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Gattuso G, Longo F, Spoto G, Ricci D, Lavoro A, Candido S, Di Cataldo A, Broggi G, Salvatorelli L, Magro G, Libra M, Falzone L. Diagnostic and Prognostic Significance of a Four-miRNA Signature in Colorectal Cancer. Int J Mol Sci 2025; 26:1219. [PMID: 39940987 PMCID: PMC11818852 DOI: 10.3390/ijms26031219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and one of the leading causes of cancer death worldwide. Despite diagnostic and therapeutic advances, CRC mortality remains high, especially in industrialized countries. Numerous studies have highlighted the pathogenetic role of altered microRNA (miRNA) expression among the various factors contributing to the development and progression of colorectal cancer (CRC). However, the data regarding specific miRNAs involved in CRC pathogenesis remain inconsistent, and no miRNAs have been recognized so far as reliable or effective biomarkers for the diagnosis of this tumor type. To identify novel miRNA biomarkers in CRC, this study validated the expression levels of a four-miRNA signature predicted to be involved in CRC by analyzing both tissue and liquid biopsy samples. Our experimental and bioinformatics results highlighted the diagnostic potential of hsa-miR-21-5p, hsa-miR-503-5p, and hsa-miR-375, as well as the potential prognostic value of hsa-miR-497-5p overexpression and hsa-miR-375-3p downregulation. Overall, the results obtained suggest the diagnostic and prognostic significance of this four-miRNA signature in CRC.
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Affiliation(s)
- Giuseppe Gattuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
| | - Federica Longo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
| | - Graziana Spoto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
| | - Daria Ricci
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
| | - Alessandro Lavoro
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
| | - Antonio Di Cataldo
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (A.D.C.); (G.B.); (L.S.); (G.M.)
| | - Giuseppe Broggi
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (A.D.C.); (G.B.); (L.S.); (G.M.)
| | - Lucia Salvatorelli
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (A.D.C.); (G.B.); (L.S.); (G.M.)
| | - Gaetano Magro
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (A.D.C.); (G.B.); (L.S.); (G.M.)
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.G.); (F.L.); (G.S.); (D.R.); (A.L.); (S.C.)
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Negi RR, Rana SV, Gupta V, Gupta R, Dhawan DK. Evaluation of the Plasma Expression Levels of miR-21 and miR-145 as Potential Non-Invasive Biomarkers for Early Detection of Colorectal Cancer. Asian Pac J Cancer Prev 2024; 25:2797-2804. [PMID: 39205577 PMCID: PMC11495435 DOI: 10.31557/apjcp.2024.25.8.2797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Indexed: 09/04/2024] Open
Abstract
PURPOSE Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world. Early detection would be greatly enhanced if accurate and cost-effective diagnostic biomarkers for CRC were accessible. The development of blood tests would evidently lower the screening cost of CRC detection. The aim of the present study was to examine the prospective of plasma miRNAs as non-invasive biomarkers for CRC screening. METHODS The expressions of miR-21 and miR-145 in the plasma of colorectal adenocarcinomas and normal healthy controls were quantified by using TaqMan miRNA assays. MiRNA expression levels were also correlated with commonly used clinicopathological features of CRC. RESULTS Out of 30 CRC patients, 19 were male and 11 were female. The Mean age of patients was 51.3 ±14.6 years. A statistically significant increase in expression of miR-21 was observed in CRC patients' as compared to healthy controls (p<0.001). A significant association between miR-21 expression and age group (p=0.002) was noticed. Also, a statistically significant difference (p=0.015) between miR-21 expression and tumor location in the proximal and distal sites of the colon was observed in CRC patients. Further, a statistically significant downregulation of miR-145 expression was observed in the plasma of CRC patients as compared to healthy controls (p<0.05). This is the first study to report a significant association between miR-21 expression, age group, and tumor location in CRC patients. CONCLUSION The present study thus emphasises that the appraisal of miR-21 and miR-145 plasma levels may serve as a promising non-invasive screening tool for the early detection of colorectal cancer.
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Affiliation(s)
- Ram Rattan Negi
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, India.
| | - Satya Vati Rana
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India.
| | - Vikas Gupta
- Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India.
| | - Rajesh Gupta
- Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India.
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Orang A, Marri S, McKinnon RA, Petersen J, Michael MZ. Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study. Cancers (Basel) 2024; 16:2055. [PMID: 38893174 PMCID: PMC11171104 DOI: 10.3390/cancers16112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. METHODS The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs. RESULTS Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. CONCLUSIONS This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
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Affiliation(s)
- Ayla Orang
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Shashikanth Marri
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Ross A. McKinnon
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, SA 5042, Australia
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Minutentag IW, Seneda AL, Barros-Filhos MC, de Carvalho M, Souza VGP, Hasimoto CN, Moraes MPT, Marchi FA, Lam WL, Reis PP, Drigo SA. Discovery of Novel miRNAs in Colorectal Cancer: Potential Biological Roles and Clinical Utility. Noncoding RNA 2023; 9:65. [PMID: 37987361 PMCID: PMC10660700 DOI: 10.3390/ncrna9060065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 09/27/2023] [Accepted: 10/11/2023] [Indexed: 11/22/2023] Open
Abstract
Deregulated miRNAs are associated with colorectal cancer (CRC), with alterations depending on the tumor location. Novel tissue-specific miRNAs have been identified in different tumors and are associated with cancer. We used miRMaster to identify novel miRNAs in CRC from the TCGA and GEO data (discovery and validation groups). We used TCGA data from five tissues to analyze miRNA tissue specificity. miRDB was used to predict miRNA targets, and the UCSC Xena Browser was used to evaluate target expression. After successive analyses, we identified 15 novel miRNAs with the same expression patterns in CRC in both the discovery and validation groups. Four molecules (nov-miR-13844-5p, nov-miR-7154-5p, nov-miR-5035-3p, and nov-miR-590-5p) were differentially expressed in proximal and distal CRC. The nov-miR-3345-5p and nov-miR-13172-3p, which are upregulated in tumors, are only expressed in colorectal tissues. These molecules have been linked to a worse prognosis in right-sided colon and rectal carcinomas. An analysis revealed an association between eight novel miRNAs and 81 targets, mostly cancer-related genes, with varying expression based on tumor location. These findings provide new miRNAs with potential biological relevance, molecular biomarkers, and therapeutic targets for CRC treatment.
