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Hedayati N, Safaei Naeini M, Ale Sahebfosoul MM, Mafi A, Eshaghi Milasi Y, Rizaneh A, Nabavi N, Farahani N, Alimohammadi M, Ghezelbash B. MicroRNA dysregulation and its impact on apoptosis-related signaling pathways in myelodysplastic syndrome. Pathol Res Pract 2024; 261:155478. [PMID: 39079383 DOI: 10.1016/j.prp.2024.155478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 07/12/2024] [Accepted: 07/16/2024] [Indexed: 08/18/2024]
Abstract
Myelodysplastic syndrome (MDS) holds a unique position among blood cancers, encompassing a spectrum of blood-related disorders marked by impaired maturation of blood cell precursors, bone marrow abnormalities, genetic instability, and a higher likelihood of progressing to acute myeloid leukemia. MicroRNAs (miRNAs), short non-coding RNA molecules typically 18-24 nucleotides in length, are known to regulate gene expression and contribute to various biological processes, including cellular differentiation and programmed cell death. Additionally, miRNAs are involved in many aspects of cancer development, influencing cell growth, transformation, and apoptosis. In this study, we explore the impact of microRNAs on cellular apoptosis in MDS.
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Affiliation(s)
- Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Mobina Safaei Naeini
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Anahita Rizaneh
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia, Canada.
| | - Najma Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behrooz Ghezelbash
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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2
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Chen H. microRNA-Based Cancer Diagnosis and Therapy. Int J Mol Sci 2023; 25:230. [PMID: 38203401 PMCID: PMC10778828 DOI: 10.3390/ijms25010230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally by impeding mRNA translation or stability [...].
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Affiliation(s)
- Hexin Chen
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
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3
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Szelągowski A, Kozakiewicz M. A Glance at Biogenesis and Functionality of MicroRNAs and Their Role in the Neuropathogenesis of Parkinson's Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:7759053. [PMID: 37333462 PMCID: PMC10270766 DOI: 10.1155/2023/7759053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 05/11/2023] [Accepted: 05/20/2023] [Indexed: 06/20/2023]
Abstract
MicroRNAs (miRNAs) are short, noncoding RNA transcripts. Mammalian miRNA coding sequences are located in introns and exons of genes encoding various proteins. As the central nervous system is the largest source of miRNA transcripts in living organisms, miRNA molecules are an integral part of the regulation of epigenetic activity in physiological and pathological processes. Their activity depends on many proteins that act as processors, transporters, and chaperones. Many variants of Parkinson's disease have been directly linked to specific gene mutations which in pathological conditions are cumulated resulting in the progression of neurogenerative changes. These mutations can often coexist with specific miRNA dysregulation. Dysregulation of different extracellular miRNAs has been confirmed in many studies on the PD patients. It seems reasonable to conduct further research on the role of miRNAs in the pathogenesis of Parkinson's disease and their potential use in future therapies and diagnosis of the disease. This review presents the current state of knowledge about the biogenesis and functionality of miRNAs in the human genome and their role in the neuropathogenesis of Parkinson's disease (PD)-one of the most common neurodegenerative disorders. The article also describes the process of miRNA formation which can occur in two ways-the canonical and noncanonical one. However, the main focus was on miRNA's use in in vitro and in vivo studies in the context of pathophysiology, diagnosis, and treatment of PD. Some issues, especially those regarding the usefulness of miRNAs in PD's diagnostics and especially its treatment, require further research. More standardization efforts and clinical trials on miRNAs are needed.
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Affiliation(s)
- Adam Szelągowski
- Nicolaus Copernicus University in Toruń Ludwik Rydygier Collegium Medicum in Bydgoszcz, Faculty of Health Sciences, Department of Geriatrics, Bydgoszcz, Poland
| | - Mariusz Kozakiewicz
- Nicolaus Copernicus University in Toruń Ludwik Rydygier Collegium Medicum in Bydgoszcz, Faculty of Health Sciences, Department of Geriatrics, Bydgoszcz, Poland
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Kabzinski J, Maczynska M, Majsterek I. MicroRNA as a Novel Biomarker in the Diagnosis of Head and Neck Cancer. Biomolecules 2021; 11:844. [PMID: 34198889 PMCID: PMC8228566 DOI: 10.3390/biom11060844] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023] Open
Abstract
Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast and reliable biomarker that allows early diagnosis. This niche can be filled by microRNA, small single-stranded non-coding RNA molecules, which are expressed in response to specific events in the body. This article presents the potential use of microRNAs in the diagnosis of HNSCC, compares the advances in this field to other diseases, especially other cancers, and discusses the detailed use of miRNA as a biomarker in profiling and predicting the treatment outcome with radiotherapy and immunotherapy. Potential problems and difficulties related to the development of this promising technology, and areas on which future research should be focused in order to overcome these difficulties, were also indicated.
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Affiliation(s)
| | | | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, al. Kościuszki 4, 90-419 Łódź, Poland; (J.K.); (M.M.)
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Ren Y, Zhang L, Zhang W, Gao Y. MiR-30a suppresses clear cell renal cell carcinoma proliferation and metastasis by targeting LRP6. Hum Cell 2021; 34:598-606. [PMID: 33400244 DOI: 10.1007/s13577-020-00472-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/06/2020] [Indexed: 10/22/2022]
Abstract
Recently, the role of miR-30a in tumor development has attracted extensive attention. In this study, we aimed to elucidate the role of miR-30a and its associated target low-density lipoprotein receptor-related protein 6 (LRP6) in clear cell renal cell carcinoma (ccRCC) cells. Here, miR-30a was markedly down-regulated in ccRCC tissues and cells, and was correlated with the advanced TNM stage and poor prognosis. By contrast, LRP6 protein level was increased in ccRCC specimens and cell lines, and inversely correlated with miR-30a expression. Stable overexpression of miR-30a suppressed cell proliferation in vitro, impeded tumor growth in vivo, prevented migration and invasion, and triggered apoptosis of ccRCC cells. Also, over-expression of miR-30a in ccRCC cells promoted the expression of the epithelial marker E-cadherin and reduced the levels of mesenchymal markers. Mechanistically, the dual-luciferase reporter, RNA immunoprecipitation and western blot assays confirmed that miR-30a directly targeted the 3'-untranslated regions of LRP6 to inhibit its expression. Further, miR-30a-mediated effect was partially reversed by co-transfection with LRP6 plasmids or enhanced by silencing of LRP6. In conclusion, miR-30a exhibits effective antitumor properties by targeting LRP6 in proliferation and metastasis of ccRCC. This study could provide new insights into the treatment of ccRCC.
