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Tout I, Bougarn S, Toufiq M, Gopinath N, Hussein O, Sathappan A, Chin-Smith E, Rehaman F, Mathew R, Mathew L, Wang K, Liu L, Salhab A, Soloviov O, Tomei S, Hasan W, Da'as S, Bejaoui Y, Hajj NE, Maalej KM, Dermime S, Rasul K, Dellabona P, Casorati G, Turdo A, Todaro M, Stassi G, Ferrone S, Wang X, Maccalli C. The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses. J Transl Med 2025; 23:193. [PMID: 39962504 PMCID: PMC11834280 DOI: 10.1186/s12967-025-06176-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) initiating cells (CICs) possess self-renewal capabilities and are pivotal in tumor recurrence and resistance to conventional therapies, including immunotherapy. The mechanisms underlying their interaction with immune cells remain unclear. METHODS We conducted a multi-omics analysis-encompassing DNA methylation, total RNA sequencing, and microRNAs (miRNAs; N = 800) profiling on primary CICs and differentiated tumor cell lines, including autologous pairs. Functional immunological assays were performed to assess the impact of miRNA modulation. RESULTS CICs exhibited distinct methylation patterns, transcriptomic profiles, and miRNA expressions compared to differentiated tumor cells (p < 0.05 or 0.01). Notably, miRNA-15a and -196a were implicated in regulating tumorigenic pathways, such as epithelial-to-mesenchymal transition (EMT), TGF-β signaling, and immune modulation. The transfection of CICs with miRNA mimics led to the downregulation of oncogenic EMT markers (CRKL, lncRNA SOX2-OT, JUNB, SMAD3) and TGF-β pathway, resulting in a significant reduction of the in vitro proliferation and the tumorigenicity and migration in a zebrafish xenograft model. Additionally, miRNA-15a enhanced the expression of antigen processing machinery and decreased the expression of immune checkpoints (PD-L1, PD-L2, CTLA-4) and immunosuppressive cytokines (IL-4). The co-culture of HLA-matched lymphocytes with CICs overexpressing the miRNA-15a, elicited robust tumor-specific immune responses, characterized by a shift toward central and effector memory T cell phenotypes and prevented their terminal differentiation and exhaustion. The combination of miRNA modulation with Indoleamine 2,3-dioxygenase blockade and immunomodulating agents further potentiated these effects. CONCLUSIONS Our study demonstrates that the modulation of miRNA-15a in CICs not only suppresses the tumorigenic properties but also enhances their visibility to the immune system by upregulating antigen presentation and reducing immunomodulatory molecules. These findings suggest that combining miRNA modulation with epigenetic or immunomodulatory agents holds significant promise for overcoming treatment resistance in CRC.
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Affiliation(s)
- Issam Tout
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Salim Bougarn
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Mohammed Toufiq
- Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Neha Gopinath
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Ola Hussein
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
- College of Pharmacy, Qatar University, Doha, Qatar
| | | | - Evonne Chin-Smith
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Fazulur Rehaman
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Rebecca Mathew
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Lisa Mathew
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Kun Wang
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Li Liu
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Abdulrahman Salhab
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Oleksandr Soloviov
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Sara Tomei
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Waseem Hasan
- Zebrafish Functional Genomics Core, Research Department, Sidra Medicine, Doha, Qatar
| | - Sahar Da'as
- Zebrafish Functional Genomics Core, Research Department, Sidra Medicine, Doha, Qatar
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Yosra Bejaoui
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Nady El Hajj
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Karama Makni Maalej
- Translational Cancer Research Facility, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, Hamad Medical Corporation, Doha, Qatar
| | - Kakil Rasul
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Paolo Dellabona
- Experimental Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Hospital, Milan, Italy
| | - Giulia Casorati
- Experimental Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Hospital, Milan, Italy
| | - Alice Turdo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Giorgio Stassi
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Xinhui Wang
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina Maccalli
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar.
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Chavoshi H, Bornehdeli S, Asadi M, Dolatkhah R, Caner A, Raeisi M. microRNAs Regulate Survivin in Colorectal Cancer Patients. Adv Biomed Res 2023; 12:227. [PMID: 38073748 PMCID: PMC10699232 DOI: 10.4103/abr.abr_233_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 02/27/2023] [Accepted: 03/15/2023] [Indexed: 12/02/2024] Open
Abstract
BACKGROUND Impaired levels of surviving are associate with increased survival of tumor cells. In this study, we intended to profile the microRNAs (miRNAs) targeting survivin in the tumoral and marginal tissues obtained from Iranian patients with colorectal cancer (CRC). MATERIALS AND METHODS Fifty CRC patients of Iranian Azari ethnicity were recruited. The RNA content of the tumoral and marginal tissues was isolated and the transcript levels of miR-34a, miR-16, miR-150, and miR-203a and survivin were determined through quantitative Real-time PCR. RESULTS The mRNA expression of survivin was significantly increased (fold change = 3.21, P = 0.0029) in the tumoral tissues in comparison to the marginal tissues. There was significant downregulation of miR-16 (fold change = 0.28, P = 0.003) and miR-203a (fold change = 0.36, P = 0.014) in the tumoral samples in comparison to marginal samples. There was an inverse significant correlation (rho = -0.81; P < 0.001) between the expression of miR-203a and mRNA expression of survivin in the tumoral tissues of CRC patients. The mRNA expression of survivin was higher significantly in the tumoral tissues of CRC patients with lymph node metastasis in comparison to those without lymph node metastasis (P = 0.020). In addition, there was a significantly higher miR-203 expression level in the tumoral tissues of CRC patients with lymph node metastasis in comparison to those without lymph node metastasis (P = 0.011). CONCLUSION It is suggested that miR-203 plays an oncogenic role in CRC cancer by regulating survivin and lymph node metastasis.
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Affiliation(s)
- Hadi Chavoshi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soghra Bornehdeli
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Department of Basic Oncology of Health Institute of Ege University, Izmir, Turkey
| | - Roya Dolatkhah
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayse Caner
- Department of Basic Oncology of Health Institute of Ege University, Izmir, Turkey
| | - Mortaza Raeisi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Lipid Handling Protein Gene Expression in Colorectal Cancer: CD36 and Targeting miRNAs. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122127. [PMID: 36556492 PMCID: PMC9786157 DOI: 10.3390/life12122127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Abstract
The reprogramming of lipid metabolism has been highlighted in colorectal cancer (CRC) studies, suggesting a critical role for the scavenger receptor CD36 and fatty acid synthase (FASN) in this malignancy. In this study, we analyzed the gene expression levels of CD36, FASN, the cell surface glypican 4 (GPC4), and the two transporters SLC27A3 and SLC27A4 in 39 paired tumoral and peritumoral tissues from patients with CRC compared with 18 normal colonic mucosae. Moreover, the levels of seven miRNAs targeting CD36 and most of the analyzed genes were evaluated. We found a significant impairment of the expression of all the analyzed genes except GPC4 as well as the differential expression of miR-16-5p, miR-26b-5p, miR-107, miR-195-5p, and miR-27a-3p in the colonic mucosa of CRC patients. Interestingly, CD36 and miR-27a-3p were downregulated and upregulated, respectively, in tumoral tissues compared to peritumoral and control tissues, with a significant negative correlation in the group of patients developing lymph node metastasis. Our results sustain the relationship between CRC and fatty acid metabolism and emphasize the importance of related miRNAs in developing new therapeutic strategies.
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Volovat SR, Augustin I, Zob D, Boboc D, Amurariti F, Volovat C, Stefanescu C, Stolniceanu CR, Ciocoiu M, Dumitras EA, Danciu M, Apostol DGC, Drug V, Shurbaji SA, Coca LG, Leon F, Iftene A, Herghelegiu PC. Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI. Cancers (Basel) 2022; 14:4834. [PMID: 36230757 PMCID: PMC9562853 DOI: 10.3390/cancers14194834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota's composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.
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Affiliation(s)
- Simona-Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Iolanda Augustin
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Daniela Zob
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Florin Amurariti
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Constantin Volovat
- Department of Medical Oncology, “Euroclinic” Center of Oncology, 2 Vasile Conta Str., 700106 Iasi, Romania
| | - Cipriana Stefanescu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eduard Alexandru Dumitras
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Anesthesiology and Intensive Care, Regional Institute of Oncology, 700115 Iasi, Romania
| | - Mihai Danciu
- Pathology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | | | - Vasile Drug
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Sinziana Al Shurbaji
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Lucia-Georgiana Coca
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Florin Leon
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
| | - Adrian Iftene
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Paul-Corneliu Herghelegiu
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
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Dohmen J, Semaan A, Kobilay M, Zaleski M, Branchi V, Schlierf A, Hettwer K, Uhlig S, Hartmann G, Kalff JC, Matthaei H, Lingohr P, Holdenrieder S. Diagnostic Potential of Exosomal microRNAs in Colorectal Cancer. Diagnostics (Basel) 2022; 12:diagnostics12061413. [PMID: 35741223 PMCID: PMC9221658 DOI: 10.3390/diagnostics12061413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/01/2022] [Accepted: 05/27/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Despite the significance of colonoscopy for early diagnosis of colorectal adenocarcinoma (CRC), population-wide screening remains challenging, mainly because of low acceptance rates. Herein, exosomal (exo-miR) and free circulating microRNA (c-miR) may be used as liquid biopsies in CRC to identify individuals at risk. Direct comparison of both compartments has shown inconclusive results, which is why we directly compared a panel of 10 microRNAs in this entity. Methods: Exo-miR and c-miR levels were measured using real-time quantitative PCR after isolation from serum specimens in a cohort of 69 patients. Furthermore, results were compared to established tumor markers CEA and CA 19-9. Results: Direct comparison of exo- and c-miR biopsy results showed significantly higher microRNA levels in the exosomal compartment (p < 0.001). Exo-Let7, exo-miR-16 and exo-miR-23 significantly differed between CRC and healthy controls (all p < 0.05), while no c-miR showed this potential. Sensitivity and specificity can be further enhanced using combinations of multiple exosomal miRNAs. Conclusions: Exosomal microRNA should be considered as a promising biomarker in CRC for future studies. Nonetheless, results may show interference with common comorbidities, which must be taken into account in future studies.