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Affiliation(s)
- Iael Weissberg Minutentag
- Department of Surgery and Orthopedics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil; (A.L.S.); (C.N.H.)
- Experimental Research Unity (UNIPEX), São Paulo State University (UNESP), Botucatu 18618-687, Brazil;
| | - Ana Laura Seneda
- Department of Surgery and Orthopedics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil; (A.L.S.); (C.N.H.)
- Experimental Research Unity (UNIPEX), São Paulo State University (UNESP), Botucatu 18618-687, Brazil;
| | - Mateus C. Barros-Filhos
- Centro Internacional de Pesquisa (CIPE)—A. C. Camargo Cancer Center, São Paulo 01508-010, Brazil
| | - Márcio de Carvalho
- School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Vanessa G. P. Souza
- Experimental Research Unity (UNIPEX), São Paulo State University (UNESP), Botucatu 18618-687, Brazil;
- Department of Genetics, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Claudia N. Hasimoto
- Department of Surgery and Orthopedics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil; (A.L.S.); (C.N.H.)
| | - Marcelo P. T. Moraes
- Department of Surgery and Orthopedics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil; (A.L.S.); (C.N.H.)
- Department of Pathology, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Fabio A. Marchi
- Department of Head and Neck Surgery, Medical School and São Paulo State Cancer Institute (ICESP), University of São Paulo (USP), São Paulo 01246-903, Brazil
| | - Wan L. Lam
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
| | - Patricia P. Reis
- Department of Surgery and Orthopedics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil; (A.L.S.); (C.N.H.)
- Experimental Research Unity (UNIPEX), São Paulo State University (UNESP), Botucatu 18618-687, Brazil;
| | - Sandra A. Drigo
- Department of Surgery and Orthopedics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil; (A.L.S.); (C.N.H.)
- Experimental Research Unity (UNIPEX), São Paulo State University (UNESP), Botucatu 18618-687, Brazil;
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Zhou L, Yang Y, Ma J, Liu M, Liu R, Ma X, Qiao C. Comprehensive analysis of alternative splicing signatures in pancreatic head cancer. IET Syst Biol 2022; 17:14-26. [PMID: 36479597 PMCID: PMC9931058 DOI: 10.1049/syb2.12056] [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: 03/14/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
The correlation between dysregulation of splicing and cancers has been increasingly recognised and confirmed. The identification of valuable alternative splicing (AS) in pancreatic head cancer (PHC) has a great significance. AS profiles in PHC were generated using the data from The Cancer Genome Atlas and TCGASpliceSeq. Then, the NMF clustering method was performed to identify overall survival-associated AS (OS-AS) subtypes in PHC patients. Subsequently, we used least absolute shrinkage and selection operator Cox regression analysis to construct an AS-related risk model. The splicing regulatory network was uncovered by Cytoscape 3.7. A total of 1694 OS-AS events were obtained. The PHC patients were divided into clusters 1 and 2. Cluster 1 had poorer prognosis and lower infiltration of immune cells. Subsequently, a prognostic signature was established that showed good performance in predicting OS and progression-free survival. The risk score of this signature was associated with the unique tumour immunity. Moreover, a nomogram incorporating the risk score and clinicopathological parameters was established. Finally, a splicing factor-AS regulatory network was developed. A comprehensive analysis of the AS events in PHC associated with prognosis and tumour immunity may help provide reliable information to guide individual treatment strategies.