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Affiliation(s)
- Yanjun Ren
- Department of Spine Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Li Zhang
- Department of Ultrasound, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Wei Zhang
- Department of Intensive Care Unit, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, No.11, Central Wuying Hill Road, Jinan, 250031, Shandong, China
| | - Yikai Gao
- Department of Intensive Care Unit, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, No.11, Central Wuying Hill Road, Jinan, 250031, Shandong, China.
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Bonini A, Poma N, Vivaldi F, Kirchhain A, Salvo P, Bottai D, Tavanti A, Di Francesco F. Advances in biosensing: The CRISPR/Cas system as a new powerful tool for the detection of nucleic acids. J Pharm Biomed Anal 2021; 192:113645. [PMID: 33039910 PMCID: PMC7513908 DOI: 10.1016/j.jpba.2020.113645] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 12/26/2022]
Abstract
A main challenge in the development of biosensing devices for the identification and quantification of nucleic acids is to avoid the amplification of the genetic material from the sample by polymerase chain reaction (PCR), which is at present necessary to enhance sensitivity and selectivity of assays. PCR has undoubtedly revolutionized genetic analyses, but it requires careful purification procedures that are not easily implemented in point of care (POC) devices. In recent years, a new strategy for nucleic acid detection based on clustered regularly interspaced short palindromic repeats (CRISPR) and associated protein systems (Cas) seems to offer unprecedented possibilities. The coupling of the CRISPR/Cas system with recent isothermal amplification methods is fostering the development of innovative optical and electrochemical POC devices. In this review, the mechanisms of action of several new CRISRP/Cas systems are reported together with their use in biosensing of nucleic acids.
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Affiliation(s)
- Andrea Bonini
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, Pisa, Italy.
| | - Noemi Poma
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, Pisa, Italy
| | - Federico Vivaldi
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, Pisa, Italy,Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, Pisa, Italy
| | - Arno Kirchhain
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, Pisa, Italy
| | - Pietro Salvo
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, Pisa, Italy
| | - Daria Bottai
- Department of Biology, University of Pisa, Via San Zeno 35-39, Pisa, Italy
| | - Arianna Tavanti
- Department of Biology, University of Pisa, Via San Zeno 35-39, Pisa, Italy
| | - Fabio Di Francesco
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, Pisa, Italy
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Ye Y, Yuan XH, Wang JJ, Wang YC, Li SL. The diagnostic value of miRNA-141 in prostate cancer: A systematic review and PRISMA-compliant meta-analysis. Medicine (Baltimore) 2020; 99:e19993. [PMID: 32481368 DOI: 10.1097/md.0000000000019993] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND miR-141 has gradually demonstrated its value in the diagnosis of prostate cancer. However, the diagnostic parameters in previous studies differ. A systematic review was conducted to explore the diagnostic value of miR-141 in prostate cancer. METHODS A comprehensive search of the literature in the PubMed, Medline, Cochrane Library, and Embase databases was performed. The included 7 studies assessed the diagnostic value of miR-141 in patients with prostate cancer up to October 31, 2019. We used meta-disc version 1.4 and STATA software version 12.0 to analyze the data. RESULTS The pooled sensitivity and specificity were 0.70 (95% confidence interval [CI] 0.64-0.75) and 0.73 (95% CI 0.64-0.80), respectively. The positive likelihood ratio was 2.88 (95% CI 1.40-5.93), and the negative likelihood ratio was 0.38 (95% CI 0.20-0.71). Further, we note that the pooled diagnostic odds ratio of miR-141 for prostate cancer was 9.94 (95% CI: 2.55-38.80). The summary area under the receiver operating characteristic curve was 0.83 (95% CI: 0.79-0.86). The results of meta-regression suggested that heterogeneity was mainly derived from patient age. The results of the Fagan nomogram showed that it was increased significantly by testing miR-141 for diagnosing prostate cancer. CONCLUSION This meta-analysis suggests that miR-141 has a high diagnostic value for prostate cancer. In the future, large-scale prospective studies are needed to verify and evaluate this result.
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Affiliation(s)
- Yun Ye
- Department of Laboratory Medicine
| | | | - Jian-Jun Wang
- Emergency Department, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
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Condrat CE, Thompson DC, Barbu MG, Bugnar OL, Boboc A, Cretoiu D, Suciu N, Cretoiu SM, Voinea SC. miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis. Cells 2020; 9:E276. [PMID: 31979244 PMCID: PMC7072450 DOI: 10.3390/cells9020276] [Citation(s) in RCA: 786] [Impact Index Per Article: 157.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/14/2020] [Accepted: 01/21/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing on their potential use in both the research and the clinical field. This review aims at improving the current understanding of these molecules and their applicability in the medical field. A thorough analysis of the literature consulting resources available in online databases such as NCBI, PubMed, Medline, ScienceDirect, and UpToDate was performed. There is promising evidence that in spite of the lack of standardized protocols regarding the use of miRNAs in current clinical practice, they constitute a reliable tool for future use. These molecules meet most of the required criteria for being an ideal biomarker, such as accessibility, high specificity, and sensitivity. Despite present limitations, miRNAs as biomarkers for various conditions remain an impressive research field. As current techniques evolve, we anticipate that miRNAs will become a routine approach in the development of personalized patient profiles, thus permitting more specific therapeutic interventions.
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Affiliation(s)
- Carmen Elena Condrat
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
| | - Dana Claudia Thompson
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
| | - Madalina Gabriela Barbu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
| | - Oana Larisa Bugnar
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
| | - Andreea Boboc
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
| | - Dragos Cretoiu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania
| | - Nicolae Suciu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, 020395 Bucharest, Romania; (C.E.C.); (D.C.T.); (M.G.B.); (O.L.B.); (A.B.); (D.C.); (N.S.)