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Affiliation(s)
- Jonas Dohmen
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Alexander Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Makbule Kobilay
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
| | - Martin Zaleski
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
| | - Vittorio Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Anja Schlierf
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Karina Hettwer
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Steffen Uhlig
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Gunther Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Jörg C. Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Hanno Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Stefan Holdenrieder
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
- Correspondence:
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Gurer T, Aytekin A, Caki E, Gezici S. miR-485-3p and miR-4728-5p as Tumor Suppressors in Pathogenesis of Colorectal Cancer. Mol Biol 2022. [DOI: 10.1134/s0026893322030062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Sanaei MJ, Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Shahrokh S, Zali MR, Bashash D. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles. J Cell Physiol 2021; 237:1720-1752. [PMID: 34897682 DOI: 10.1002/jcp.30655] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest human malignancies worldwide. Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K/Akt/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K/Akt/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K/Akt pathway-associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K/Akt/mTOR pathway inhibition whether by chemical-based drugs or by natural-based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life-threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Kudelova E, Holubekova V, Grendar M, Kolkova Z, Samec M, Vanova B, Mikolajcik P, Smolar M, Kudela E, Laca L, Lasabova Z. Circulating miRNA expression over the course of colorectal cancer treatment. Oncol Lett 2021; 23:18. [PMID: 34868358 PMCID: PMC8630815 DOI: 10.3892/ol.2021.13136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/20/2021] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer (CRC) is the third-most common cancer type in males and the second-most common cancer type in females, and has the second-highest overall mortality rate worldwide. Approximately 50% of patients in stage I–III develop metastases, mostly localized to the liver. All physiological conditions occurring in the organism are also reflected in the levels of circulating microRNAs (miRNAs/miRs) in patients. miRNAs are a class of small, non-coding, single-stranded RNAs consisting of 18–25 nucleotides, which have important roles in various cellular processes. The aim of the present study was to evaluate a panel of seven circulating miRNAs (miR-106a-5p, miR-210-5p, miR-155-5p, miR-21-5p, miR-103a-3p, miR-191-5p and miR-16-5p) as biomarkers for monitoring patients undergoing adjuvant treatment of CRC. Total RNA was extracted from the plasma of patients with CRC prior to surgery, in the early post-operative period (n=60) and 3 months after surgery (n=14). The levels of the selected circulating miRNAs were measured with the miRCURY LNA miRNA PCR system and fold changes were calculated using the standard ∆∆Cq method. DIANA-miRPath analysis was used to evaluate the role of significantly deregulated miRNAs. The results indicated significant upregulation of miR-155-5p, miR-21-5p and miR-191-5p, and downregulation of miR-16-5p directly after the surgery. In paired follow-up samples, the most significant upregulation was detected for miR-106a-5p and miR-16-5p, and the most significant downregulation was for miR-21-5p. Pathway analysis outlined the role of the differentially expressed miRNAs in cancer development, but the same pathways are also involved in wound healing and regeneration of intestinal epithelium. It may be suggested that these processes should also be considered in studies investigating sensitive and easily detectable circulating biomarkers for recurrence in patients.
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Affiliation(s)
- Eva Kudelova
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Veronika Holubekova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marian Grendar
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Zuzana Kolkova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marek Samec
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Barbora Vanova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Peter Mikolajcik
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marek Smolar
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Erik Kudela
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Ludovit Laca
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
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Huang Y, Zou Y, Xiong Q, Zhang C, Sayagués JM, Shelat VG, Wang X. Development of a novel necroptosis-associated miRNA risk signature to evaluate the prognosis of colon cancer patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1800. [PMID: 35071494 PMCID: PMC8756225 DOI: 10.21037/atm-21-6576] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Necroptosis is a recently discovered caspase-independent form of cell death which plays an important role in the occurrence and development of cancer. As an important regulatory factor in necroptosis, microRNAs (miRNAs) are important for the development of colon cancer. This study established a novel necroptosis-related miRNA risk signature to evaluate the prognosis of patients with colon adenocarcinoma (COAD). METHODS The necroptosis-related miRNAs were selected by assessing the differential expression of miRNAs in 459 COAD patient samples and 8 control samples from The Cancer Genome Atlas (TCGA). Selection operator Cox analyses and survival analyses were used to establish the risk signature of 7 miRNAs related to necroptosis. Functional enrichment analysis and nomograms were used to explore the potential effects of necroptosis-related miRNAs on prognosis and metastasis. The target genes of the necroptosis-related miRNAs were predicted using online databases and the genes related to overall survival (OS) were screened. RESULTS The risk signature was based on 7 necroptosis-related miRNAs. Nomograms showed that the risk signature was effective at predicting the prognosis and TNM stage of COAD patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that these miRNAs play an important role in cancer development, metastasis, and prognosis. A total of 38 target genes for these miRNAs were found to be associated with the OS in COAD patients. CONCLUSIONS This study provided novel evidence that necroptosis-related miRNAs are associated with the prognosis of COAD patients. A risk signature established based on these miRNAs could effectively predict the prognosis and metastasis of COAD in patients.
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Affiliation(s)
- Yang Huang
- General Surgery Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanyuan Zou
- General Surgery Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiru Xiong
- General Surgery Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chao Zhang
- General Surgery Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - José María Sayagués
- Servicio de Anatomía Patológica, Hospital Clínico Universitario de Salamanca e Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Salamanca, Spain
| | - Vishal G. Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Xingyu Wang
- Emergency Surgery Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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10
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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11
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Tumor Suppressor Protein p53 and Inhibitor of Apoptosis Proteins in Colorectal Cancer-A Promising Signaling Network for Therapeutic Interventions. Cancers (Basel) 2021; 13:cancers13040624. [PMID: 33557398 PMCID: PMC7916307 DOI: 10.3390/cancers13040624] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Tumor suppressor 53 (p53) is a multifunctional protein that regulates cell cycle, DNA repair, apoptosis and metabolic pathways. In colorectal cancer (CRC), mutations of the gene occur in 60% of patients and are associated with a more aggressive tumor phenotype and resistance to anti-cancer therapy. In addition, inhibitor of apoptosis (IAP) proteins are distinguished biomarkers overexpressed in CRC that impact on a diverse set of signaling pathways associated with the regulation of apoptosis/autophagy, cell migration, cell cycle and DNA damage response. As these mechanisms are further firmly controlled by p53, a transcriptional and post-translational regulation of IAPs by p53 is expected to occur in cancer cells. Here, we aim to review the molecular regulatory mechanisms between IAPs and p53 and discuss the therapeutic potential of targeting their interrelationship by multimodal treatment options. Abstract Despite recent advances in the treatment of colorectal cancer (CRC), patient’s individual response and clinical follow-up vary considerably with tumor intrinsic factors to contribute to an enhanced malignancy and therapy resistance. Among these markers, upregulation of members of the inhibitor of apoptosis protein (IAP) family effects on tumorigenesis and radiation- and chemo-resistance by multiple pathways, covering a hampered induction of apoptosis/autophagy, regulation of cell cycle progression and DNA damage response. These mechanisms are tightly controlled by the tumor suppressor p53 and thus transcriptional and post-translational regulation of IAPs by p53 is expected to occur in malignant cells. By this, cellular IAP1/2, X-linked IAP, Survivin, BRUCE and LIVIN expression/activity, as well as their intracellular localization is controlled by p53 in a direct or indirect manner via modulating a multitude of mechanisms. These cover, among others, transcriptional repression and the signal transducer and activator of transcription (STAT)3 pathway. In addition, p53 mutations contribute to deregulated IAP expression and resistance to therapy. This review aims at highlighting the mechanistic and clinical importance of IAP regulation by p53 in CRC and describing potential therapeutic strategies based on this interrelationship.