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Affiliation(s)
- Lingshan Zhou
- Department of Geriatrics Ward 2the First Hospital of Lanzhou UniversityLanzhouChina
| | - Yuan Yang
- The First Clinical Medical CollegeLanzhou UniversityLanzhouChina,Department of Gastroenterologythe First Hospital of Lanzhou UniversityLanzhouChina,Gansu Key Laboratory of GastroenterologyLanzhou UniversityLanzhouChina
| | - Jian Ma
- Department of General Surgerythe First Hospital of Lanzhou UniversityLanzhouChina
| | - Min Liu
- Department of Gastroenterologythe First Hospital of Lanzhou UniversityLanzhouChina,Gansu Key Laboratory of GastroenterologyLanzhou UniversityLanzhouChina
| | - Rong Liu
- Department of Geriatrics Ward 2the First Hospital of Lanzhou UniversityLanzhouChina
| | - Xiaopeng Ma
- The First Clinical Medical CollegeLanzhou UniversityLanzhouChina,Department of General Surgerythe First Hospital of Lanzhou UniversityLanzhouChina
| | - Chengdong Qiao
- Department of Geriatrics Ward 2the First Hospital of Lanzhou UniversityLanzhouChina
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Adam RS, Poel D, Ferreira Moreno L, Spronck JMA, de Back TR, Torang A, Gomez Barila PM, ten Hoorn S, Markowetz F, Wang X, Verheul HMW, Buffart TE, Vermeulen L. Development of a miRNA-based classifier for detection of colorectal cancer molecular subtypes. Mol Oncol 2022; 16:2693-2709. [PMID: 35298091 PMCID: PMC9297751 DOI: 10.1002/1878-0261.13210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 01/10/2022] [Accepted: 03/15/2022] [Indexed: 11/16/2022] Open
Abstract
Previously, colorectal cancer (CRC) has been classified into four distinct molecular subtypes based on transcriptome data. These consensus molecular subtypes (CMSs) have implications for our understanding of tumor heterogeneity and the prognosis of patients. So far, this classification has been based on the use of messenger RNAs (mRNAs), although microRNAs (miRNAs) have also been shown to play a role in tumor heterogeneity and biological differences between CMSs. In contrast to mRNAs, miRNAs have a smaller size and increased stability, facilitating their detection. Therefore, we built a miRNA-based CMS classifier by converting the existing mRNA-based CMS classification using machine learning (training dataset of n = 271). The performance of this miRNA-assigned CMS classifier (CMS-miRaCl) was evaluated in several datasets, achieving an overall accuracy of ~ 0.72 (0.6329-0.7987) in the largest dataset (n = 158). To gain insight into the biological relevance of CMS-miRaCl, we evaluated the most important features in the classifier. We found that miRNAs previously reported to be relevant in microsatellite-instable CRCs or Wnt signaling were important features for CMS-miRaCl. Following further studies to validate its robustness, this miRNA-based alternative might simplify the implementation of CMS classification in clinical workflows.
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Affiliation(s)
- Ronja S. Adam
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Dennis Poel
- Department of Medical OncologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Leandro Ferreira Moreno
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Joey M. A. Spronck
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Tim R. de Back
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Arezo Torang
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Patricia M. Gomez Barila
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Sanne ten Hoorn
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | | | - Xin Wang
- Department of Biomedical SciencesCity University of Hong KongKowloon TongHong Kong
- Shenzhen Research InstituteCity University of Hong KongShenzhenChina
| | - Henk M. W. Verheul
- Department of Medical OncologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Tineke E. Buffart
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Department of Gastrointestinal OncologyNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
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Elgeshy KM, Abdel Wahab AHA. The Role, Significance, and Association of MicroRNA-10a/b in Physiology of Cancer. Microrna 2022; 11:118-138. [PMID: 35616665 DOI: 10.2174/2211536611666220523104408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/21/2022] [Accepted: 04/04/2022] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of mRNA and protein, mainly at the posttranscriptional level. Global expression profiling of miRNAs has demonstrated a broad spectrum of aberrations that correlated with several diseases, and miRNA- 10a and miRNA-10b were the first examined miRNAs to be involved in abnormal activities upon dysregulation, including many types of cancers and progressive diseases. It is expected that the same miRNAs behave inconsistently within different types of cancer. This review aims to provide a set of information about our updated understanding of miRNA-10a and miRNA-10b and their clinical significance, molecular targets, current research gaps, and possible future applications of such potent regulators.
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Affiliation(s)
- Khaled M Elgeshy
- Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt
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Turner KM, Delman AM, Ammann AM, Sohal D, Olowokure O, Choe KA, Smith MT, Kharofa JR, Ahmad SA, Wilson GC, Patel SH. Is There a Benefit to Adjuvant Chemotherapy in Resected, Early Stage Pancreatic Ductal Adenocarcinoma? Ann Surg Oncol 2022; 29:10.1245/s10434-022-11580-7. [PMID: 35357614 DOI: 10.1245/s10434-022-11580-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/21/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The role of systemic therapy for Stage IA pancreatic ductal adenocarcinoma (PDAC) is unclear. The aim of our study was to evaluate the impact of adjuvant chemotherapy (AC) on survival in patients with early stage disease. METHODS The National Cancer Database was queried from 2006 to 2017 for resected pT1N0M0 (Stage 1A) PDAC. Exclusion criteria included neoadjuvant therapy, radiation, or those who suffered a 90-day mortality. RESULTS Of the 1526 patients included in the study, 42.2% received AC and 57.8% underwent surgery alone. Patients who received AC were younger, had fewer comorbidities, and were more likely to have private insurance, compared with those treated with surgery alone. Patients who received AC had longer median overall survival (OS) compared with those who underwent surgery alone (105.7 months vs 72.0 months, p < 0.01). Subset analyses based on individual "good" prognostic features (size ≤ 1.0 cm, lymphovascular invasion negative, well/moderately differentiated, margin negative resection) demonstrated improved OS with AC. Following propensity score matching based on key clinicopathologic features, AC remained associated with improved median OS (83.7 months vs 59.8 months, p < 0.01). However, in the cohort with body/tail tumors (101.2 months vs 95.0 months, p = 0.19) and those with all "good" prognostic features (95.9 months vs 90.6 months, p = 0.15), AC was not associated with improved survival. CONCLUSIONS In resected, Stage IA PDAC, AC is associated with improved overall survival in the vast majority of patients; however, in select cohorts the role of AC is unclear. Further study is needed to tailor treatment to individual patients with PDAC.