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania
- Department of Obstetrics and Gynecology, Polizu Clinical Hospital, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
| | - Sanda Maria Cretoiu
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania
| | - Silviu Cristian Voinea
- Department of Surgical Oncology, Prof. Dr. Alexandru Trestioreanu Oncology Institute, Carol Davila University of Medicine and Pharmacy, 252 Fundeni Rd., 022328 Bucharest, Romania;
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Wei J, Yang L, Wu YN, Xu J. Serum miR-1290 and miR-1246 as Potential Diagnostic Biomarkers of Human Pancreatic Cancer. J Cancer 2020; 11:1325-1333. [PMID: 32047539 PMCID: PMC6995378 DOI: 10.7150/jca.38048] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Background: Pancreatic cancer (PC) is a highly malignant tumor with no effective early diagnostic biomarkers. This study was performed to screen and identify serum microRNAs (miRNAs) as noninvasive biomarkers for PC diagnosis. Methods: Two upregulated miRNAs were selected by integrated analysis of three independent GEO datasets. Then, the expressions of two miRNAs in serum were determined by quantitative reverse-transcription PCR among 120 PC patients, 40 benign disease controls and 40 healthy controls. The correlation between serum miRNAs and clinical characteristics was analyzed. The diagnostic utility of miRNAs was compared to CA19-9 using receiver operating characteristic curve analysis. Results: We discovered miR-1290 and miR-1246 were upregulated in PC patients through GEO datasets analysis. Serum miR-1290 and miR-1246 expression levels were elevated in PC patients compared to all controls and dramatically decreased after tumor resection (all P<0.001). The area under the curve (AUC) for miR-1290 was larger than miR-1246 and CA19-9 (miR-1290: 0.91; miR-1246: 0.81; CA19-9: 0.82). The combined diagnosis of individual or both miRNAs with CA19-9 was more effective for discriminating PC from all controls than the single CA19-9 assay (miR-1290+CA19-9: 0.96, miR-1246+CA19-9: 0.93, miR-1290+miR-1246+CA19-9: 0.97). The abundance of serum miR-1290 and miR-1246 was associated with tumor stage and size respectively and logistic modeling proved that both of them were independent risk factors for PC. Conclusion: Serum miR-1290 and miR-1246 might be promising biomarkers for PC diagnosis and the combined detection of CA19-9, together with miR-1290 or miR-1246, could improve the diagnostic accuracy of PC.
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Affiliation(s)
- Jia Wei
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Lu Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,National Key Clinical Department of Laboratory Medicine, Nanjing 210029, China
| | - Yi-Ning Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jian Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,National Key Clinical Department of Laboratory Medicine, Nanjing 210029, China
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Elemeery MN, Mohamed MA, Madkour MA, Shamseya MM, Issa NM, Badr AN, Ghareeb DA, Pan CH. MicroRNA signature in patients with hepatocellular carcinoma associated with type 2 diabetes. World J Gastroenterol 2019; 25:6322-6341. [PMID: 31754293 PMCID: PMC6861851 DOI: 10.3748/wjg.v25.i42.6322] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/29/2019] [Accepted: 11/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis-related cirrhosis is one of the liver complications in type 2 diabetes mellitus (T2DM) and reported to be a risk factor for developing hepatocellular carcinoma (HCC). A reliable screening biomarker of liver cirrhosis (LC) and HCC among T2DM patients is important to reduce the morbidity and mortality of this disease. MicroRNA (miRNA) is considered a key player in HCC and T2DM, and it might be a hidden culprit in diabetes-associated HCC, making it a promising reliable prognostic tool.
AIM To investigate the signature of serum miRNAs as early biomarkers for the screening of HCC among diabetic patients.
METHODS Expression profiles of miRNAs in serum samples of diabetic LC and diabetic HCC patients were assessed using Illumina sequencing; then, RT-qPCR was used to validate significantly altered miRNAs between the two groups. Candidate miRNAs were tested in serum samples of 200 T2DM patients, 270 LC patients, 200 HCC patients, and 225 healthy control subjects. Additionally, receiver operating characteristic (ROC) analysis, with area under the curve (AUC), was performed to assess the diagnostic performance of the screened miRNAs for discriminating HCC from LC and nonmalignant patients (LC + T2DM).
RESULTS Expression of the sequenced miRNAs in serum was different in HCC vs LC-positive T2DM patients. Two miRNAs (miR-34a, miR-221) were significantly up-regulated and five miRNAs (miR-16, miR-23-3p, miR-122-5p, miR-198, miR-199a-3p) were significantly down-regulated in HCC compared to LC patients. Analysis of ROC curve demonstrated that the combination of these seven miRNAs can be used as a reliable biomarker for detection of HCC in diabetic patients, as it could identify HCC with high diagnostic accuracy in diabetic LC patients (AUC = 0.993) and in diabetic nonmalignant patients (AUC = 0.961).
CONCLUSION This study validates a panel of serum miRNAs that can be used as a reliable noninvasive screening biomarker of HCC among T2DM cirrhotic and noncirrhotic patients. The study recommends further research to shed light on a possible role of c-Met in T2DM-associated HCC via the miRNA regulatory pathway.
