as biomarkers in diagnosing human bladder cancer (BC). However, the results are discordant. Consequently, the possibility of miRNAs to be BC biomarkers was summarized in this meta-analysis. METHODS In this study, the relevant articles were systematically searched from CBM, PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI). The bivariate model was used to calculate the pooled diagnostic parameters and summary receiver operator characteristic (SROC) curve in this meta-analysis, thereby estimating the whole predictive performance. STATA software was used during the whole analysis. RESULTS Thirty-one studies from 10 articles, including 1556 cases and 1347 controls, were explored in this meta-analysis. In short, the pooled sensitivity, area under the SROC curve, specificity, positive likelihood ratio, diagnostic odds ratio, and negative likelihood ratio were 0.72 (95%CI 0.66-0.76), 0.80 (0.77-0.84), 0.76 (0.71-0.81), 3.0 (2.4-3.8), 8 (5.0-12.0), and 0.37 (0.30-0.46) respectively. Additionally, sub-group and meta-regression analyses revealed that there were significant differences between ethnicity, miRNA profiling, and specimen sub-groups. These results suggested that Asian population-based studies, multiple-miRNA profiling, and blood-based assays might yield a higher diagnostic accuracy than their counterparts. CONCLUSIONS This meta-analysis demonstrated that miRNAs, particularly multiple miRNAs in the blood, might be novel, useful biomarkers with relatively high sensitivity and specificity and can be used for the diagnosis of BC. However, further prospective studies with more samples should be performed for further validation.
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Affiliation(s)
- Hong-Bin Shi
- Department of Urology, Ningxia People's Hospital, No. 301 North Zhengyuan Street, Jinfeng District, Yinchuan, 750021, Ningxia, China
| | - Jia-Xing Yu
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jian-Xiu Yu
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Zheng Feng
- Department of Urology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Chao Zhang
- Department of Urology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Guang-Yong Li
- Department of Urology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Rui-Ning Zhao
- Department of Urology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Xiao-Bo Yang
- Department of Urology, Ningxia People's Hospital, No. 301 North Zhengyuan Street, Jinfeng District, Yinchuan, 750021, Ningxia, China.
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17
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Gasparri ML, Casorelli A, Bardhi E, Besharat AR, Savone D, Ruscito I, Farooqi AA, Papadia A, Mueller MD, Ferretti E, Benedetti Panici P. Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer. Tumour Biol 2017; 39:1010428317695525. [PMID: 28459207 DOI: 10.1177/1010428317695525] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common malignancy in women worldwide, and ovarian cancer is the most lethal gynecological malignancy. Women carrying a BRCA1/2 mutation have a very high lifetime risk of developing breast and ovarian cancer. The only effective risk-reducing strategy in BRCA-mutated women is a prophylactic surgery with bilateral mastectomy and bilateral salpingo-oophorectomy. However, many women are reluctant to undergo these prophylactic surgeries due to a consequent mutilated body perception, unfulfilled family planning, and precocious menopause. In these patients, an effective screening strategy is available only for breast cancer, but it only consists in close radiological exams with a significant burden for the health system and a significant distress to the patients. No biomarkers have been shown to effectively detect breast and ovarian cancer at an early stage. MicroRNAs (miRNAs) are key regulatory molecules operating in a post-transcriptional regulation of gene expression. Aberrant expression of miRNAs has been documented in several pathological conditions, including solid tumors, suggesting their involvement in tumorigenesis. miRNAs can be detected in blood and urine and could be used as biomarkers in solid tumors. Encouraging results are emerging in gynecological malignancy as well, and suggest a different pattern of expression of miRNAs in biological fluids of breast and ovarian cancer patients as compared to healthy control. Aim of this study is to highlight the role of the urinary miRNAs which are specifically associated with cancer and to investigate their role in early diagnosis and in determining the prognosis in breast and ovarian cancer.