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Affiliation(s)
- Kevin M Turner
- Cincinnati Research in Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Aaron M Delman
- Cincinnati Research in Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Allison M Ammann
- Cincinnati Research in Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Davendra Sohal
- Department of Internal Medicine, Division of Hematology & Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Olugbenga Olowokure
- Department of Internal Medicine, Division of Hematology & Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kyuran A Choe
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Milton T Smith
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jordan R Kharofa
- Department of Radiation Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Syed A Ahmad
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Gregory C Wilson
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sameer H Patel
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Ionica E, Gaina G, Tica M, Chifiriuc MC, Gradisteanu-Pircalabioru G. Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients' Stratification. Front Oncol 2022; 11:811486. [PMID: 35198435 PMCID: PMC8859258 DOI: 10.3389/fonc.2021.811486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
In order to ensure that primary endpoints of clinical studies are attained, the patients' stratification is an important aspect. Selection criteria include age, gender, and also specific biomarkers, such as inflammation scores. These criteria are not sufficient to achieve a straightforward selection, however, in case of multifactorial diseases, with unknown or partially identified mechanisms, occasionally including host factors, and the microbiome. In these cases, the efficacy of interventions is difficult to predict, and as a result, the selection of subjects is often random. Colorectal cancer (CRC) is a highly heterogeneous disease, with variable clinical features, outcomes, and response to therapy; the CRC onset and progress involves multiple sequential steps with accumulation of genetic alterations, namely, mutations, gene amplification, and epigenetic changes. The gut microbes, either eubiotic or dysbiotic, could influence the CRC evolution through a complex and versatile crosstalk with the intestinal and immune cells, permanently changing the tumor microenvironment. There have been significant advances in the development of personalized approaches for CRC screening, treatment, and potential prevention. Advances in molecular techniques bring new criteria for patients' stratification-mutational analysis at the time of diagnosis to guide treatment, for example. Gut microbiome has emerged as the main trigger of gut mucosal homeostasis. This may impact cancer susceptibility through maintenance of the epithelial/mucus barrier and production of protective metabolites, such as short-chain fatty acids (SCFAs) via interactions with the hosts' diet and metabolism. Microbiome dysbiosis leads to the enrichment of cancer-promoting bacterial populations, loss of protective populations or maintaining an inflammatory chronic state, all of which contribute to the development and progression of CRC. Meanwhile, variations in patient responses to anti-cancer immuno- and chemotherapies were also linked to inter-individual differences in intestine microbiomes. The authors aim to highlight the contribution of epithelial and gut microbiome inflammatory biomarkers in the improvement of CRC patients' stratification towards a personalized approach of early diagnosis and treatment.
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Affiliation(s)
- Elena Ionica
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Gisela Gaina
- Laboratory of Cell Biology, Neuroscience and Experimental Miology, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Mihaela Tica
- Bucharest Emergency University Hospital, Bucharest, Romania
| | - Mariana-Carmen Chifiriuc
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
- Biological Science Division, Romanian Academy of Sciences, Bucharest, Romania
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10
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Grillo TG, Quaglio AEV, Beraldo RF, Lima TB, Baima JP, Di Stasi LC, Sassaki LY. MicroRNA expression in inflammatory bowel disease-associated colorectal cancer. World J Gastrointest Oncol 2021; 13:995-1016. [PMID: 34616508 PMCID: PMC8465441 DOI: 10.4251/wjgo.v13.i9.995] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/30/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are non-coding RNA molecules composed of 19-25 nucleotides that regulate gene expression and play a central role in the regulation of several immune-mediated disorders, including inflammatory bowel diseases (IBD). IBD, represented by ulcerative colitis and Crohn's disease, is characterized by chronic intestinal inflammation associated with an increased risk of colorectal cancer (CRC). CRC is one of the most prevalent tumors in the world, and its main risk factors are obesity, physical inactivity, smoking, alcoholism, advanced age, and some eating habits, in addition to chronic intestinal inflammatory processes and the use of immunosuppressants administered to IBD patients. Recent studies have identified miRNAs associated with an increased risk of developing CRC in this population. The identification of miRNAs involved in this tumorigenic process could be useful to stratify cancer risk development for patients with IBD and to monitor and assess prognosis. Thus, the present review aimed to summarize the role of miRNAs as biomarkers for the diagnosis and prognosis of IBD-associated CRC. In the future, therapies based on miRNA modulation could be used both in clinical practice to achieve remission of the disease and restore the quality of life for patients with IBD, and to identify the patients with IBD at high risk for tumor development.
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Affiliation(s)
- Thais Gagno Grillo
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Ana Elisa Valencise Quaglio
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| | - Rodrigo Fedatto Beraldo
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Talles Bazeia Lima
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Julio Pinheiro Baima
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
| | - Luiz Claudio Di Stasi
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu 18618-689, São Paulo, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu 18618-686, São Paulo, Brazil
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11
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Martínez-Casillas KCE, Saucedo-Sariñana AM, Barros-Núñez P, Gallegos-Arreola MP, Pineda-Razo TD, Marín-Contreras ME, Flores-Martínez SE, Rosales-Reynoso MA. MKK4 variants rs3826392 and rs3809728 are associated with susceptibility and clinicopathological features in colorectal cancer patients. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1033-1040. [PMID: 34804420 PMCID: PMC8591758 DOI: 10.22038/ijbms.2021.56874.12690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/05/2021] [Indexed: 11/06/2022]
Abstract
OBJECTIVES The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in several processes like inflammation, apoptosis, and tumorigenesis. Several authors have proposed that genetic variations in these genes may alter their expression with subsequent cancer risk. This study aimed to examine the possible association of MKK4 rs3826392 and rs3809728 variants in Mexican patients with colorectal cancer (CRC). These variants were also compared with clinical features as sex, age, TNM stage, and tumor location. MATERIALS AND METHODS The study included genomic DNA from 218 control subjects and 250 patients. Genotyping of the MKK4 variants was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure. RESULTS Individuals with A/T and T/T genotypes for the rs3809728 (-1044 A>T) variant showed a significantly increased risk for CRC (P=0.012 and 0.007, respectively); while individuals with the G/G genotype for the rs3826392 (-1304 T>G) variant showed a decreased risk for CRC (P=0.012). Genotypes of the MKK4 rs3809728 variant were also significantly related to colon localization and advanced TNM stage in CRC patients. T-T haplotype (rs3826392 and rs3809728) of the MKK4 gene was associated with risk in patients with CRC. CONCLUSION The rs3826392 variant in the MKK4 gene could be a cancer protective factor, while the rs3809728 variant could be a risk factor. These variants play a significant role in CRC risk.