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Affiliation(s)
- Moustafa Nouh Elemeery
- Département de Neurosciences, CRCHUM, Université de Montréal, Montréal, Quebec H2X 3E4, Canada
- Medical Biotechnology Laboratory, Genetic Engineering and Biotechnology Research Division, National Research Centre, Cairo 12622, Egypt
- Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, South Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, South Korea
| | - Marwa Anwar Mohamed
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Marwa Ahmed Madkour
- Experimental and Clinical Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Mohammed Mohammed Shamseya
- Experimental and Clinical Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Noha Mahmoud Issa
- Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Ahmed Noah Badr
- Food Toxicology and Contaminates Department, National Research Centre, Dokki, Cairo 12622, Egypt
| | - Doaa Ahmed Ghareeb
- Bioscreening and preclinical trial lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 12522, Egypt
- Pharmaceutical and fermentation industries development center, the city of scientific research and technological applications, Alexandria 26411, Egypt
| | - Cheol-Ho Pan
- Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, South Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, South Korea
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11
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Bottani M, Banfi G, Lombardi G. Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Common Solid Tumors: Focus on Lung, Breast, Prostate Cancers, and Osteosarcoma. J Clin Med 2019; 8:E1661. [PMID: 31614612 PMCID: PMC6833074 DOI: 10.3390/jcm8101661] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/04/2019] [Accepted: 10/06/2019] [Indexed: 12/22/2022] Open
Abstract
An early cancer diagnosis is essential to treat and manage patients, but it is difficult to achieve this goal due to the still too low specificity and sensitivity of classical methods (imaging, actual biomarkers), together with the high invasiveness of tissue biopsies. The discovery of novel, reliable, and easily collectable cancer markers is a topic of interest, with human biofluids, especially blood, as important sources of minimal invasive biomarkers such as circulating microRNAs (miRNAs), the most promising. MiRNAs are small non-coding RNAs and known epigenetic modulators of gene expression, with specific roles in cancer development/progression, which are next to be implemented in the clinical routine as biomarkers for early diagnosis and the efficient monitoring of tumor progression and treatment response. Unfortunately, several issues regarding their validation process are still to be resolved. In this review, updated findings specifically focused on the clinical relevance of circulating miRNAs as prognostic and diagnostic biomarkers for the most prevalent cancer types (breast, lung, and prostate cancers in adults, and osteosarcoma in children) are described. In addition, deep analysis of pre-analytical, analytical, and post-analytical issues still affecting the circulation of miRNAs' validation process and routine implementation is included.
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Affiliation(s)
- Michela Bottani
- IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry and Molecular Biology, Via Riccardo Galeazzi 4, 20161 Milano, Italy.
| | - Giuseppe Banfi
- IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry and Molecular Biology, Via Riccardo Galeazzi 4, 20161 Milano, Italy.
- Vita-Salute San Raffaele University, 20132 Milano, Italy.
| | - Giovanni Lombardi
- IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry and Molecular Biology, Via Riccardo Galeazzi 4, 20161 Milano, Italy.
- Dept. of Physiology and Pharmacology, Gdańsk University of Physical Education and Sport, Gdańsk, ul. Kazimierza Górskiego 1, 80-336 Pomorskie, Poland.
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Wang H, Wang H, Zhang M, Jia Y, Li Z. A label-free aptamer-based biosensor for microRNA detection by the RNA-regulated fluorescence of malachite green. RSC Adv 2019; 9:32906-32910. [PMID: 35529731 PMCID: PMC9073149 DOI: 10.1039/c9ra07552f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 10/02/2019] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) have been considered as promising molecular biomarkers for disease diagnosis, prognosis, as well as drug development. Herein, we wish to report a low background and label-free aptamer-based biosensor for miRNA assay by RNA-regulated fluorescence of malachite green (MG). In this biosensor-based strategy, target miRNA can specifically hybridize with the DNA extension template to form the T7 in vitro transcription system. Then the following transcription amplification produces a large number of MG RNA aptamers (MGAs) which light up the fluorescence of the MG, achieving significant fluorescence enhancement for miRNA quantitative analysis. The aptamer-based biosensor exhibits high sensitivity with a quite low detection limit of 10 amol target miRNA and high specificity to clearly discriminate very similar miRNA family members, even only one base difference. Furthermore, we have demonstrated that the biosensor is practical and reliable for the quantitative detection of miRNA in complex real samples.
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Affiliation(s)
- Honghong Wang
- School of Chemistry and Biology Engineering, University of Science and Technology Beijing Beijing 100083 P. R. China
| | - Hui Wang
- School of Chemistry and Biology Engineering, University of Science and Technology Beijing Beijing 100083 P. R. China
| | - Mai Zhang
- School of Chemistry and Biology Engineering, University of Science and Technology Beijing Beijing 100083 P. R. China
| | - Yuting Jia
- School of Chemistry and Biology Engineering, University of Science and Technology Beijing Beijing 100083 P. R. China
| | - Zhengping Li
- School of Chemistry and Biology Engineering, University of Science and Technology Beijing Beijing 100083 P. R. China
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13
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Zou X, Li M, Huang Z, Zhou X, Liu Q, Xia T, Zhu W. Circulating miR-532-502 cluster derived from chromosome X as biomarkers for diagnosis of breast cancer. Gene 2019; 722:144104. [PMID: 31493506 DOI: 10.1016/j.gene.2019.144104] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 08/17/2019] [Accepted: 09/02/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Xuan Zou
- First Clinical College of Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China
| | - Minghui Li
- Department of Breast Surgery, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China
| | - Zebo Huang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China; Department of Oncology, the Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi 214062, Jiangsu Province, PR China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China
| | - Qingxie Liu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China
| | - Tiansong Xia
- Department of Breast Surgery, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China.
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China; Department of Oncology and Radiotherapy, Nanjing Pukou Central Hospital, 166 Shanghe Street, Pukou District, Nanjing 211800, PR China.
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14
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Recent advances on nanomaterials-based fluorimetric approaches for microRNAs detection. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 104:110007. [PMID: 31500008 DOI: 10.1016/j.msec.2019.110007] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/09/2019] [Accepted: 07/19/2019] [Indexed: 12/18/2022]
Abstract
MicroRNAs are types of small single-stranded endogenous highly conserved non-coding RNAs, which play main regulatory functions in a wide range of cellular and physiological events, such as proliferation, differentiation, neoplastic transformation, and cell regeneration. Recent findings have proved a close association between microRNAs expression and the development of many diseases, indicating the importance of microRNAs as clinical biomarkers and targets for drug discovery. However, due to a number of prominent characteristics like small size, high sequence similarity and low abundance, sensitive and selective identification of microRNAs has rather been a hardship through routine traditional assays, including quantitative polymerase chain reaction, microarrays, and northern blotting analysis. More recently, the soaring progression in nanotechnology and fluorimetric methodologies in combination with nanomaterials have promised microRNAs detection with high sensitivity, efficiency and selectivity, excellent reproducibility and lower cost. Therefore, this review will represent an overview of latest advances in microRNAs detection through nanomaterials-based fluorescent methods, like gold nanoparticles, silver and copper nanoclusters, graphene oxide, and magnetic silicon nanoparticles.