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12
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Imas JJ, Ruiz Zamarreño C, Zubiate P, Sanchez-Martín L, Campión J, Matías IR. Optical Biosensors for the Detection of Rheumatoid Arthritis (RA) Biomarkers: A Comprehensive Review. SENSORS (BASEL, SWITZERLAND) 2020; 20:E6289. [PMID: 33158306 PMCID: PMC7663853 DOI: 10.3390/s20216289] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/23/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022]
Abstract
A comprehensive review of optical biosensors for the detection of biomarkers associated with rheumatoid arthritis (RA) is presented here, including microRNAs (miRNAs), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), interleukin-6 (IL-6) and histidine, which are biomarkers that enable RA detection and/or monitoring. An overview of the different optical biosensors (based on fluorescence, plasmon resonances, interferometry, surface-enhanced Raman spectroscopy (SERS) among other optical techniques) used to detect these biomarkers is given, describing their performance and main characteristics (limit of detection (LOD) and dynamic range), as well as the connection between the respective biomarker and rheumatoid arthritis. It has been observed that the relationship between the corresponding biomarker and rheumatoid arthritis tends to be obviated most of the time when explaining the mechanism of the optical biosensor, which forces the researcher to look for further information about the biomarker. This review work attempts to establish a clear association between optical sensors and rheumatoid arthritis biomarkers as well as to be an easy-to-use tool for the researchers working in this field.
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Affiliation(s)
- José Javier Imas
- Electrical, Electronics and Communications Engineering Department, Public University of Navarra, 31006 Pamplona, Spain; (J.J.I.); (P.Z.); (I.R.M.)
- Institute of Smart Cities (ISC), Public University of Navarra, 31006 Pamplona, Spain
| | - Carlos Ruiz Zamarreño
- Electrical, Electronics and Communications Engineering Department, Public University of Navarra, 31006 Pamplona, Spain; (J.J.I.); (P.Z.); (I.R.M.)
- Institute of Smart Cities (ISC), Public University of Navarra, 31006 Pamplona, Spain
| | - Pablo Zubiate
- Electrical, Electronics and Communications Engineering Department, Public University of Navarra, 31006 Pamplona, Spain; (J.J.I.); (P.Z.); (I.R.M.)
| | | | - Javier Campión
- Making Genetics S.L., Plaza CEIN 5, 31110 Noáin, Spain; (L.S.-M.); (J.C.)
| | - Ignacio Raúl Matías
- Electrical, Electronics and Communications Engineering Department, Public University of Navarra, 31006 Pamplona, Spain; (J.J.I.); (P.Z.); (I.R.M.)
- Institute of Smart Cities (ISC), Public University of Navarra, 31006 Pamplona, Spain
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13
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Mehrgou A, Ebadollahi S, Seidi K, Ayoubi-Joshaghani MH, Ahmadieh Yazdi A, Zare P, Jaymand M, Jahanban-Esfahlan R. Roles of miRNAs in Colorectal Cancer: Therapeutic Implications and Clinical Opportunities. Adv Pharm Bull 2020; 11:233-247. [PMID: 33880345 PMCID: PMC8046386 DOI: 10.34172/apb.2021.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/03/2020] [Accepted: 07/26/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most disseminated diseases across the globe engaging the digestive system. Various therapeutic methods from traditional to the state-of-the-art ones have been applied in CRC patients, however, the attempts have been unfortunate to lead to a definite cure. MiRNAs are a smart group of non-coding RNAs having the capabilities of regulating and controlling coding genes. By utilizing this stock-in-trade biomolecules, not only disease’s symptoms can be eliminated, there may also be a good chance for the complete cure of the disease in the near future. Herein, we provide a comprehensive review delineating the therapeutic relationship between miRNAs and CRC. To this, various clinical aspects of miRNAs which act as a tumor suppressor and/or an oncogene, their underlying cellular processes and clinical outcomes, and, in particular, their effects and expression level changes in patients treated with chemo- and radiotherapy are discussed. Finally, based on the results deducted from scientific research studies, therapeutic opportunities based on targeting/utilizing miRNAs in the preclinical as well as clinical settings are highlighted.
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Affiliation(s)
- Amir Mehrgou
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Ebadollahi
- Department of Biochemistry and Biophysics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Khaled Seidi
- Biotechnology Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | - Mohammad Hosein Ayoubi-Joshaghani
- Drug Applied Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Student Research Committees, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | | | - Peyman Zare
- Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.,Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, 01-938 Warsaw, Poland
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Rana Jahanban-Esfahlan
- Stem Cell Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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14
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Association of the Expression Level of miR-16 with Prognosis of Solid Cancer Patients: A Meta-Analysis and Bioinformatic Analysis. DISEASE MARKERS 2020; 2020:8815270. [PMID: 32774515 PMCID: PMC7397416 DOI: 10.1155/2020/8815270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/19/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
Objective To assess the association between the expression level of miR-16 and prognosis of solid cancer patients by meta-analysis and bioinformatic analysis. Methods PubMed, Web of Science, and Embase databases were searched until October 31, 2019, to identify eligible studies reporting the association of the miR-16 status with the prognosis of solid cancer patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled, and a heterogeneity test was conducted. Sensitivity analysis and a publication bias test were also carried out. Furthermore, the miRpower database was used to validate the association. Results Thirteen articles with 2303 solid cancer patients were included in the meta-analysis. Solid cancer patients with low expression level of miR-16 had shorter survival time (I2 = 84.0%, HR = 1.47, 95% CI: 1.13-1.91, P = 0.004). In the subgroup analyses of cancer sites, low miR-16 expression level was associated with poor prognosis in the reproductive system cancers (I2 = 33.3%, HR = 1.24, 95% CI: 1.06-1.45, P = 0.008). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Begg's test and Egger's test revealed no publication bias in the meta-analysis. In bioinformatic analysis, the significant association between miR-16 level and prognosis of patients with reproductive system cancers was further confirmed (HR = 1.21, 95% CI: 1.03-1.42, P = 0.017). Conclusion Low expression level of miR-16 is an indicator for poor prognosis of solid cancer patients, particularly in reproductive system cancers.
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15
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Wang M, Su Z, Amoah Barnie P. Crosstalk among colon cancer-derived exosomes, fibroblast-derived exosomes, and macrophage phenotypes in colon cancer metastasis. Int Immunopharmacol 2020; 81:106298. [PMID: 32058925 DOI: 10.1016/j.intimp.2020.106298] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/13/2022]
Abstract
Cellular crosstalk is an important mechanism in the pathogenesis of inflammatory disorders and cancers. One significant means by which cells communicate with each other is through the release of exosomes. Exosomes are extracellular vesicles formed by the outward budding of plasma membranes, which are then released from cells into the extracellular space. Many studies have suggested that microvesicles released by colon cancer cells initiate crosstalk and modulate the fibroblast activities and macrophage phenotypes. Interestingly, crosstalk among colon cancer cells, macrophages and cancer-associated fibroblasts maximizes the mechanical composition of the stromal extracellular matrix (ECM). Exosomes contribute to cancer cell migration and invasion, which are critical for colon cancer progression to metastasis. The majority of the studies on colorectal cancers (CRCs) have focused on developing exosomal biomarkers for the early detection and prediction of CRC prognosis. This study highlights the crosstalk among colon cancer-derived exosomes, macrophage phenotypes and fibroblasts during colon cancer metastasis.
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Affiliation(s)
- Meiyun Wang
- Department of Nephrology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, PR China.
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang 212013, Jiangsu Province, PR China.
| | - Prince Amoah Barnie
- International Genome Center, Jiangsu University, Zhenjiang 212013, Jiangsu Province, PR China; Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana.
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16
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Lv Y, Duanmu J, Fu X, Li T, Jiang Q. Identifying a new microRNA signature as a prognostic biomarker in colon cancer. PLoS One 2020; 15:e0228575. [PMID: 32049961 PMCID: PMC7015317 DOI: 10.1371/journal.pone.0228575] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 01/17/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The aim was to identify a novel prognostic miRNA signature for colon cancer (CC) in silico. METHODS Data on the expression of miRNAs and relevant clinical information for 407 patients were obtained from The Cancer Genome Atlas (TCGA), and the samples were randomly split into a validation set (n = 203) and training set (n = 204). The differential expression of miRNAs between normal tissues and patients with CC was analyzed. We detected a miRNA expression signature in the training dataset by using a Cox proportional hazard regression model. Then, we verified the signature in the validation set. Association of the miRNA signature with overall survival was assessed in the validation cohort and combined cohort by log-rank test and based on Kaplan-Meier curves. The receiver operating characteristic and disease-free survival analyses were performed to evaluate the miRNA signature of CC in the combined cohort. Multivariate and univariate Cox analyses related to survival for the miRNA signature were performed, and a nomogram was built as a prognostic model for CC. To explore the function of target genes of the miRNA signature, Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used. RESULTS Between the matched normal tissues and colon cancer tissues, 267 differentially expressed miRNAs were detected, and a single-factor CoxPH model showed that 13 miRNAs were related to overall survival in the training cohort. Then, a five-miRNA signature was identified using a CoxPH regression model with multiple factors. The five-miRNA signature had significant prognostic value in the training cohort and was validated in the validation cohort and combined cohort. A total of 193 target genes of the miRNA signature were identified. According to the results of functional analysis of the target genes, the signaling pathways MAPK, AMPK and PI3K-Akt, focal adhesion, and microRNAs in cancer were remarkably enriched. CONCLUSION A five-miRNA signature had increased prognostic value for CC, which may provide important biological insights for the discovery and development of molecular predictors to improve the prognosis of patients with CC.