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Affiliation(s)
| | - Anilú Margarita Saucedo-Sariñana
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Patricio Barros-Núñez
- Unidad de Investigación Seguimiento Enfermedades Metabólicas, Unidad Médica de Alta Especialidad Pediatría, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco. México
| | - Martha Patricia Gallegos-Arreola
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Tomás Daniel Pineda-Razo
- Servicio de Oncología Médica, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - María Eugenia Marín-Contreras
- Servicio de Gastroenterología, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Silvia Esperanza Flores-Martínez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Mónica Alejandra Rosales-Reynoso
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México,Corresponding author: Mónica Alejandra Rosales-Reynoso. División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México. Tel/ Fax: +52-3336683000;
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12
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Bendova P, Pardini B, Susova S, Rosendorf J, Levy M, Skrobanek P, Buchler T, Kral J, Liska V, Vodickova L, Landi S, Soucek P, Naccarati A, Vodicka P, Vymetalkova V. Genetic variations in microRNA-binding sites of solute carrier transporter genes as predictors of clinical outcome in colorectal cancer. Carcinogenesis 2021; 42:378-394. [PMID: 33319241 DOI: 10.1093/carcin/bgaa136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/01/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.
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Affiliation(s)
- Petra Bendova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Barbara Pardini
- IIGM Italian Institute for Genomic Medicine, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Simona Susova
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic.,Toxicogenomics Unit, National Institute of Public Health, Srobarova, Prague, Czech Republic
| | - Jachym Rosendorf
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Miloslav Levy
- Department of Surgery, Thomayer University Hospital, Videnska, Prague, Czech Republic
| | - Pavel Skrobanek
- Department of Oncology, Thomayer Hospital, Videnska, Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, Thomayer Hospital, Videnska, Prague, Czech Republic
| | - Jan Kral
- Institute for Clinical and Experimental Medicine, IKEM, Prague, Czech Republic
| | - Vaclav Liska
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Stefano Landi
- Department of Biology, University of Pisa, Via Derna, Pisa, Italy
| | - Pavel Soucek
- Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic.,Toxicogenomics Unit, National Institute of Public Health, Srobarova, Prague, Czech Republic
| | - Alessio Naccarati
- IIGM Italian Institute for Genomic Medicine, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov, Prague, Czech Republic.,Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej Svobody, Pilsen, Czech Republic
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13
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Eslamizadeh S, Zare AA, Talebi A, Tabaeian SP, Eshkiki ZS, Heydari-Zarnagh H, Akbari A. Differential Expression of miR-20a and miR-145 in Colorectal Tumors as Potential Location-specific miRNAs. Microrna 2020; 10:66-73. [PMID: 33349227 DOI: 10.2174/2211536609666201221123604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/16/2020] [Accepted: 11/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs), as tissue specific regulators of gene transcription, may be served as biomarkers for Colorectal Cancer (CRC). OBJECTIVE This study aimed to investigate the potential role of the cancer-related hsa-miRNAs as biomarkers in Colon Cancer (CC) and Rectal Cancer (RC). METHODS A total of 148 CRC samples (74 rectum and 74 colon) and 74 adjacent normal tissues were collected to examine the differential expression of selected ten hsa-miRNAs using quantitative Reverse Transcriptase PCR (qRT-PCR). RESULTS The significantly elevated levels of miR-21, miR-133b, miR-18a, miR-20a, and miR-135b, and decreased levels of miR-34a, miR-200c, miR-145, and let-7g were detected in colorectal tumors compared to the healthy tissues (P<0.05). Hsa-miR-20a was significantly overexpressed in rectum compared to colon (p =0.028) from a cut-off value of 3.15 with a sensitivity of 66% and a specificity of 60% and an AUC value of 0.962. Also, hsa-miR-145 was significantly overexpressed in colon compared to the rectum (p =0.02) from a cut-off value of 3.9 with a sensitivity of 55% and a specificity of 61% and an AUC value of 0.91. CONCLUSION In conclusion, hsa-miR-20a and hsa-miR-145, as potential tissue-specific biomarkers for distinguishing RC and CC, improve realizing the molecular differences between these local tumors.