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15
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Zou X, Wei J, Huang Z, Zhou X, Lu Z, Zhu W, Miao Y. Identification of a six-miRNA panel in serum benefiting pancreatic cancer diagnosis. Cancer Med 2019; 8:2810-2822. [PMID: 31006985 PMCID: PMC6558458 DOI: 10.1002/cam4.2145] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/27/2019] [Accepted: 03/18/2019] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer (PC) has posed a great health threat to a growing number of people all over the world. Detection of serum miRNAs, being sensitive, noninvasive, and easy to obtain, has a great potential of being a novel screening method for PC patients. In this study, we investigated miRNA expression levels in serum by qRT-PCR. The study was divided into four phases: the screening, training, testing, and external validation stage. We firstly chose candidate miRNAs using Exiqon panels in the screening phase. Then, a total of 129 PC serum samples and 107 normal controls (NCs) were further analyzed in the following training and testing phases to identify differently expressed miRNAs. A cohort of 30 PC serum samples vs 30 NCs was used to confirm the diagnostic value of the identified miRNAs in the external validation phase. Moreover, miRNA expressions in additional 44 PC tumor tissue samples and the matched adjacent normal tissue samples as well as 32 pairs of serum-derived exosomes samples were also further explored. As a result, we identified six significantly upregulated miRNAs in the serum of PC: let-7b-5p, miR-192-5p, miR-19a-3p, miR-19b-3p, miR-223-3p, and miR-25-3p. A six-miRNA panel in serum was then established. The area under the receiver operating characteristic curves (AUC) for the panel was 0.910 for the combined training and testing phases, which showed higher diagnostic value than the individual miRNA. Prognostic value prediction using Cox's proportional hazards model and Kaplan-Meier curves showed that increased serum miR-19a-3p was closely related to worse overall survival (OS). In addition, significant upregulation of miR-192-5p, miR-19a-3p, and miR-19b-3p was observed in both PC tissue and serum-derived exosomes samples. In conclusion, we identified a six-miRNA (let-7b-5p, miR-192-5p, miR-19a-3p, miR-19b-3p, miR-223-3p, and miR-25-3p) panel in the serum for PC early and noninvasive diagnosis.
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Affiliation(s)
- Xuan Zou
- First Clinical College of Nanjing Medical University, Nanjing, PR China
| | - Jishu Wei
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, PR China
| | - Zebo Huang
- Department of Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, PR China
- Department of Oncology, The Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Xin Zhou
- Department of Oncology, The Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Zipeng Lu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, PR China
| | - Wei Zhu
- Department of Oncology, The Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
- Department of Oncology, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, PR China
| | - Yi Miao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, PR China
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16
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The Impact of Pre-analytical Factors on the Reliability of miRNA Measurements. CURRENT PATHOBIOLOGY REPORTS 2019. [DOI: 10.1007/s40139-019-00191-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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17
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Yuan HL, Wang T, Zhang KH. MicroRNAs as potential biomarkers for diagnosis, therapy and prognosis of gastric cancer. Onco Targets Ther 2018; 11:3891-3900. [PMID: 30013369 PMCID: PMC6039071 DOI: 10.2147/ott.s156921] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite the widespread use of endoscopy and conventional tumor biomarkers, gastric cancer (GC) remains one of the most frequent causes of cancer-related deaths worldwide due to its late diagnosis and poor response to treatment. Valuable and practical biomarkers are urgently needed to screen patients with a high risk of GC that can complement endoscopic diagnosis. Such biomarkers will enable the efficient prediction of therapeutic response and prognosis of GC patients and favor the establishment of an effective treatment strategy for each and every patient. MicroRNAs (miRNAs) are a class of small non-coding RNA sequences that play important roles in modulating key biological processes by regulating the expression of target genes. Expectedly, miRNAs are abnormally expressed within the tumor tissue and in associated biological fluids of GC patients including their blood, gastric juice, and urine. Accumulating evidence indicates that miRNAs are potential biomarkers with multiple diagnostic functions for GC. Here, we review recent advances and challenges in using miRNAs, particularly biofluid miRNAs, as GC biomarkers with potential clinical applications including diagnosing, clinically staging, and predicting malignant behaviors, therapy response, recurrence after surgery and survival time.
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Affiliation(s)
- Hai-Liang Yuan
- Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People's Republic of China,
| | - Ting Wang
- Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People's Republic of China,
| | - Kun-He Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People's Republic of China,
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18
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Chen L, Yang J, Lü J, Cao S, Zhao Q, Yu Z. Identification of aberrant circulating miRNAs in Parkinson's disease plasma samples. Brain Behav 2018; 8:e00941. [PMID: 29670823 PMCID: PMC5893342 DOI: 10.1002/brb3.941] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 01/12/2018] [Accepted: 01/14/2018] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE To detect the aberrant expression of circulating miRNAs and explore the potential early diagnostic biomarkers in patients with Parkinson's disease (PD). METHODS Plasma samples were collected from 25 treatment-naïve PD-diagnosed patients and 25 healthy controls followed by a real-time PCR-based miRNA screening analysis of neuron disease-related miRNAs. RESULTS A subset of miRNAs with aberrant expression levels in the plasma of PD-diagnosed patients were identified including upregulation of miR-27a and downregulation of let-7a, let-7f, miR-142-3p, and miR-222 with the AUC values more than 0.8 derived from the receiver operating characteristic curves. CONCLUSIONS The high sensitivity and specificity of the circulating miRNAs may enable early diagnosis of PD. The study provides a group of novel miRNA candidates for detecting PD.