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Affiliation(s)
- Maria Luisa Gasparri
- 1 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy.,2 Department of Obstetrics and Gynecology, University Hospital of Berne, University of Berne, Berne, Switzerland
| | - Assunta Casorelli
- 1 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
| | - Erlisa Bardhi
- 1 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
| | - Aris Raad Besharat
- 1 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
| | - Delia Savone
- 1 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
| | - Ilary Ruscito
- 1 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
| | - Ammad Ahmad Farooqi
- 3 Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan
| | - Andrea Papadia
- 2 Department of Obstetrics and Gynecology, University Hospital of Berne, University of Berne, Berne, Switzerland
| | - Michael David Mueller
- 2 Department of Obstetrics and Gynecology, University Hospital of Berne, University of Berne, Berne, Switzerland
| | - Elisabetta Ferretti
- 4 Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.,5 Neuromed Institute, Pozzilli, Italy
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18
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Liu X, Liu X, Wu Y, Wu Q, Wang Q, Yang Z, Li L. MicroRNAs in biofluids are novel tools for bladder cancer screening. Oncotarget 2017; 8:32370-32379. [PMID: 28423688 PMCID: PMC5458291 DOI: 10.18632/oncotarget.16026] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in basic cellular processes, including differentiation, proliferation, apoptosis and autophagy. They are also involved in various stages of tumorigenesis and play key roles in bladder cancer initiation and progression. Notably, the altered expression of miRNAs in the tumors is reflected in body fluids, including blood and urine, which opens avenues for non-invasive diagnosis and prognosis. Many studies have demonstrated that epigenetic changes extensively alter tumoral microRNA expression. The high reproducibility, specificity and sensitivity of miRNA levels in body fluids suggest their potential use as biomarkers for cancer screening and diagnosis. For example, recent technological advances have made it possible to detect miRNAs in urine for bladder cancer screening. In this review, we focus mainly on the current knowledge and future challenges for incorporating miRNAs in body fluids, like urine and blood, for making clinical diagnoses and assessing prognoses in bladder cancer.
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Affiliation(s)
- Xiaobing Liu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Xin Liu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Yuqi Wu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Qingjian Wu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Qingqing Wang
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Zhenxing Yang
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Longkun Li
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
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19
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Fendler A, Stephan C, Yousef GM, Kristiansen G, Jung K. The translational potential of microRNAs as biofluid markers of urological tumours. Nat Rev Urol 2016; 13:734-752. [DOI: 10.1038/nrurol.2016.193] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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20
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MicroRNAs as noninvasive biomarkers in bladder cancer detection: a diagnostic meta-analysis based on qRT-PCR data. Int J Biol Markers 2016; 31:e276-85. [PMID: 26954073 DOI: 10.5301/jbm.5000199] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2016] [Indexed: 02/08/2023]
Abstract
OBJECTIVE As the diagnostic significance of microRNAs (miRNAs) in the detection of bladder cancer is controversial, we aimed to perform a meta-analysis to comprehensively assess the diagnostic value of miRNAs in blood and urine for detecting bladder cancer. METHODS A systematic literature search of public databases was conducted to obtain qualified studies. Sensitivity was utilized to plot the summary receiver operator characteristic (SROC) curve against specificity and the area under the SROC curve (AUC) was generated to evaluate the pooled diagnostic efficiency. Subgroup analyses and meta-regression were applied to investigate the underlying sources of heterogeneity. The STATA 12.0 software was used to perform all statistic analyses. RESULTS A total of 58 studies from 22 articles comprising 4,558 bladder cancer patients and 4,456 controls were included in our meta-analysis. MiRNAs in blood and urine manifested relatively good diagnostic efficiency in detecting bladder cancer, with a sensitivity of 0.74, a specificity of 0.78, and an AUC of 0.83. Multiple-miRNA assays were more accurate than single-miRNA ones in bladder cancer diagnosis. Blood-based miRNA assays displayed better diagnostic performance than urine-based ones. In addition, miRNAs showed reduced diagnostic value in bladder cancer among Caucasians compared with Asians. CONCLUSIONS MiRNAs in blood and urine, especially the combination of multiple miRNAs, may serve as hopeful noninvasive biomarkers for early diagnosis of bladder cancer. Further extensive prospective research is needed to verify their clinical significance in bladder cancer diagnosis.