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Affiliation(s)
- Yunxia Lv
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Jinzhong Duanmu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Xiaorui Fu
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Taiyuan Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Qunguang Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
- * E-mail:
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17
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Farace C, Pisano A, Griñan-Lison C, Solinas G, Jiménez G, Serra M, Carrillo E, Scognamillo F, Attene F, Montella A, Marchal JA, Madeddu R. Deregulation of cancer-stem-cell-associated miRNAs in tissues and sera of colorectal cancer patients. Oncotarget 2020; 11:116-130. [PMID: 32010426 PMCID: PMC6968784 DOI: 10.18632/oncotarget.27411] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is a deadly tumour in Western countries characterized by high cellular/molecular heterogeneity. Cancer stem cells (CSC) act in cancer recurrence, drug-resistance and in metastatic epithelial-to-mesenchymal transition. microRNAs (miRNAs) contribute to cancer is increasing, and miRNA roles in CSC phenotype and fate and their utility as CRC biomarkers have also been reported. Here, we investigated miR-21, miR-221, miR-18a, miR-210, miR-31, miR-34a, miR-10b and miR-16 expression in experimental ALDH+ and CD44+/CD326+ colorectal CSCs obtained from the human CRC cell lines HCT-116, HT-29 and T-84. Then, we moved our analysis in cancer tissue (CT), healthy tissue (HT) and serum (S) of adult CRC patients (n=12), determining relationships with clinical parameters (age, sex, metastasis, biochemical serum markers). Specific miRNA patterns were evident in vitro (normal, monolayers and CSCs) and in patients’ samples stratified by TNM stage (LOW vs HIGH) or metastasis (Met vs no-Met). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the CSCs phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in CT ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of LOW/HIGH grade and no-Met patients. Our results identify miRNAs useful as colorectal CSC biomarker and that miR-21, miR-210, miR-10b and miR-31b are promising markers of CRC. A specific role of miR-18a as metastatic CRC serum biomarker in adult patients was also highlighted.
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Affiliation(s)
- Cristiano Farace
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,National Institute of Biostructures and Biosystems, Rome, Italy
| | - Andrea Pisano
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Carmen Griñan-Lison
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain
| | - Giuliana Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Gema Jiménez
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Bio-Health Research Foundation of Eastern Andalusia - Alejandro Otero (FIBAO), Granada, Spain
| | - Marina Serra
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Esmeralda Carrillo
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | | | - Federico Attene
- O.U. of Surgery I (Surgical Pathology), A.O.U. Sassari, Sassari, Italy
| | - Andrea Montella
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Roberto Madeddu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,National Institute of Biostructures and Biosystems, Rome, Italy
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18
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Sabit H, Cevik E, Tombuloglu H. Colorectal cancer: The epigenetic role of microbiome. World J Clin Cases 2019; 7:3683-3697. [PMID: 31799293 PMCID: PMC6887622 DOI: 10.12998/wjcc.v7.i22.3683] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 10/23/2019] [Accepted: 10/30/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men (746000 cases per year) and the second most common cancer in women globally (614000 cases per year). The incidence rate of CRC in developed countries (737000 cases per year) is higher than that in less developed countries (624000 cases per year). CRC can arise from genetic causes such as chromosomal instability and microsatellite instability. Several etiologic factors underlie CRC including age, diet, and lifestyle. Gut microbiota represent a proven cause of the disease, where they play pivotal roles in modulating and reshaping the host epigenome. Several active microbial metabolites have been found to drive carcinogenesis, invasion, and metastasis via modifying both the methylation landscape along with histone structure in intestinal cells. Gut microbiota, in response to diet, can exert both beneficial and harmful functions in humans, according to the intestinal balance of number and types of these bacteria. Although the intestinal microbial community is diverse among individuals, these microbes cumulatively produce 100-fold more proteins than the human genome itself, which calls for further studies to elaborate on the complicated interaction between these microorganisms and intestinal cells. Therefore, understanding the exact role that gut microbiota play in inducing CRC will help attain reliable strategies to precisely diagnose and treat this fatal disease.
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Affiliation(s)
- Hussein Sabit
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Emre Cevik
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Huseyin Tombuloglu
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
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19
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Hossian AKMN, Mackenzie GG, Mattheolabakis G. miRNAs in gastrointestinal diseases: can we effectively deliver RNA-based therapeutics orally? Nanomedicine (Lond) 2019; 14:2873-2889. [PMID: 31735124 DOI: 10.2217/nnm-2019-0180] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nucleic acid-based therapeutics are evaluated for their potential of treating a plethora of diseases, including cancer and inflammation. Short nucleic acids, such as miRNAs, have emerged as versatile regulators for gene expression and are studied for therapeutic purposes. However, their inherent instability in vivo following enteral and parenteral administration has prompted the development of novel methodologies for their delivery. Although research on the oral delivery of siRNAs is progressing, with the development and utilization of promising carrier-based methodologies for the treatment of a plethora of gastrointestinal diseases, research on miRNA-based oral therapeutics is lagging behind. In this review, we present the potential role of miRNAs in diseases of the GI tract, and analyze current research and the cardinal features of the novel carrier systems used for nucleic acid oral delivery that can be expanded for oral miRNA administration.
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Affiliation(s)
- A K M Nawshad Hossian
- School of Basic Pharmaceutical & Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
| | | | - George Mattheolabakis
- School of Basic Pharmaceutical & Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
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20
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Tian YQ, Fan ZJ, Liu S, Wu YJ, Liu SY. Value of microRNAs in diagnosis and prognosis of colorectal cancer. Shijie Huaren Xiaohua Zazhi 2019; 27:1278-1284. [DOI: 10.11569/wcjd.v27.i20.1278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Some new treatment methods have been explored to delay the recurrence of colorectal cancer (CRC). Early diagnosis plays an important role in the improvement of curative effect. The conventional methods used to diagnose and monitor CRC are fecal occult blood test (FOBT) and colonoscopy. However, FOBT has an unsatisfactory sensitivity, while colonoscopy is expensive and invasive. As new biomarkers, microRNAs, which can be detected in CRC tissues, cells, and body fluid as tumor suppressors or oncogenes, can be used in early diagnosis, the monitoring of metastasis and treatment, as well prognostic evaluation of CRC. This article reviews the diagnostic and prognostic value of microRNAs in CRC.
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Affiliation(s)
- Ya-Qiong Tian
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Zhi-Juan Fan
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Shuang Liu
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Yu-Jing Wu
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Shu-Ye Liu
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
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21
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Manoel-Caetano FS, Rossi AFT, Calvet de Morais G, Severino FE, Silva AE. Upregulation of the APE1 and H2AX genes and miRNAs involved in DNA damage response and repair in gastric cancer. Genes Dis 2019; 6:176-184. [PMID: 31194025 PMCID: PMC6545450 DOI: 10.1016/j.gendis.2019.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 03/28/2019] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer remains one of the leading causes of cancer-related death worldwide, and most of the cases are associated with Helicobacter pylori infection. This bacterium promotes the production of reactive oxygen species (ROS), which cause DNA damage in gastric epithelial cells. In this study, we evaluated the expression of important genes involved in the recognition of DNA damage (ATM, ATR, and H2AX) and ROS-induced damage repair (APE1) and the expression of some miRNAs (miR-15a, miR-21, miR-24, miR-421 and miR-605) that target genes involved in the DNA damage response (DDR) in 31 fresh tissues of gastric cancer. Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network. Analysis performed by real-time quantitative PCR exhibited significantly increased levels of the APE1 (RQ = 2.55, p < 0.0001) and H2AX (RQ = 2.88, p = 0.0002) genes beyond the miR-421 and miR-605 in the gastric cancer samples. In addition, significantly elevated levels of miR-21, miR-24 and miR-421 were observed in diffuse-type gastric cancer. Correlation analysis reinforced some of the gene:gene (ATM/ATR/H2AX) and miRNA:mRNA relationships obtained also with the interaction network. Thus, our findings show that tumor cells from gastric cancer presents deregulation of genes and miRNAs that participate in the recognition and repair of DNA damage, which could confer an advantage to cell survival and proliferation in the tumor microenvironment.