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Affiliation(s)
- Lei Chen
- Department of NeurologyTianjin Huan Hu Hospital Jinnan District, Tianjin China.,Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases Tianjin China
| | - Junxiu Yang
- Department of Neurology Hospital of Integrated Traditional and Western Medicine Cangzhou China
| | - Jinhui Lü
- Research Center for Translational Medicine East Hospital Tongji University School of Medicine Shanghai China
| | - Shanshan Cao
- Department of NeurologyTianjin Huan Hu Hospital Jinnan District, Tianjin China.,Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases Tianjin China
| | - Qian Zhao
- Research Center for Translational Medicine East Hospital Tongji University School of Medicine Shanghai China
| | - Zuoren Yu
- Research Center for Translational Medicine East Hospital Tongji University School of Medicine Shanghai China
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19
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Bayraktar R, Van Roosbroeck K, Calin GA. Cell-to-cell communication: microRNAs as hormones. Mol Oncol 2017; 11:1673-1686. [PMID: 29024380 PMCID: PMC5709614 DOI: 10.1002/1878-0261.12144] [Citation(s) in RCA: 257] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 09/24/2017] [Indexed: 12/11/2022] Open
Abstract
Mammalian cells can release different types of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies. Accumulating evidence suggests that EVs play a role in cell-to-cell communication within the tumor microenvironment. EVs' components, such as proteins, noncoding RNAs [microRNAs (miRNAs), and long noncoding RNAs (lncRNAs)], messenger RNAs (mRNAs), DNA, and lipids, can mediate paracrine signaling in the tumor microenvironment. Recently, miRNAs encapsulated in secreted EVs have been identified in the extracellular space. Mature miRNAs that participate in intercellular communication are released from most cells, often within EVs, and disseminate through the extracellular fluid to reach remote target cells, including tumor cells, whose phenotypes they can influence by regulating mRNA and protein expression either as tumor suppressors or as oncogenes, depending on their targets. In this review, we discuss the roles of miRNAs in intercellular communication, the biological function of extracellular miRNAs, and their potential applications for diagnosis and therapeutics. We will give examples of miRNAs that behave as hormones.
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Affiliation(s)
- Recep Bayraktar
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Katrien Van Roosbroeck
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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20
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Boldrup L, Troiano G, Gu X, Coates P, Fåhraeus R, Wilms T, Norberg-Spaak L, Wang L, Nylander K. Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue. Oncotarget 2017; 8:103437-103448. [PMID: 29262574 PMCID: PMC5732740 DOI: 10.18632/oncotarget.21402] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 09/13/2017] [Indexed: 01/30/2023] Open
Abstract
Despite intense research, squamous cell carcinoma of the tongue remains a devastating disease with a five-year survival of around 60%. Late detection and recurrence are the main causes for poor survival. The identification of circulating factors for early diagnosis and/or prognosis of cancer is a rapidly evolving field of interest, with the hope of finding stable and reliable markers of clinical significance. The aim of this study was to evaluate circulating miRNAs and proteins as potential factors for distinguishing patients with tongue squamous cell carcinoma from healthy controls. Array-based profiling of 372 miRNAs in plasma samples showed broad variations between different patients and did not show any evidence for their use in diagnosis of tongue cancer. Although one miRNA, miR-150, was significantly down-regulated in plasma from patients compared to controls. Surprisingly, the corresponding tumor tissue showed an up-regulation of miR-150. Among circulating proteins, 23 were identified as potential markers of squamous cell carcinoma of the tongue. These findings imply that circulating proteins are a more promising source of biomarkers for tongue squamous cell carcinomas than circulating miRNAs. The data also highlight that circulating markers are not always directly associated with tumor cell properties.
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Affiliation(s)
- Linda Boldrup
- Department of Medical Biosciences/Pathology, Umeå University, SE - 901 85 Umeå, Sweden
| | - Giuseppe Troiano
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Xiaolian Gu
- Department of Medical Biosciences/Pathology, Umeå University, SE - 901 85 Umeå, Sweden
| | - Philip Coates
- RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Robin Fåhraeus
- Department of Medical Biosciences/Pathology, Umeå University, SE - 901 85 Umeå, Sweden.,RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.,Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010 Paris, France
| | - Torben Wilms
- Department of Clinical Sciences/ENT, Umeå University, SE - 901 85 Umeå, Sweden
| | - Lena Norberg-Spaak
- Department of Clinical Sciences/ENT, Umeå University, SE - 901 85 Umeå, Sweden
| | - Lixiao Wang
- Department of Medical Biosciences/Pathology, Umeå University, SE - 901 85 Umeå, Sweden
| | - Karin Nylander
- Department of Medical Biosciences/Pathology, Umeå University, SE - 901 85 Umeå, Sweden
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21
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Lamadrid-Romero M, Solís KH, Cruz-Reséndiz MS, Pérez JE, Díaz NF, Flores-Herrera H, García-López G, Perichart O, Reyes-Muñoz E, Arenas-Huertero F, Eguía-Aguilar P, Molina-Hernández A. Central nervous system development-related microRNAs levels increase in the serum of gestational diabetic women during the first trimester of pregnancy. Neurosci Res 2017; 130:8-22. [PMID: 28803788 DOI: 10.1016/j.neures.2017.08.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 08/03/2017] [Accepted: 08/07/2017] [Indexed: 01/14/2023]
Abstract
MicroRNAs are heterochronic molecules important during brain development, which could be altered by gestational diabetes mellitus (GDM). To explore these molecules in maternal serum, we performed an RT-qPCR analysis. Our results revealed the heterochronic character of some neural development-related microRNA in serum samples of pregnant women. In relation to the first trimester, higher levels of miR-183-5p, -200b-3p, and -125-5p in the second trimester, and higher levels of miR-137 in the third trimester, were found. Furthermore, an insult such as GDM led to higher levels of miR-183-5p, -200b-3p, -125-5p, and -1290 relative to the control in the first trimester, which might be related to changes in neurogenesis and cell proliferation. An in silico analysis suggested that increased microRNAs in the second trimester in the control contributed to cell proliferation and neuron differentiation and that the rise in miR-137 in the third trimester led to neuron maturation. In the diabetic, higher levels of the microRNAs in the first trimester suggested alterations in cell proliferation and neuron differentiation. In conclusion, we showed that fetal-related microRNAs can be detected in the serum of pregnant woman and exhibit temporary regulation during pregnancy and that microRNAs involved in cell proliferation and neuron differentiation are upregulated under GDM.