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21
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Nakamura K, Sawada K, Yoshimura A, Kinose Y, Nakatsuka E, Kimura T. Clinical relevance of circulating cell-free microRNAs in ovarian cancer. Mol Cancer 2016; 15:48. [PMID: 27343009 PMCID: PMC4921011 DOI: 10.1186/s12943-016-0536-0] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 06/16/2016] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to normalize for circulating miRNA levels, as well as differing extraction and quantification methods, are the pitfalls to be resolved before clinical application. There is still a long way, however, before this can be achieved, and further evidence would make it possible to apply circulating cell-free miRNAs not only as biomarkers but also as potential therapeutic targets for ovarian cancer in the future.
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Affiliation(s)
- Koji Nakamura
- Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kenjiro Sawada
- Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Akihiko Yoshimura
- Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yasuto Kinose
- Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Erika Nakatsuka
- Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tadashi Kimura
- Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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22
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Enokida H, Yoshino H, Matsushita R, Nakagawa M. The role of microRNAs in bladder cancer. Investig Clin Urol 2016; 57 Suppl 1:S60-76. [PMID: 27326409 PMCID: PMC4910767 DOI: 10.4111/icu.2016.57.s1.s60] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 04/17/2016] [Indexed: 12/20/2022] Open
Abstract
Bladder cancer (BC) is the fifth most common cancer worldwide and is associated with significant morbidity and mortality. The prognosis of muscle invasive BC is poor, and recurrence is common after radical surgery or chemotherapy. Therefore, new diagnostic methods and treatment modalities are critical. MicroRNAs (miRNAs), a class of small noncoding RNAs, regulate the expression of protein-coding genes by repressing translation or cleaving RNA transcripts in a sequence-specific manner. miRNAs have important roles in the regulation of genes involved in cancer development, progression, and metastasis. The availability of genomewide miRNA expression profiles by deep sequencing technology has facilitated rapid and precise identification of aberrant miRNA expression in BC. Indeed, several miRNAs that are either upregulated or downregulated have been shown to have associations with significant cancer pathways. Furthermore, many miRNAs, including those that can be detected in urine and blood, have been studied as potential noninvasive tumor markers for diagnostic and prognostic purposes. Here, we searched PubMed for publications describing the role of miRNAs in BC by using the keywords "bladder cancer" and "microRNA" on March 1, 2016. We found 374 papers and selected articles written in English in which the level of scientific detail and reporting were sufficient and in which novel findings were demonstrated. In this review, we summarize these studies from the point of view of miRNA-related molecular networks (specific miRNAs and their targets) and miRNAs as tumor markers in BC. We also discuss future directions of miRNA studies in the context of therapeutic modalities.
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Affiliation(s)
- Hideki Enokida
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hirofumi Yoshino
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Ryosuke Matsushita
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masayuki Nakagawa
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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23
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Wang H. Predicting MicroRNA Biomarkers for Cancer Using Phylogenetic Tree and Microarray Analysis. Int J Mol Sci 2016; 17:E773. [PMID: 27213352 PMCID: PMC4881592 DOI: 10.3390/ijms17050773] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/13/2016] [Accepted: 05/16/2016] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are shown to be involved in the initiation and progression of cancers in the literature, and the expression of miRNAs is used as an important cancer prognostic tool. The aim of this study is to predict high-confidence miRNA biomarkers for cancer. We adopt a method that combines miRNA phylogenetic structure and miRNA microarray data analysis to discover high-confidence miRNA biomarkers for colon, prostate, pancreatic, lung, breast, bladder and kidney cancers. There are 53 miRNAs selected through this method that either have potential to involve a single cancer's development or to involve several cancers' development. These miRNAs can be used as high-confidence miRNA biomarkers of these seven investigated cancers for further experiment validation. miR-17, miR-20, miR-106a, miR-106b, miR-92, miR-25, miR-16, miR-195 and miR-143 are selected to involve a single cancer's development in these seven cancers. They have the potential to be useful miRNA biomarkers when the result can be confirmed by experiments.
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Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Chiao Tung University, Hsinchu 30010, Taiwan.
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24
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Larrea E, Sole C, Manterola L, Goicoechea I, Armesto M, Arestin M, Caffarel MM, Araujo AM, Araiz M, Fernandez-Mercado M, Lawrie CH. New Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies. Int J Mol Sci 2016; 17:ijms17050627. [PMID: 27128908 PMCID: PMC4881453 DOI: 10.3390/ijms17050627] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Revised: 04/18/2016] [Accepted: 04/18/2016] [Indexed: 12/19/2022] Open
Abstract
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these “liquid biopsies” ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice.