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Affiliation(s)
- Fernanda S Manoel-Caetano
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
| | - Ana Flávia T Rossi
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
| | - Gabriela Calvet de Morais
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
| | - Fábio Eduardo Severino
- Department of Surgery and Orthopedics, Faculty of Medicine, UNESP, São Paulo State University, Campus of Botucatu, Av. Prof. Mário Rubens Guimarães Montenegro, s/n, 18.618-687, Botucatu, São Paulo, Brazil
| | - Ana Elizabete Silva
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
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22
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Prognostic Value of MicroRNA-15a in Human Cancers: A Meta-Analysis and Bioinformatics. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2063823. [PMID: 31061821 PMCID: PMC6466945 DOI: 10.1155/2019/2063823] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
Abstract
Background Although several studies have proved the relationship between the prognostic value of miRNA-15a and different types of cancer, the result remains controversial. Thus, a meta-analysis was conducted to clarify the prognostic value of miRNA-15a expression level in human cancers. Methods We enrolled appropriate literature by searching the databases of PubMed, Embase, and Web of Science. Subsequently, we extracted HRs and their 95% CIs and calculated pooled results of miRNA-15a for overall survival (OS) and disease-free survival (DFS). Besides, subgroup analysis, sensitivity analysis, and publication bias were also revealed in this study. We also further validated this meta-analysis using the Kaplan-Meier plotter database. Result 10 studies, including 1616 patients, were embraced in our meta-analysis. The result showed the lower expression of miRNA-15a significantly predicted adverse OS (HR=2.17, 95% CI: 1.41-3.34), but there is no significant association between the expressing level and DFS in cancer patient (HR=2.04, 95% CI: 0.60-6.88). Based on Kaplan-Meier plotter database, we found the same results in bladder Carcinoma, head-neck squamous cell carcinoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, pancreatic ductal adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma, but opposite results were found in cervical squamous cell carcinoma and esophageal carcinoma. Conclusion Low expressing levels of miRNA-15a indicated poor OS, while miRNA-15a can be used as a prediction biomarker in different cancer types.
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23
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Madadi S, Soleimani M. Comparison of miR-16 and cel-miR-39 as reference controls for serum miRNA normalization in colorectal cancer. J Cell Biochem 2019; 120:4802-4803. [PMID: 30609138 DOI: 10.1002/jcb.28174] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Soheil Madadi
- Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Meysam Soleimani
- Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
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Gopalan V, Ebrahimi F, Islam F, Vider J, Qallandar OB, Pillai S, Lu CT, Lam AKY. Tumour suppressor properties of miR-15a and its regulatory effects on BCL2 and SOX2 proteins in colorectal carcinomas. Exp Cell Res 2018; 370:245-253. [PMID: 29958837 DOI: 10.1016/j.yexcr.2018.06.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 06/21/2018] [Accepted: 06/23/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVES In this study, we aimed to investigate the expression pattern, clinicopathological significance and tumour suppressive properties of miR-15a in patients with colorectal carcinomas. METHODS Tissue samples from 87 patients with primary colorectal carcinomas, 50 matched metastatic lymph node and 37 non-neoplastic colon (control) were prospectively recruited. The expression level of miR-15a was measured by quantitative real-time polymerase chain reaction. Restoration/overexpression of the miR-15a was achieved by exogenous transfection. Four colon cancer cell lines (SW480, CaCO2, SW48 and HCT116) and a non-cancer colon cell line (FHC) were also used for examining the miR-15a induced tumour suppression properties using various in-vitro and immunological assays. RESULTS Downregulation of miR-15a was noted in ~ 62% of the colorectal carcinoma tissues and it was positively correlated with the presence of cancer recurrence in patients with colorectal carcinomas (p = 0.05). Also, these patients with low miR-15a expression showed relatively shorter survival time when compared to those with miR-15a overexpression. Following miR-15a exogenous overexpression, colon cancer cells showed reduced cell proliferation, low colony formation, less cell invasion properties and mitochondrial respiration when compared to control cells. In addition, BCL2 and SOX2 proteins showed a significant downregulation following miR-15a overexpression suggesting its regulatory role in cancer growth, apoptosis and stemness. CONCLUSION This study has confirmed the tumour suppressor properties of miR-15a in colorectal cancers. Therefore, its modulation has potential implications in controlling various biological and pathogenic processes in colon carcinogenesis via targeting its downstream proteins such as BCL2 and SOX2.
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Affiliation(s)
- Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia; School of Medical Science, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.
| | - Faeza Ebrahimi
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Farhadul Islam
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia; Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Jelena Vider
- School of Medical Science, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Omel Baneen Qallandar
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Suja Pillai
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia; Faculty of Medicine, School of Biomedical Science, University of Queensland, Queensland, Australia
| | - Cu-Tai Lu
- Department of Surgery, Gold Coast Hospital, Gold Coast, Queensland, Australia
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.
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25
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Hasáková K, Bezakova J, Vician M, Reis R, Zeman M, Herichova I. Gender-dependent expression of leading and passenger strand of miR-21 and miR-16 in human colorectal cancer and adjacent colonic tissues. Physiol Res 2018; 66:S575-S582. [PMID: 29355387 DOI: 10.33549/physiolres.933808] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
miRNAs are small regulatory RNA molecules involved in posttranscriptional gene silencing. Their biosynthesis results in the formation of duplex consisting of a leading and a passenger strand of mature miRNA. The leading strand exhibits the main activity but recent findings indicate a certain role of the passenger strand as well. Deregulated levels of miRNA were found in many types of cancers including colorectal cancer. miR-21 and miR-16 were indicated as possible markers of colorectal cancer, however, small attention to gender differences in their expression was paid so far. Therefore, the aim of our study was to investigate the expression of miR-21-5p, miR-21-3p, miR-16-5p and miR-16-3p in human colorectal cancer tissue and compare it to the adjacent tissues taken during surgery in men and women separately. Our results showed an up-regulation of all measured miRNAs in tumor tissue compared to adjacent tissues. As expected, tumors and adjacent tissues exhibited a significantly higher expression of leading miRNAs compared to passenger strand of miR-21 and miR-16. The expression of leading and passenger strand of miR-21 and miR-16 positively correlated exhibiting the highest correlation coefficient in the distal tissue. The expression pattern showed gender-dependent differences, with higher levels of miRNA in men than in women. Our findings indicate a gender-related expression pattern of miRNA, which should be considered as an important factor in generating new prognostic or diagnostic biomarkers.
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Affiliation(s)
- K Hasáková
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, Slovak Republic.
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To KKW, Tong CWS, Wu M, Cho WCS. MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside. World J Gastroenterol 2018; 24:2949-2973. [PMID: 30038463 PMCID: PMC6054943 DOI: 10.3748/wjg.v24.i27.2949] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/28/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that can post-transcriptionally regulate the expression of various oncogenes and tumor suppressor genes. Dysregulated expression of many miRNAs have been shown to mediate the signaling pathways critical in the multistep carcinogenesis of colorectal cancer (CRC). MiRNAs are stable and protected from RNase-mediated degradation, thereby enabling its detection in biological fluids and archival tissues for biomarker studies. This review focuses on the role and application of miRNAs in the prognosis and therapy of CRC. While stage II CRC is potentially curable by surgical resection, a significant percentage of stage II CRC patients do develop recurrence. MiRNA biomarkers may be used to stratify such high-risk population for adjuvant chemotherapy to provide better prognoses. Growing evidence also suggests that miRNAs are involved in the metastatic process of CRC. Certain of these miRNAs may thus be used as prognostic biomarkers to identify patients more likely to have micro-metastasis, who could be monitored more closely after surgery and/or given more aggressive adjuvant chemotherapy. Intrinsic and acquired resistance to chemotherapy severely hinders successful chemotherapy in CRC treatment. Predictive miRNA biomarkers for response to chemotherapy may identify patients who will benefit the most from a particular regimen and also spare the patients from unnecessary side effects. Selection of patients to receive the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Lastly, forced expression of tumor suppressor miRNA or silencing of oncogenic miRNA in tumors by gene therapy can also be adopted to treat CRC alone or in combination with other chemotherapeutic drugs.
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Affiliation(s)
- Kenneth KW To
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Christy WS Tong
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Mingxia Wu
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - William CS Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
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27
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Long Noncoding RNAs in Colorectal Adenocarcinoma; an in silico Analysis. Pathol Oncol Res 2018; 25:1387-1394. [PMID: 29948619 DOI: 10.1007/s12253-018-0428-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 05/28/2018] [Indexed: 12/20/2022]
Abstract
Long noncoding RNAs (lncRNAs) are lengthy noncoding transcripts which are involved in critical signaling pathways including cell cycle and apoptosis so it is not surprising to see their altered expression in human tumors. Colorectal adenocarcinoma is one the most frequent malignancies worldwide. The role of lncRNAs in colorectal adenocarcinoma is not well understood. To study the significance of lncRNAs in colorectal adenocarcinoma, we retrieved 189 approved lncRNAs from HGNC. The genes were imported into the cBioPortal database for transcriptomic analyses. We queried all the samples from TCGA provisional colorectal adenocarcinoma with RNA-seq v2 data in our study and considered RNA dysregulation with Z-score: ±2. The lncRNA which was altered in most of the patients were considered as "significant lncRNA" for further analyses. We considered the association of candidate lncRNAs with clinicopathologic parameters of samples including tumor disease anatomic site, neoplasm histologic types, tumor stage and survival. We also compute the specificity of the significant lncRNAs expression in colorectal adenocarcinoma comparing with other human cancers in cancer portal. Our analysis showed that lncRNAs SNHG6, PVT1 and ZFAS1 allocated the maximum alteration among the colorectal cases. The expression of SNHG6 and ZFAS1 was more in rectal adenocarcinoma than the colon carcinoma while the PVT1 showed the same expression levels in both tissues. However, we found that upregulation of PVT1 has been reduced the overall survival in patients. Altogether these data showed SNHG6, PVT1 and ZFAS1, are promising candidates for experimental research on colorectal adenocarcinoma to discover novel biomarker for this prevalent cancer.