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Affiliation(s)
- M Lamadrid-Romero
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico; Posgrado en Ciencias Biológicas, Facultad de Ciencias-UNAM, Ciudad de México, Mexico
| | - K H Solís
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - M S Cruz-Reséndiz
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico; Posgrado en Ciencias Biológicas, Facultad de Ciencias-UNAM, Ciudad de México, Mexico
| | - J E Pérez
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - N F Díaz
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - H Flores-Herrera
- Instituto Nacional de Perinatología "Isidro Espinosa de Los Reyes", Departamento de Inmunobioquímica, Mexico
| | - G García-López
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico
| | - O Perichart
- Instituto Nacional de Perinatología "Isidro Espinosa de Los Reyes", Departamento de Nutrición, Mexico
| | - E Reyes-Muñoz
- Instituto Nacional de Perinatología "Isidro Espinosa de Los Reyes", Departamento de Endocrionología, Mexico
| | - F Arenas-Huertero
- Hospital Infantil de México "Federico Gómez", Laboratorio de Investigación en Patología Experimental, Mexico
| | - P Eguía-Aguilar
- Hospital Infantil de México "Federico Gómez", Departamento de Patología, Mexico
| | - A Molina-Hernández
- Instituto Nacional de Perinatología "Isidro Espinosa de los Reyes", Departamento de Fisiología y Desarrollo Celular (Laboratorio de Investigación en Células Troncales y Biología del Desarrollo), Mexico.
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22
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Understanding the Role of Non-Coding RNAs in Bladder Cancer: From Dark Matter to Valuable Therapeutic Targets. Int J Mol Sci 2017; 18:ijms18071514. [PMID: 28703782 PMCID: PMC5536004 DOI: 10.3390/ijms18071514] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 06/22/2017] [Accepted: 07/07/2017] [Indexed: 02/07/2023] Open
Abstract
The mortality and morbidity that characterize bladder cancer compel this malignancy into the category of hot topics in terms of biomolecular research. Therefore, a better knowledge of the specific molecular mechanisms that underlie the development and progression of bladder cancer is demanded. Tumor heterogeneity among patients with similar diagnosis, as well as intratumor heterogeneity, generates difficulties in terms of targeted therapy. Furthermore, late diagnosis represents an ongoing issue, significantly reducing the response to therapy and, inevitably, the overall survival. The role of non-coding RNAs in bladder cancer emerged in the last decade, revealing that microRNAs (miRNAs) may act as tumor suppressor genes, respectively oncogenes, but also as biomarkers for early diagnosis. Regarding other types of non-coding RNAs, especially long non-coding RNAs (lncRNAs) which are extensively reviewed in this article, their exact roles in tumorigenesis are—for the time being—not as evident as in the case of miRNAs, but, still, clearly suggested. Therefore, this review covers the non-coding RNA expression profile of bladder cancer patients and their validated target genes in bladder cancer cell lines, with repercussions on processes such as proliferation, invasiveness, apoptosis, cell cycle arrest, and other molecular pathways which are specific for the malignant transformation of cells.
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23
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Armand-Labit V, Pradines A. Circulating cell-free microRNAs as clinical cancer biomarkers. Biomol Concepts 2017; 8:61-81. [DOI: 10.1515/bmc-2017-0002] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/21/2017] [Indexed: 12/23/2022] Open
Abstract
AbstractMicroRNAs (miRNAs) are non-coding small RNAs that are master regulators of genic expression and consequently of many cellular processes. But their expression is often deregulated in human tumors leading to cancer development. Recently miRNAs were discovered in body fluids (serum, plasma and others) and their levels have often been reported to be altered in patients. Circulating miRNAs became one of the most promising biomarkers in oncology for early diagnosis, prognosis and therapeutic response prediction. Here we describe the origins and roles of miRNAs, and summarize the most recent studies focusing on their usefulness as cancer biomarkers in lung, breast, colon, prostate, ovary cancers and melanoma. Lastly, we describe the main methodologies related to miRNA detection, which should be standardized for their use in clinical practice.
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Affiliation(s)
- Virginie Armand-Labit
- Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France
- Institut Claudius Regaud, IUCT-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France
| | - Anne Pradines
- Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France
- Institut Claudius Regaud, IUCT-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France
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24
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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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Fumagalli C, Bianchi F, Raviele PR, Vacirca D, Bertalot G, Rampinelli C, Lazzeroni M, Bonanni B, Veronesi G, Fusco N, Barberis M, Guerini-Rocco E. Circulating and tissue biomarkers in early-stage non-small cell lung cancer. Ecancermedicalscience 2017; 11:717. [PMID: 28194229 PMCID: PMC5295844 DOI: 10.3332/ecancer.2017.717] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE We sought to characterise circulating and tissue tumour biomarkers of patients who developed early-stage non-small cell lung cancer (NSCLC) during long-term follow-up of a chemoprevention trial (NCT00321893). MATERIALS AND METHODS Blood and sputum samples were collected from 202 high-risk asymptomatic individuals with CT-detected stable lung nodules. Real-time PCR was performed on plasma to quantify free circulating DNA. Baseline serum was investigated with a previously validated test based on 13 circulating miRNAs (miR-Test). Promoter methylation status of p16, RASSF1a and RARβ2 and telomerase activity were assessed in sputum samples. DNA was extracted from each tumour developed during follow-up and subjected to a mutation survey using the LungCarta panel on the Sequenom MassARRAY platform. RESULTS During follow-up (9 years) six individuals underwent surgery for stage I NSCLC with a median time of disease onset of 20.5 months. MiR-Test scores were positive (range: 0.14-7.24) in four out of six baseline pre-disease onset sera. No association was identified between free circulating DNA or sputum biomarkers and disease onset. All tumours harboured at least one somatic mutation in well-known cancer genes, including KRAS (n = 4), BRAF (n = 1), and TP53 (n = 3). CONCLUSION Circulating miRNA tests may represent valuable tools to detect clinically-silent tumours. Early-stage lung adenocarcinomas harbour recurrent genetic events similar to those described in advanced-stage NSCLCs.