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Affiliation(s)
- Sara Eslamizadeh
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Zare
- Young Researchers and Elites club, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hafez Heydari-Zarnagh
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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14
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De Palma FDE, Luglio G, Tropeano FP, Pagano G, D’Armiento M, Kroemer G, Maiuri MC, De Palma GD. The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer. Int J Mol Sci 2020; 21:7040. [PMID: 32987896 PMCID: PMC7582560 DOI: 10.3390/ijms21197040] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 02/08/2023] Open
Abstract
The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely affect patients' survival. The difficulty in separating in advances responder from non-responder patients affected by LARC highlights the need for valid biomarkers that guide clinical decision-making. In this context, microRNAs (miRNAs) seem to be promising candidates for predicting LARC prognosis and/or therapy response, particularly due to their stability, facile detection, and disease-specific expression in human tissues, blood, serum, or urine. Although a considerable number of studies involving potential miRNA predictors to nCRT have been conducted over the years, to date, the identification of the perfect miRNA signatures or single miRNA, as well as their use in the clinical practice, is still representing a challenge for the management of LARC patients. In this review, we will first introduce LARC and its difficult management. Then, we will trace the scientific history and the key obstacles for the identification of specific miRNAs that predict responsiveness to nCRT. There is a high potential to identify non-invasive biomarkers that circulate in the human bloodstream and that might indicate the LARC patients who benefit from the watch-and-wait approach. For this, we will critically evaluate recent advances dealing with cell-free nucleic acids including miRNAs and circulating tumor cells as prognostic or predictive biomarkers.
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Affiliation(s)
- Fatima Domenica Elisa De Palma
- Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Université, Université of Paris, 75005 Paris, France; (G.K.); (M.C.M.)
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94800 Villejuif, France
- CEINGE-Biotecnologie Avanzate, 80131 Naples, Italy
| | - Gaetano Luglio
- Department of Public Health, University of Naples “Federico II”, 80138 Naples, Italy; (G.L.); (M.D.)
| | - Francesca Paola Tropeano
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy; (F.P.T.); (G.P.)
| | - Gianluca Pagano
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy; (F.P.T.); (G.P.)
| | - Maria D’Armiento
- Department of Public Health, University of Naples “Federico II”, 80138 Naples, Italy; (G.L.); (M.D.)
| | - Guido Kroemer
- Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Université, Université of Paris, 75005 Paris, France; (G.K.); (M.C.M.)
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94800 Villejuif, France
- Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou 100864, China
- Department of Women’s and Children’s Health, Karolinska Institutet, 171 77 Stockholm, Sweden
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Maria Chiara Maiuri
- Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Université, Université of Paris, 75005 Paris, France; (G.K.); (M.C.M.)
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94800 Villejuif, France
| | - Giovanni Domenico De Palma
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy; (F.P.T.); (G.P.)
- Centro Interuniversitario di Studi per l’Innovazione Tecnologica in Chirurgia, University of Naples Federico II, 80138 Naples, Italy
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15
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Márquez-González RM, Saucedo-Sariñana AM, Barros-Núñez P, Gallegos-Arreola MP, Pineda-Razo TD, Marin-Contreras ME, Flores-Martínez SE, Sánchez-Corona J, Rosales-Reynoso MA. CD44 Genotypes Are Associated with Susceptibility and Tumor Characteristics in Colorectal Cancer Patients. TOHOKU J EXP MED 2020; 250:109-119. [PMID: 32115493 DOI: 10.1620/tjem.250.109] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Colorectal cancer is the third cause of cancer and the second leading cause of death worldwide. The CD44 gene plays a key role in malignant processes, including growth, survival, epithelial to mesenchymal transition and metastasis. It is also known that some variants as rs187116 (c.67+4883G>A) and rs7116432 (c.2024+779A>G) can modulate the function of the CD44 gene and malignant transformation in several neoplasms. This study aims to explore, for the first time, the association of the CD44 rs187116 and rs7116432 variants in patients with colorectal cancer. Genomic DNA from 250 patients and 250 healthy blood donors were analyzed. The identification of variants was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test and multivariate analysis. Individuals carrying the G/A and A/A genotypes for the rs187116 polymorphism showed an increased risk for colorectal cancer (OR = 3.11, 95% CI: 1.87-5.16, P = 0.001 and OR = 3.59, 95% CI: 2.06-6.25, P = 0.001, respectively). After adjusting for age and gender, these same genotypes and the G/G genotype of the rs7116432 polymorphism were associated with TNM stage and tumor location in the colon. Moreover, the A-G (rs187116 and rs7116432) haplotype was associated with increased risk; while, the haplotype G-A (rs187116 and rs7116432) was related with decreased risk. In conclusion, our results suggest that the here analyzed CD44 variants are involved with risk, TNM stage and tumor location in colorectal cancer.