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Affiliation(s)
- Erika Larrea
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - Carla Sole
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - Lorea Manterola
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - Ibai Goicoechea
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María Armesto
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María Arestin
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María M Caffarel
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
| | - Angela M Araujo
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
| | - María Araiz
- Hematology Department, Donostia Hospital, 20014 San Sebastián, Spain.
| | | | - Charles H Lawrie
- Molecular Oncology, Biodonostia Research Institute, 20014 San Sebastián, Spain.
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, UK.
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Sasaki H, Yoshiike M, Nozawa S, Usuba W, Katsuoka Y, Aida K, Kitajima K, Kudo H, Hoshikawa M, Yoshioka Y, Kosaka N, Ochiya T, Chikaraishi T. Expression Level of Urinary MicroRNA-146a-5p Is Increased in Patients With Bladder Cancer and Decreased in Those After Transurethral Resection. Clin Genitourin Cancer 2016; 14:e493-e499. [PMID: 27157639 DOI: 10.1016/j.clgc.2016.04.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Revised: 03/18/2016] [Accepted: 04/03/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Bladder cancer is the most prevalent malignancy involving the urinary system and exhibits a markedly high recurrence rate. Therefore, reliable and noninvasive diagnostic and surveillance methods are desperately needed. PATIENTS AND METHODS Candidate microRNAs (miRNAs) were selected from the miRNAs that were differentially expressed in bladder cancer cell lines (T24 and RT4) compared to normal ureteral epithelial tissue using miRNA-microarray analysis. The candidate miRNAs were validated by quantitative reverse transcription polymerase chain reaction assay using voided urine samples. RESULTS We identified 3 miRNAs (miR-301b, -563, and -146a-5p) that demonstrated > 2-fold higher expression levels in cancer cell lines than in the normal ureteral epithelial tissue. Of these, only miR-146a-5p was consistently and significantly higher in urine samples from the patients with bladder cancer than in those from the normal individuals (P = .0014). The patients with high-grade tumors exhibited significantly higher urinary miR-146a-5p levels than those with low-grade tumors, and the patients with invasive tumors tended to show higher urinary miR-146a-5p levels than those with noninvasive tumors. Elevated urinary miR-146a-5p levels in patients with bladder cancer were decreased to the normal level after transurethral resection of the tumors (P = .0214). CONCLUSION Our study suggested that urinary miR-146a-5p might be useful as a new noninvasive diagnostic marker, therapeutic target, or anticancer agent for bladder cancer, as well as for increasing our understanding of cancer biology.
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Affiliation(s)
- Hideo Sasaki
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
| | - Miki Yoshiike
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Shiari Nozawa
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Wataru Usuba
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Yuichi Katsuoka
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Kouichirou Aida
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Kazuki Kitajima
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Hiroya Kudo
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Masahiro Hoshikawa
- Department of Pathology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Nobuyoshi Kosaka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Tatsuya Chikaraishi
- Department of Urology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
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LI YIFAN, CHEN DUQUN, SU ZHENGMING, LI YUCHI, LIU JIAJU, JIN LU, SHI MIN, JIANG ZHIMAO, QI ZHENGYU, GUI YAOTING, YANG SHANGQI, MAO XIANGMING, WU XIONGHUI, LAI YONGQING. MicroRNA-106b functions as an oncogene in renal cell carcinoma by affecting cell proliferation, migration and apoptosis. Mol Med Rep 2016; 13:1420-6. [DOI: 10.3892/mmr.2015.4656] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 11/05/2015] [Indexed: 12/21/2022] Open
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27
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Current Status of Urinary Biomarkers for Detection and Surveillance of Bladder Cancer. Urol Clin North Am 2016; 43:47-62. [DOI: 10.1016/j.ucl.2015.08.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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28
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Huang YK, Yu JC. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: An update and review. World J Gastroenterol 2015; 21:9863-9886. [PMID: 26379393 PMCID: PMC4566381 DOI: 10.3748/wjg.v21.i34.9863] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 05/15/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common cancer and the third leading cause of cancer mortality worldwide. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most popular non-coding RNAs in cancer research. To date, the roles of miRNAs and lncRNAs have been extensively studied in GC, suggesting that miRNAs and lncRNAs represent a vital component of tumor biology. Furthermore, circulating miRNAs and lncRNAs are found to be dysregulated in patients with GC compared with healthy individuals. Circulating miRNAs and lncRNAs may function as promising biomarkers to improve the early detection of GC. Multiple possibilities for miRNA secretion have been elucidated, including active secretion by microvesicles, exosomes, apoptotic bodies, high-density lipoproteins and protein complexes as well as passive leakage from cells. However, the mechanism underlying lncRNA secretion and the functions of circulating miRNAs and lncRNAs have not been fully illuminated. Concurrently, to standardize results of global investigations of circulating miRNAs and lncRNAs biomarker studies, several recommendations for pre-analytic considerations are put forward. In this review, we summarize the known circulating miRNAs and lncRNAs for GC diagnosis. The possible mechanism of miRNA and lncRNA secretion as well as methodologies for identification of circulating miRNAs and lncRNAs are also discussed. The topics covered here highlight new insights into GC diagnosis and screening.