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Affiliation(s)
- Caterina Fumagalli
- Division of Pathology, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Fabrizio Bianchi
- Institute for Stem-cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, Foggia, Italy
| | - Paola Rafaniello Raviele
- Division of Pathology, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Davide Vacirca
- Division of Pathology, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Giovanni Bertalot
- Molecular Medicine Programme IEO, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Cristiano Rampinelli
- Department of Radiology, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Matteo Lazzeroni
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Giulia Veronesi
- Division of Thoracic Surgery, Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano Milan, Italy
| | - Nicola Fusco
- Division of Pathology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy
| | - Massimo Barberis
- Division of Pathology, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
| | - Elena Guerini-Rocco
- Division of Pathology, European Institute of Oncology, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
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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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Singh R, Ramasubramanian B, Kanji S, Chakraborty AR, Haque SJ, Chakravarti A. Circulating microRNAs in cancer: Hope or hype? Cancer Lett 2016; 381:113-21. [PMID: 27471105 DOI: 10.1016/j.canlet.2016.07.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/29/2016] [Accepted: 07/02/2016] [Indexed: 12/20/2022]
Abstract
Circulating miRNAs are a novel class of stable, minimally invasive disease biomarkers that are considered to be valuable in diagnosis, prognosis and treatment response monitoring. Unlike intracellular miRNAs, circulating miRNAs are released from their producer cells and, based on their targeted functions, they may shuttle in and out of circulation. Their discovery has opened up new avenues for clinical realms and led to a quest for targeted biomarkers. Subsequently, as more cell-free miRNAs are being discovered, their expression is expected to provide precise information regarding disease progression and treatment outcomes, thereby fostering personalized therapeutic strategies. The significance of circulating miRNAs capitalizes on the fact that they are highly stable in body fluids and their expression levels can be detected by common techniques such as qPCR and microarray. However, discrepancies have started to emerge in terms of their reliability and their response under physiological and pathological conditions. Functional studies are still pending, which may determine whether circulating miRNAs play a role as a central component or just as an auxiliary tuner. Also, the distinct clinical signatures that they display have never been subjected to an extensive critical review and experimental validation. As a consequence, the applicability of circulating miRNAs remains a matter of deliberation, despite many intriguing perspectives about their competency. In this review, we highlight some ambiguous issues with the application of circulating miRNAs, which may warrant an immediate consideration. We propose that the circulating miRNA domain needs to be reevaluated to authenticate their specific role and to probe whether they actually carry any clinical weightage.
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Affiliation(s)
- Rajbir Singh
- Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Brinda Ramasubramanian
- Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Suman Kanji
- Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Arup R Chakraborty
- Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Saikh Jaharul Haque
- Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Arnab Chakravarti
- Department of Radiation Oncology, James Cancer Hospital and Solove Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
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Chandra V, Kim JJ, Mittal B, Rai R. MicroRNA aberrations: An emerging field for gallbladder cancer management. World J Gastroenterol 2016; 22:1787-1799. [PMID: 26855538 PMCID: PMC4724610 DOI: 10.3748/wjg.v22.i5.1787] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/12/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer (GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment options. These necessitate development of early prognostic/predictive markers and novel therapeutic interventions. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a key role in tumor biology by functioning like tumor suppressor- or onco- genes and their aberrant expression are associated with the pathogenesis of several neoplasms with overwhelming clinical implications. Since miRNA signature is tissue specific, here, we focused on current data concerning the miRNAs abberations in GBC pathogenesis. In GBC, miRNAs with tumor suppressor activity (miR-135-5p, miR-335, miR-34a, miR-26a, miR-146b-5p, Mir-218-5p, miR-1, miR-145, mir-130a) were found downregulated, while those with oncogenic property (miR-20a, miR-182, mir-155) were upregulated. The expression profile of miRNAs was significantly associated with GBC prognosis and prediction, and forced over-expression/ inhibition of these miRNAs was shown to affect tumor growth and development. Further, differential expression of miRNAs in the blood samples of GBC patients suggest miRNAs as promising noninvasive biomarker. Thus, miRNAs represent potential candidate for GBC management, though many hurdles need to be overcome before miRNAs therapy can be clinically applied to GBC prevention and treatment.
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Fabris L, Calin GA. Circulating free xeno-microRNAs - The new kids on the block. Mol Oncol 2016; 10:503-8. [PMID: 26860056 DOI: 10.1016/j.molonc.2016.01.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 01/12/2016] [Accepted: 01/13/2016] [Indexed: 12/18/2022] Open
Abstract
The role of circulating free microRNAs (cfmiRNAs) as promising tools for cancer screening, prognosis and monitoring of anticancer therapies has been widely studied in the past decades. cfmiRNAs have all the characteristics of the perfect biomarkers owing high stability under storage and handling conditions and being detectable not only in plasma, but in almost all body fluids. Moreover, their levels in plasma are likely to resemble ones in the primary tumor. Recently, viral and plant miRNAs have been found in plasma of healthy individuals through deep sequencing technique, and subsequently the same ones were deregulated in patients. Growing body of literature is recently focusing on understanding the potential cross-kingdom regulation of human mRNAs by miRNAs most likely absorbed with food ingestion. In this article we will review the literature concerning the xenomiRs detected in plasma and their role in influencing cancer onset and progression. XenomiRs could potentially be used not only as early screening tool, but also for patients' prognosis.
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Affiliation(s)
- Linda Fabris
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George Adrian Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Liquid Profiling in Lung Cancer - Quantification of Extracellular miRNAs in Bronchial Lavage. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 924:33-37. [PMID: 27753015 DOI: 10.1007/978-3-319-42044-8_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Extracellular miRNAs cannot only be isolated from different body fluids like plasma and serum, but also from bronchial lavage samples (BL) obtained by bronchoscopy. Alterations in the expression of microRNAs might be useful for a discrimination of lung cancer patients from patients with a benign lung disease. We profiled extracellular microRNAs from three BL pools of lung cancer patients and three BL pools from a control group (patients with a benign lung disease) with TaqMan MicroRNA Array cards. For the confirmation of these results, we analyzed a panel of eight miRNAs in a qRT-PCR of the BL of 30 different lung cancer and non-cancerous patients. For the data normalization, we used exogenously added cel-miR-39 RNA. Using microRNA arrays, we found a panel of eight microRNAs (hsa-miR 19b-1, 1285, 1289, 1303, 217, 29a-5p, 548-3p, 650) that were differentially expressed between the lung cancer and the non-cancerous group. Further investigation by qPCR revealed five microRNAs (U6 snRNA, hsa-miR 1285, 1303, 29a-5p, 650) that were significantly up-regulated in patients with lung cancer. In bronchial lavage samples, the five microRNAs identified in this study may have a diagnostic potential to be used as biomarkers in lung cancer.
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