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Affiliation(s)
- Rosa María Márquez-González
- Molecular Medicine Division, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)
| | | | - Patricio Barros-Núñez
- Research Unit of Metabolic Diseases, Pediatric UMAE, Instituto Mexicano del Seguro Social (IMSS)
| | | | | | | | | | - José Sánchez-Corona
- Molecular Medicine Division, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)
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16
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Song N, Pei Z, Fu G. MiR‐1224‐5p acts as a tumor suppressor via inhibiting the malignancy of rectal cancer through targeting SLC29A3. IUBMB Life 2020; 72:2204-2213. [DOI: 10.1002/iub.2352] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/05/2020] [Accepted: 07/07/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Na‐Sha Song
- Department of Thoracic Surgery Luoyang Central Affiliated to Zhengzhou university Luoyang P. R. China
| | - Zhi‐Dong Pei
- Department of Thoracic Surgery Luoyang Central Affiliated to Zhengzhou university Luoyang P. R. China
| | - Gui Fu
- Department of Thoracic Surgery Luoyang Central Affiliated to Zhengzhou university Luoyang P. R. China
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17
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Eshghifar N, Badrlou E, Pouresmaeili F. The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article. Hum Antibodies 2020; 28:273-285. [PMID: 32623393 DOI: 10.3233/hab-200417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFβ, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Badrlou
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Bader El Din NG, Ibrahim MK, El-Shenawy R, Salum GM, Farouk S, Zayed N, Khairy A, El Awady M. MicroRNAs expression profiling in Egyptian colorectal cancer patients. IUBMB Life 2020; 72:275-284. [PMID: 31512372 DOI: 10.1002/iub.2164] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 08/28/2019] [Indexed: 12/15/2022]
Abstract
Egypt has increased incidence and high rate of early onset colorectal cancer (CRC). This study aimed to profile the expression levels of 84 circulating microRNAs (miRNAs) in Egyptian CRC patients and to evaluate the diagnostic accuracy of some selected miRNAs as diagnostic biomarkers for CRC patients. A total of 129 subjects (84 CRC patients and 45 healthy controls) were enrolled in two independent sample sets: the screening set (39 subjects) and the validation set (90 subjects). The expression profiles of 84 miRNAs were studied by miRNA PCR array in the screening set. Then four miRNAs (let-7c, 21, 26a, 146a) were selected to be studied by quantitative real-time PCR in the validation set. The PCR array results revealed significant up regulation of 20 miRNAs and downregulation of two miRNAs in CRC patients compared to the healthy subjects. Moreover, the expression levels of the four selected miRNAs were significantly higher in CRC serum samples than controls. The ROC analysis revealed that miRNAs (let-7c, 21, 26a and 146a) can effectively discriminate between CRC patients and the controls. The combination of the four miRNAs showed AUC of 0.950 (95% CI [0.898-1.002], p = .001). However, the combination of miR-21 and miR-26a showed the best diagnostic accuracy with AUC of 0.953 (95% CI [0.908-0.999], p = .001). The current data suggest that miRNAs (let-7c, 21, 26a, 146a) could play an important role in CRC development and they can be used as diagnostic biomarkers for CRC.
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Affiliation(s)
| | - Marwa K Ibrahim
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
| | - Reem El-Shenawy
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
| | - Ghada M Salum
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
| | - Sally Farouk
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
| | - Naglaa Zayed
- Endemic Medicine Department, Cairo University Kasr Alainy Faculty of Medicine, Giza, Egypt
| | - Ahmed Khairy
- Endemic Medicine Department, Cairo University Kasr Alainy Faculty of Medicine, Giza, Egypt
| | - Mostafa El Awady
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
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19
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Peng J, Liu F, Zheng H, Wu Q, Liu S. Long noncoding RNA ZFAS1 promotes tumorigenesis and metastasis in nasopharyngeal carcinoma by sponging miR-892b to up-regulate LPAR1 expression. J Cell Mol Med 2020; 24:1437-1450. [PMID: 31851778 PMCID: PMC6991699 DOI: 10.1111/jcmm.14823] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 09/30/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE In this study, we explored the NPC-specific expression of ZFAS1 and the mechanism of ZFAS1-mediated growth, aggressiveness and tumorigenesis in NPC. METHODS The expression profile of lncRNAs was detected in NPC tissues and matching para-carcinoma tissues using microarray analysis. LncRNA-miRNA and miRNA-mRNA interaction networks were constructed using the miRcode v11 and TargetScanHuman v7.2 web server and then validated using dual-luciferase assay. Western blot and RT-qPCR were performed to detect protein and RNA expression. The effects of ZFAS1, miR-892b and LPAR1 dysregulation on the proliferative, migratory and invasive abilities of NPC cells were observed using colony formation, cell counting kit-8 (CCK-8) and transwell assays in vitro. In vivo, a xenograft nude mouse model was established to detect the impact of ZFAS1 dysregulation on the tumorigenicity of NPC cells. RESULTS The expression of multiple lncRNAs, of which ZFAS1 was up-regulated, was dysregulated in NPC tissues. ZFAS1 directly targeted miR-892b, and miR-892b negatively regulated the expression of downstream LPAR1. The proliferation, migration and invasion of NPC cells could be largely enhanced by the downregulation of miR-892b as well as the up-regulation of ZFAS1 and LPAR1, while the overexpression of miR-892b and the downregulation of ZFAS1 and LPAR1 decreased these abilities. In nude mice, the growth of tumour xenografts formed by HONE1 cells was significantly suppressed when ZFAS1 was silenced. CONCLUSION The study demonstrated that lncRNA ZFAS1 may act as a promoter of tumorigenesis and metastasis in nasopharyngeal carcinoma, by up-regulating the expression of LPAR1 in a miR-892b-dependent manner.
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Affiliation(s)
- Jiaojiao Peng
- Department of Otolaryngology, Head and Neck SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Feng Liu
- Department of Otolaryngology, Head and Neck SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Hong Zheng
- Department of Otolaryngology, Head and Neck SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Qi Wu
- Department of Otolaryngology, Head and Neck SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Shixi Liu
- Department of Otolaryngology, Head and Neck SurgeryWest China HospitalSichuan UniversityChengduChina
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20
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Adjuvant chemotherapy for rectal cancer: Current evidence and recommendations for clinical practice. Cancer Treat Rev 2019; 83:101948. [PMID: 31955069 DOI: 10.1016/j.ctrv.2019.101948] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 12/24/2022]
Abstract
While adjuvant chemotherapy is an established treatment for pathological stage II and especially stage III colon cancer, its role in the multimodal management of rectal cancer remains controversial. As a result, there is substantial variation in the use of this treatment in clinical practice. Even among centres and physicians who consider adjuvant chemotherapy as a standard treatment, notable heterogeneity exists with regard to patient selection criteria and chemotherapy regimens. The controversy around this topic is confirmed by the lack of full consensus among national and international clinical guidelines. While most of the clinical trials do not support the contention that adjuvant chemotherapy may improve survival outcomes if pre-operative (chemo)radiotherapy is also given, these suffer from many limitations that preclude drawing definitive conclusions. Nevertheless, in the era of evidence-based medicine, physicians should be guided by the available data and refrain from extrapolating results of adjuvant colon cancer trials to inform treatment decisions for rectal cancer. Patients should be informed of the evidence gap, be given the opportunity to carefully discuss pros and cons of all the possible management options and be empowered in the decision making. In this article we review the available evidence on adjuvant chemotherapy for rectal cancer and propose a risk-adapted decisional algorithm that largely relies on informed patient preferences.