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28
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Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of microRNAs in colorectal cancer: a meta-analysis. Cancer Manag Res 2018; 10:907-929. [PMID: 29750053 PMCID: PMC5935085 DOI: 10.2147/cmar.s157493] [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] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have shown that miRNA levels are closely related to the survival time of patients with colon, rectal, or colorectal cancer (CRC). However, the outcomes of different investigations have been inconsistent. Accordingly, a meta-analysis was conducted to study associations among the three types of cancers. Materials and methods Studies published in English that estimated the expression levels of miRNAs with survival curves in CRC were identified until May 20, 2017 by online searches in PubMed, Embase, Web of Science, and the Cochrane Library by two independent authors. Pooled HRs with 95% CIs were used to estimate the correlation between miRNA expression and overall survival. Results A total of 63 relevant articles regarding 13 different miRNAs, with 10,254 patients were ultimately included. CRC patients with high expression of blood miR141 (HR 2.52, 95% CI 1.68-3.77), tissue miR21 (HR 1.31, 95% CI 1.12-1.53), miR181a (HR 1.52, 95% CI 1.26-1.83), or miR224 (HR 2.12, 95% CI 1.04-4.34), or low expression of tissue miR126 (HR 1.55, 95% CI 1.24-1.93) had significantly poor overall survival (P<0.05). Conclusion In general, blood miR141 and tissue miR21, miR181a, miR224, and miR126 had significant prognostic value. Among these, blood miR141 and tissue miR224 were strong biomarkers of prognosis for CRC.
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Affiliation(s)
- Song Gao
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Zhi-Ying Zhao
- School of Computer Science and Engineering, Northeastern University, Shenyang
| | - Rong Wu
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Yue Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen-Yong Zhang
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
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miR-15a-5p, A Novel Prognostic Biomarker, Predicting Recurrent Colorectal Adenocarcinoma. Mol Diagn Ther 2018; 21:453-464. [PMID: 28405803 DOI: 10.1007/s40291-017-0270-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Colorectal cancer is one of the most common gastrointestinal diseases and the second leading cause of cancer-associated deaths among adults. miR-15a-5p is a post-transcriptional regulator of the proto-oncogene MYB, a transcription factor essential for prolonged cancer cell proliferation and survival. In the current study, we assessed the potential diagnostic and prognostic utility of miR-15a-5p expression in colorectal adenocarcinoma. METHODS To accomplish this goal, total RNA was extracted from 182 colorectal adenocarcinoma specimens and 86 non-cancerous colorectal mucosae. After polyadenylation by poly(A) polymerase and subsequent reverse transcription with an oligo-dT adapter primer, miR-15a-5p expression was analyzed using an in-house developed reverse transcription quantitative real-time PCR method, based on SYBR Green chemistry. SNORD43 (RNU43) was used as an internal control gene. RESULTS miR-15a-5p was significantly upregulated in colorectal tumors compared to non-cancerous colorectal mucosae, while ROC analysis suggested its potential use for diagnostic purposes. Moreover, miR-15a-5p overexpression predicts poor disease-free survival (DFS) and overall survival (OS). Multivariate Cox regression analysis confirmed that miR-15a-5p overexpression is a significant unfavorable prognosticator of DFS in colorectal adenocarcinoma, independent of other established prognostic factors plus treatment of patients. Importantly, miR-15a-5p overexpression retains its unfavorable prognostic value in patients with T3 colorectal adenocarcinoma and in those without distant metastasis (M0). More importantly, the cumulative DFS probability of patients with early stage disease was significantly lower for those with colorectal adenocarcinoma overexpressing miR-15a-5p. DISCUSSION In conclusion, elevated expression of the cancer-associated miR-15a-5p predicts poor DFS and OS of colorectal adenocarcinoma patients. The prognostic value of miR-15a-5p expression regarding DFS is independent of clinicopathological factors currently used for colorectal adenocarcinoma prognosis.
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30
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Ultimo S, Martelli AM, Zauli G, Vitale M, Calin GA, Neri LM. Roles and clinical implications of microRNAs in acute lymphoblastic leukemia. J Cell Physiol 2018; 233:5642-5654. [DOI: 10.1002/jcp.26290] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 11/14/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Simona Ultimo
- Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
| | - Alberto M. Martelli
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBolognaItaly
| | - Giorgio Zauli
- Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
| | - Marco Vitale
- Department of Medicine and Surgery, Sport and Exercise Medicine Centre (SEM)University of ParmaParmaItaly
- CoreLabHospital‐University of ParmaParmaItaly
| | - George A. Calin
- Departments of Experimental Therapeutics and LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonTexas
- Center for RNA Interference and Non‐Coding RNAsThe University of Texas MD Anderson Cancer CenterHoustonTexas
| | - Luca M. Neri
- Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
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31
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Wu C, Zheng X, Li X, Fesler A, Hu W, Chen L, Xu B, Wang Q, Tong A, Burke S, Ju J, Jiang J. Reduction of gastric cancer proliferation and invasion by miR-15a mediated suppression of Bmi-1 translation. Oncotarget 2018; 7:14522-36. [PMID: 26894855 PMCID: PMC4924733 DOI: 10.18632/oncotarget.7392] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 01/12/2016] [Indexed: 12/14/2022] Open
Abstract
B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays important roles in gastric cancer, but the epigenetic regulatory mechanism by microRNA (miRNA) and the functional significance of Bmi-1 inhibition in gastric cancer remains elusive. In this study, we systematically investigated the functional roles of miRNA mediated Bmi-1 suppression in gastric cancer. Our results show that the expression of miR-15a is significantly reduced in gastric cancer and the protein expression levels of Bmi-1 are inversely correlated with miR-15a (P = 0.034) in gastric cancer patient samples. Functional studies revealed that ectopic expression of miR-15a decreased Bmi-1 in gastric cancer cell lines with reduced proliferation and tumor invasion. High levels of Bmi-1 in gastric cancer patients are significantly associated with better overall survival (P = 0.024) based on the Kaplan-Meier survival analysis.
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Affiliation(s)
- Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Xiao Zheng
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.,Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.,Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Andrew Fesler
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Lujun Chen
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Bin Xu
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | - Qi Wang
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
| | | | - Stephanie Burke
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Jingfang Ju
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Jingting Jiang
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
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32
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Strubberg AM, Madison BB. MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications. Dis Model Mech 2017; 10:197-214. [PMID: 28250048 PMCID: PMC5374322 DOI: 10.1242/dmm.027441] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are small single-stranded RNAs that repress mRNA translation
and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present
in the human genome, ∼250 miRNAs are reported to have changes in
abundance or altered functions in colorectal cancer. Thousands of studies have
documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported
to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their
frequent participation in feedback loops, which probably serve to reinforce or
magnify biological outcomes to manifest a particular cellular phenotype. Here,
we review the roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRNAs
(anti-oncomiRs) and miRNA regulators in colorectal cancer. Given their stability
in patient-derived samples and ease of detection with standard and novel
techniques, we also discuss the potential use of miRNAs as biomarkers in the
diagnosis of colorectal cancer and as prognostic indicators of this disease.
MiRNAs also represent attractive candidates for targeted therapies because their
function can be manipulated through the use of synthetic antagonists and miRNA
mimics. Summary: This Review provides an overview of some important
microRNAs and their roles in colorectal cancer.
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Affiliation(s)
- Ashlee M Strubberg
- Division of Gastroenterology, Washington University School of Medicine, Washington University, Saint Louis, MO 63110, USA
| | - Blair B Madison
- Division of Gastroenterology, Washington University School of Medicine, Washington University, Saint Louis, MO 63110, USA
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Masuda T, Hayashi N, Kuroda Y, Ito S, Eguchi H, Mimori K. MicroRNAs as Biomarkers in Colorectal Cancer. Cancers (Basel) 2017; 9:cancers9090124. [PMID: 28902152 PMCID: PMC5615339 DOI: 10.3390/cancers9090124] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/01/2017] [Accepted: 09/10/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRs) are small RNAs that repress mRNA translation, resulting in the degradation of mRNAs and regulation of the expression levels of various genes. Recent studies have shown that aberrant miR expression has a functional role in the initiation and progression of various malignancies, including colorectal cancer (CRC), which is one of the leading causes of cancer-related death worldwide. miRs have also been shown to have applications as diagnostic, prognostic, and predictive biomarkers because of their high tissue specificity, stability, and altered expression in tumor development. In this report, we examined the role of miRs as biomarkers in CRC through a review of meta-analyses and large-scale analyses having strong statistical confidence in the study outcomes. We also discuss current issues in the clinical application of these miRs.