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Jiang L, Li X, Cheng Q, Zhang BH. Plasma microRNA might as a potential biomarker for hepatocellular carcinoma and chronic liver disease screening. Tumour Biol 2015; 36:7167-74. [DOI: 10.1007/s13277-015-3446-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 04/08/2015] [Indexed: 12/22/2022] Open
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Regulation of growth of human bladder cancer by miR-192. Tumour Biol 2015; 36:3791-7. [PMID: 25566965 DOI: 10.1007/s13277-014-3020-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 12/23/2014] [Indexed: 01/30/2023] Open
Abstract
The regulation of microRNA-192 (miR-192) is impaired in many cancers. Here, we investigated the role of miR-192 in the proliferation, cell cycle progression, and apoptosis of bladder cancer cells. Human bladder cancer cells were transfected with human miR-192 precursor or non-specific control miRNA. The effect of miR-192 on cell proliferation was assessed by a MTT assay. The effects of miR-192 on cell cycle regulation and apoptosis were evaluated by flow cytometry. Western blot was used to analyze the protein levels of cyclin D1, p21, p27, Bcl-2, Bax, and Mcl-1. We found that overexpression of miR-192 significantly decreased the proliferation of bladder cancer cells by 22 and 54 % at 48 and 72 h, respectively. MiR-192-overexpressing cells exhibited a significant increase in G0/G1 phase and a significant decrease in S phase compared to the control miRNA-transfected cells. Moreover, overexpression of miR-192 significantly induced apoptotic death in bladder cancer cells, increased the levels of p21, p27, and Bax, and decreased the levels of cyclin D1, Bcl-2, and Mcl-1. Taken together, these data suggest that miR-192 may be a suppressor for bladder cancer cells by cell cycle regulation.
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Igaz I, Igaz P. Diagnostic Relevance of microRNAs in Other Body Fluids Including Urine, Feces, and Saliva. EXPERIENTIA SUPPLEMENTUM (2012) 2015; 106:245-252. [PMID: 26608207 DOI: 10.1007/978-3-0348-0955-9_11] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Beside blood-borne circulating miRNAs, miRNAs have been identified in other body fluid and excrements including stool, bile, saliva, and urine. Given the direct link of these body fluids to certain organs, their analysis for potential diagnostic miRNA markers is plausible. Several independent findings underline the potential utility of stool-derived miRNAs in the diagnosis of colorectal and pancreatic cancer. Given the difficulties in the diagnosis of cholangiocellular cancer, biliary miRNAs might be envisaged as useful markers. Several miRNAs have been identified in the saliva that could be associated with diseases, including tumors of the oral cavity. The urinary pool of miRNAs could be exploited for the diagnosis of urinary tract diseases and some appear to enable early diagnosis. In this chapter, we present findings supporting the potential diagnostic utility of fecal, biliary, salivary, and urinary miRNAs focusing mostly on tumors.
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Affiliation(s)
- Ivan Igaz
- Department of Gastroenterology, Szt Imre Teaching Hospital Budapest, Tétényi str. 12-16, 1115, Budapest, Hungary.
| | - Peter Igaz
- 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
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