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Affiliation(s)
- Takaaki Masuda
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Naoki Hayashi
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Yosuke Kuroda
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Shuhei Ito
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Hidetoshi Eguchi
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
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Hu F, Xu J, Chen Y. Surface Plasmon Resonance Imaging Detection of Sub-femtomolar MicroRNA. Anal Chem 2017; 89:10071-10077. [DOI: 10.1021/acs.analchem.7b02838] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Feichi Hu
- Key Laboratory of Analytical Chemistry for Living Biosystems; CAS
Research/Education Center for Excellence in Molecular Sciences; Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiying Xu
- Key Laboratory of Analytical Chemistry for Living Biosystems; CAS
Research/Education Center for Excellence in Molecular Sciences; Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Yi Chen
- Key Laboratory of Analytical Chemistry for Living Biosystems; CAS
Research/Education Center for Excellence in Molecular Sciences; Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Beijing National Laboratory for Molecular Science, Beijing 100190, China
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Reference miRNAs for colorectal cancer: analysis and verification of current data. Sci Rep 2017; 7:8413. [PMID: 28827728 PMCID: PMC5567181 DOI: 10.1038/s41598-017-08784-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 07/13/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) hold great promise in cancer research. The use of appropriate reference miRNAs for normalization of qPCR data is crucial for accurate expression analysis. We present here analysis and verification of current data, proposing a workflow strategy for identification of reference miRNAs in colorectal cancer (CRC). We performed a systematic review of studies aimed to identify stable reference miRNAs in CRC through high-throughput screening. Among the candidate miRNAs selected from the literature we excluded those predicted to target oncogenes or tumor suppressor gene. We then assessed the expression levels of the remaining candidates in exosomes, plasma and tissue samples from CRC patients and healthy controls. The expression stability was evaluated by box-plot, ∆Cq analysis, NormFinder and BestKeeper statistical algorithms. The effects of normalisers on the relative quantification of the oncogenic miR-1290 was also assessed. Our results consistently showed that different combinations of miR-520d, miR-1228 and miR-345 provided the most stably expressed reference miRNAs in the three biological matrices. We identified suitable reference miRNAs for future miRNA expression studies in exosomes plasma and tissues CRC samples. We also provided a novel conceptual framework that overcome the need of performing ex novo identification of suitable reference genes in single experimental systems.
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Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:183-204. [PMID: 27573901 DOI: 10.1007/978-3-319-42059-2_10] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC.
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Li J, Li M, Gao F, Ge X. Serum microRNA-15a level acts as a potential diagnostic and prognostic biomarker for human esophageal squamous cell carcinoma. Cancer Biomark 2017; 18:11-17. [PMID: 27802201 DOI: 10.3233/cbm-160667] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical significance of microRNA (miR)-15a in human esophageal squamous cell carcinoma (ESCC) remains unclear. OBJECTIVE To evaluate the expression level of miR-15a and to determine its potential for diagnosis and prognosis in ESCC. METHODS Quantitative reverse transcription polymerase chain reaction was performed to examine the expression levels of miR-15a in ESCC tissues and patients' sera. The diagnostic and prognostic implications of serum miR-15a level in human ESCC were further evaluated. RESULTS Expression levels of miR-15a in ESCC tissues and patients' sera were significantly decreased (both P< 0.001). Additionally, serum miR-15a had an optimal diagnostic cut-off point (2.29) for ESCC with sensitivity of 86.36% and specificity of 100.00%. Moreover, low serum miR-15a level more frequently occurred in ESCC patients with advanced tumor-node-metastasis, T and N stages (all P= 0.01) and poor tumor differentiation (P= 0.03). The Kaplan-Meier curve showed that low miR-15a expression was significantly associated with shorter overall survival (OS) and disease-free survival (DFS) of ESCC patients (both P< 0.001). Further multivariate analysis identified miR-15a as an independent prognostic factor for both OS and DFS (both P= 0.01). CONCLUSION Decreased expression of miR-15a may play a crucial role in ESCC development and progression. Serum miR-15a level could be used as a potential diagnostic and prognostic marker in clinics.
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Affiliation(s)
- Jialin Li
- Department of Radiology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Radiology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ming Li
- Department of Radiology, Huadong Hospital Affliated to Fudan University, Shanghai, China.,Department of Radiology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feng Gao
- Department of Radiology, Huadong Hospital Affliated to Fudan University, Shanghai, China
| | - Xiaojun Ge
- Department of Radiology, Huadong Hospital Affliated to Fudan University, Shanghai, China
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Masè M, Grasso M, Avogaro L, D’Amato E, Tessarolo F, Graffigna A, Denti MA, Ravelli F. Selection of reference genes is critical for miRNA expression analysis in human cardiac tissue. A focus on atrial fibrillation. Sci Rep 2017; 7:41127. [PMID: 28117343 PMCID: PMC5259703 DOI: 10.1038/srep41127] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 12/15/2016] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) are emerging as key regulators of complex biological processes in several cardiovascular diseases, including atrial fibrillation (AF). Reverse transcription-quantitative polymerase chain reaction is a powerful technique to quantitatively assess miRNA expression profile, but reliable results depend on proper data normalization by suitable reference genes. Despite the increasing number of studies assessing miRNAs in cardiac disease, no consensus on the best reference genes has been reached. This work aims to assess reference genes stability in human cardiac tissue with a focus on AF investigation. We evaluated the stability of five reference genes (U6, SNORD48, SNORD44, miR-16, and 5S) in atrial tissue samples from eighteen cardiac-surgery patients in sinus rhythm and AF. Stability was quantified by combining BestKeeper, delta-Cq, GeNorm, and NormFinder statistical tools. All methods assessed SNORD48 as the best and U6 as the worst reference gene. Applications of different normalization strategies significantly impacted miRNA expression profiles in the study population. Our results point out the necessity of a consensus on data normalization in AF studies to avoid the emergence of divergent biological conclusions.
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Affiliation(s)
- Michela Masè
- Department of Physics, University of Trento, Trento, Italy
| | | | - Laura Avogaro
- Department of Physics, University of Trento, Trento, Italy
- Centre for Integrative Biology, University of Trento, Trento, Italy
| | - Elvira D’Amato
- Department of Physics, University of Trento, Trento, Italy
| | - Francesco Tessarolo
- Healthcare Research and Innovation Program (IRCS-PAT), Bruno Kessler Foundation, Trento, Italy
- Department of Industrial Engineering, University of Trento, Trento, Italy
| | - Angelo Graffigna
- Division of Cardiac Surgery, Santa Chiara Hospital, Trento, Italy
| | | | - Flavia Ravelli
- Department of Physics, University of Trento, Trento, Italy
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Jin L, Li Y, He T, Hu J, Liu J, Chen M, Zhang Z, Gui Y, Mao X, Yang S, Lai Y. miR‑15a‑5p acts as an oncogene in renal cell carcinoma. Mol Med Rep 2017; 15:1379-1386. [PMID: 28098906 DOI: 10.3892/mmr.2017.6121] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 10/07/2016] [Indexed: 11/06/2022] Open
Abstract
miRNAs have been reported to be involved in multiple cellular processes and the tumorigenesis of various cancers. miR‑15a‑5p (also termed miR‑15a) has previously been determined to be upregulated in renal cell carcinoma (RCC) by microarray profile. However, the expression and function of miR‑15a‑5p in RCC remain to be validated. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to detect the expression levels of miR‑15a‑5p in RCC tissues and cells. The expression level of miR‑15a‑5p was upregulated or downregulated by transfecting synthesized miR‑15a‑5p mimics or inhibitors. The MTT assay, CCK‑8 assay, Transwell assay, wound healing assay, Hoechest 33342 staining and flow cytometry were conducted to investigate the role of miR‑15a‑5p in RCC. The results of the RT‑qPCR demonstrated that miR‑15a‑5p was upregulated in RCC tissues and ACHN, 786‑O and 769P RCC cells compared with paired normal tissues and HEK‑293T cells. miR‑15a‑5p was observed to be associated with RCC cell proliferation, migration, invasion and apoptosis. The results demonstrated that miR‑15a‑5p may be important as a tumor promoter in RCC. To the best of our knowledge, the present study is the first to describe miR‑15a‑5p as a tumor promoter in RCC. Further research will be performed to investigate the underlying signaling pathway of miR‑15a‑5p and the potential role of miR‑15a‑5p as a biomarker for early detection, prognosis prediction and a therapeutic target of RCC.
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Affiliation(s)
- Lu Jin
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yifan Li
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Tao He
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Jia Hu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Jiaju Liu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Mingwei Chen
- Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zeng Zhang
- Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yaoting Gui
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Xiangming Mao
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Shangqi Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yongqing Lai
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
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Cekaite L, Eide PW, Lind GE, Skotheim RI, Lothe RA. MicroRNAs as growth regulators, their function and biomarker status in colorectal cancer. Oncotarget 2016; 7:6476-505. [PMID: 26623728 PMCID: PMC4872728 DOI: 10.18632/oncotarget.6390] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/16/2015] [Indexed: 02/07/2023] Open
Abstract
Gene expression is in part regulated by microRNAs (miRNAs). This review summarizes the current knowledge of miRNAs in colorectal cancer (CRC); their role as growth regulators, the mechanisms that regulate the miRNAs themselves and the potential of miRNAs as biomarkers. Although thousands of tissue samples and bodily fluids from CRC patients have been investigated for biomarker potential of miRNAs (>160 papers presented in a comprehensive tables), none single miRNA nor miRNA expression signatures are in clinical use for this disease. More than 500 miRNA-target pairs have been identified in CRC and we discuss how these regulatory nodes interconnect and affect signaling pathways in CRC progression.
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Affiliation(s)
- Lina Cekaite
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Peter W. Eide
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Guro E. Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Rolf I. Skotheim
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Ragnhild A. Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
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miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas. Tumour Biol 2016; 37:9887-97. [PMID: 26813564 DOI: 10.1007/s13277-016-4903-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 01/20/2016] [Indexed: 12/20/2022] Open
Abstract
In the current setting, we attempted to verify and validate miRNA candidates relevant to pediatric primary brain tumor progression and outcome, in order to provide data regarding the identification of novel prognostic biomarkers. Overall, 26 resected brain tumors were studied from children diagnosed with pilocytic astrocytomas (PAs) (n = 19) and ependymomas (EPs) (n = 7). As controls, deceased children who underwent autopsy and were not present with any brain malignancy were used. The experimental approach included microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression profiles of miR-15a and miR-24-1. The multiparameter analyses were performed with MATLAB. Matching differentially expressed miRNAs were detected in both PAs and EPs, following distinct comparisons with the control cohort; however, in several cases, they exhibited tissue-specific expression profiles. On correlations between miRNA expression and EP progression or outcome, miR-15a and miR-24-1 were found upregulated in EP relapsed and EP deceased cases when compared to EP clinical remission cases and EP survivors, respectively. Taken together, following several distinct associations between miRNA expression and diverse clinical parameters, the current study repeatedly highlighted miR-15a and miR-24-1 as candidate oncogenic molecules associated with inferior prognosis in children diagnosed with ependymoma.
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Yin Z, Li H, Cui Z, Ren Y, Li X, Wu W, Guan P, Qian B, Rothman N, Lan Q, Zhou B. Polymorphisms in pre-miRNA genes and cooking oil fume exposure as well as their interaction on the risk of lung cancer in a Chinese nonsmoking female population. Onco Targets Ther 2016; 9:395-401. [PMID: 26855588 PMCID: PMC4727513 DOI: 10.2147/ott.s96870] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are suggested to be very important in the development of lung cancer. This study assesses the association between polymorphisms in miRNA-related (miR)-26a-1, miR-605, and miR-16-1 genes and risk of lung cancer, as well as the effect of gene-environment interaction between miRNA polymorphisms and cooking fume exposure on lung cancer. METHODS A case-control study including 268 diagnosed nonsmoking female lung cancer patients and 266 nonsmoking female controls was carried out. Three miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) were analyzed. Both additive and multiplicative interactions were assessed. RESULTS MiR-16-1 rs1022960 may be associated with the risk of lung cancer. Carriers with TT genotype of miR-16-1 rs1022960 were observed to have a decreased risk of lung cancer compared with CC and CT genotype carriers (odds ratio =0.550, 95% confidence interval =0.308-0.983, P=0.044). MiR-26a-1 rs7372209 and miR-605 rs2043556 showed no statistically significant associations with lung cancer risk. There were no significant associations between the three single nucleotide polymorphisms and lung adenocarcinoma. People with exposure to both risk genotypes of miR-26a-1 rs7372209 and cooking oil fumes were more likely to develop lung cancer than those with only genetic risk factor or cooking oil fumes (odds ratios were 2.136, 1.255, and 1.730, respectively). The measures of biological interaction and logistic models indicate that gene-environment interactions were not statistically significant on additive scale or multiplicative scale. CONCLUSION MiR-16-1 rs1022960 may be associated with the risk of lung cancer in a Chinese nonsmoking female population. The interactions between miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) and cooking oil fumes were not statistically significant.
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Affiliation(s)
- Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
| | - Hang Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
| | - Zhigang Cui
- China Medical University, Shenyang, People's Republic of China
| | - Yangwu Ren
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
| | - Wei Wu
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
| | - Peng Guan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
| | - Biyun Qian
- Department of Epidemiology, School of Public Health, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Qing Lan
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, People's Republic of China; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, People's Republic of China
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Kaller M, Hermeking H. Interplay Between Transcription Factors and MicroRNAs Regulating Epithelial-Mesenchymal Transitions in Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 937:71-92. [DOI: 10.1007/978-3-319-42059-2_4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Krishnan P, Ghosh S, Wang B, Li D, Narasimhan A, Berendt R, Graham K, Mackey JR, Kovalchuk O, Damaraju S. Next generation sequencing profiling identifies miR-574-3p and miR-660-5p as potential novel prognostic markers for breast cancer. BMC Genomics 2015; 16:735. [PMID: 26416693 PMCID: PMC4587870 DOI: 10.1186/s12864-015-1899-0] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 09/07/2015] [Indexed: 12/14/2022] Open
Abstract
Background Prognostication of Breast Cancer (BC) relies largely on traditional clinical factors and biomarkers such as hormone or growth factor receptors. Due to their suboptimal specificities, it is challenging to accurately identify the subset of patients who are likely to undergo recurrence and there remains a major need for markers of higher utility to guide therapeutic decisions. MicroRNAs (miRNAs) are small non-coding RNAs that function as post-transcriptional regulators of gene expression and have shown promise as potential prognostic markers in several cancer types including BC. Results In our study, we sequenced miRNAs from 104 BC samples and 11 apparently healthy normal (reduction mammoplasty) breast tissues. We used Case–control (CC) and Case-only (CO) statistical paradigm to identify prognostic markers. Cox-proportional hazards regression model was employed and risk score analysis was performed to identify miRNA signature independent of potential confounders. Representative miRNAs were validated using qRT-PCR. Gene targets for prognostic miRNAs were identified using in silico predictions and in-house BC transcriptome dataset. Gene ontology terms were identified using DAVID bioinformatics v6.7. A total of 1,423 miRNAs were captured. In the CC approach, 126 miRNAs were retained with predetermined criteria for good read counts, from which 80 miRNAs were differentially expressed. Of these, four and two miRNAs were significant for Overall Survival (OS) and Recurrence Free Survival (RFS), respectively. In the CO approach, from 147 miRNAs retained after filtering, 11 and 4 miRNAs were significant for OS and RFS, respectively. In both the approaches, the risk scores were significant after adjusting for potential confounders. The miRNAs associated with OS identified in our cohort were validated using an external dataset from The Cancer Genome Atlas (TCGA) project. Targets for the identified miRNAs were enriched for cell proliferation, invasion and migration. Conclusions The study identified twelve non-redundant miRNAs associated with OS and/or RFS. These signatures include those that were reported by others in BC or other cancers. Importantly we report for the first time two new candidate miRNAs (miR-574-3p and miR-660-5p) as promising prognostic markers. Independent validation of signatures (for OS) using an external dataset from TCGA further strengthened the study findings. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1899-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Preethi Krishnan
- Department of Laboratory Medicine and Pathology, University of Alberta, 11560-University Avenue, Edmonton, AB, T6G 1Z2, Canada.
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton, AB, Canada. .,Cross Cancer Institute, Edmonton, AB, Canada.
| | - Bo Wang
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada.
| | - Dongping Li
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada.
| | - Ashok Narasimhan
- Department of Laboratory Medicine and Pathology, University of Alberta, 11560-University Avenue, Edmonton, AB, T6G 1Z2, Canada.
| | - Richard Berendt
- Department of Oncology, University of Alberta, Edmonton, AB, Canada. .,Cross Cancer Institute, Edmonton, AB, Canada.
| | - Kathryn Graham
- Department of Oncology, University of Alberta, Edmonton, AB, Canada.
| | - John R Mackey
- Department of Oncology, University of Alberta, Edmonton, AB, Canada. .,Cross Cancer Institute, Edmonton, AB, Canada.
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada.
| | - Sambasivarao Damaraju
- Department of Laboratory Medicine and Pathology, University of Alberta, 11560-University Avenue, Edmonton, AB, T6G 1Z2, Canada. .,Cross Cancer Institute, Edmonton, AB, Canada.
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Schwarzenbach H, da Silva AM, Calin G, Pantel K. Data Normalization Strategies for MicroRNA Quantification. Clin Chem 2015; 61:1333-42. [PMID: 26408530 DOI: 10.1373/clinchem.2015.239459] [Citation(s) in RCA: 362] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 08/25/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Different technologies, such as quantitative real-time PCR or microarrays, have been developed to measure microRNA (miRNA) expression levels. Quantification of miRNA transcripts implicates data normalization using endogenous and exogenous reference genes for data correction. However, there is no consensus about an optimal normalization strategy. The choice of a reference gene remains problematic and can have a serious impact on the actual available transcript levels and, consequently, on the biological interpretation of data. CONTENT In this review article we discuss the reliability of the use of small RNAs, commonly reported in the literature as miRNA expression normalizers, and compare different strategies used for data normalization. SUMMARY A workflow strategy is proposed for normalization of miRNA expression data in an attempt to provide a basis for the establishment of a global standard procedure that will allow comparison across studies.
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Affiliation(s)
- Heidi Schwarzenbach
- Department of Tumour Biology, Center of Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreia Machado da Silva
- Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX; Instituto de Investigação em Saúde, Universidade do Porto, Porto, Portugal; INEB, Institute of Biomedical Engineering, Universidade do Porto, Porto, Portugal
| | - George Calin
- Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Klaus Pantel
- Department of Tumour Biology, Center of Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
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