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21
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Wang Y, Mu L, Huang M. MicroRNA‑195 suppresses rectal cancer growth and metastasis via regulation of the PI3K/AKT signaling pathway. Mol Med Rep 2019; 20:4449-4458. [PMID: 31702045 PMCID: PMC6797947 DOI: 10.3892/mmr.2019.10717] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 07/15/2019] [Indexed: 12/18/2022] Open
Abstract
MicroRNAs (miRNAs) play a vital role in the progression of cancer, however, only limited data on miRNAs in rectal cancer are available. The aim of the present study was to investigate whether miR‑195 could inhibit the progression of rectal cancer. The miR‑195 mimic was transfected into 2 types of human rectal cancer cells (SW837 and SW1463). Cell viability and apoptosis were analyzed by Cell Counting Kit‑8 (CCK‑8) assay and flow cytometry, and cell migration and invasion were assessed by scratch test and Transwell assay. The results revealed that insulin‑like growth factor 1 (IGF1) was predicted as a potential target of miR‑195 by Targetscan7.2, and the result was verified by dual‑luciferase reporter assay. The co‑transfection of IGF1 was performed to confirm the underlying mechanism of tumor suppressor of miR‑195 in rectal cancer. The activation of PI3K/AKT signaling was determined by western blotting. The levels of miR‑195 in SW837 and SW1463 cells were revealed to be lower than in human rectal mucosa epithelial cells. After the transfection with miR‑195, the cell viability was decreased, while the apoptosis was significantly increased (SW837: 5.21% vs. 20.96%; SW1463: 4.19% vs. 25.22%). Moreover, cell migration and invasion were significantly inhibited in the mimic group. miR‑195 specifically targeted IGF1, however, the co‑transfection of IGF1 could partially reverse the inhibitory effects of miR‑195 on rectal cancer cells. It was also determined that the phosphorylation of PI3K and AKT were significantly inhibited in the mimic group. The tumor suppressive ability of miR‑195 in rectal cancer cell proliferation and metastasis was mediated by blocking IGF1 expression and inhibiting the PI3K/AKT pathway.
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Affiliation(s)
- Yeli Wang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Linsong Mu
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Miaoling Huang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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22
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Winer LK, Dhar VK, Wima K, Morris MC, Lee TC, Shah SA, Ahmad SA, Patel SH. The Impact of Tumor Location on Resection and Survival for Pancreatic Ductal Adenocarcinoma. J Surg Res 2019; 239:60-66. [DOI: 10.1016/j.jss.2019.01.061] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 01/16/2019] [Accepted: 01/25/2019] [Indexed: 12/11/2022]
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23
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Shirmohamadi M, Eghbali E, Najjary S, Mokhtarzadeh A, Kojabad AB, Hajiasgharzadeh K, Lotfinezhad P, Baradaran B. Regulatory mechanisms of microRNAs in colorectal cancer and colorectal cancer stem cells. J Cell Physiol 2019; 235:776-789. [PMID: 31264216 DOI: 10.1002/jcp.29042] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 06/13/2019] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is one of the most lethal and hard-to-treat cancers in the world, which in its advanced stages, surgery and chemotherapy are the main common treatment approaches. The microRNAs (miRNAs), as novel markers for CRC detection, promote their regulatory effects via the 3'-untranslated binding region (3'-UTR) of target messenger RNA in posttranscriptional regulation of genes and also play a pivotal role in modulating resistance to chemotherapeutic agents. These small noncoding RNAs have also a critical role in CRC stem cells (CRCSCs) regulation, comprising self-renewal, differentiation, and tumorigenesis. Cancer stem cells (CSCs) are distinctive cell types inside a tumor tissue that are believed to derive from normal somatic stem cells. The CSCs have self-renewal abilities, angiogenesis, as well as specific surface markers expression characteristics. Furthermore, they are frequently criticized for tumor maintenance, treatment resistance, tumor development, and distant metastasis. In this review, we discuss the current understandings of CRCSCs and their environment with a focus on the role of miRNAs on the regulation of CSCs and their targeting application in CRC treatment.
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Affiliation(s)
- Masoud Shirmohamadi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Eghbali
- Medical Radiation Sciences Research Group, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shiva Najjary
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Parisa Lotfinezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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24
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Roman-Canal B, Tarragona J, Moiola CP, Gatius S, Bonnin S, Ruiz-Miró M, Sierra JE, Rufas M, González E, Porcel JM, Gil-Moreno A, Falcón-Pérez JM, Ponomarenko J, Matias-Guiu X, Colas E. EV-associated miRNAs from peritoneal lavage as potential diagnostic biomarkers in colorectal cancer. J Transl Med 2019; 17:208. [PMID: 31221189 PMCID: PMC6585099 DOI: 10.1186/s12967-019-1954-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/13/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Current systematic methods for diagnosing have inherent limitations so development of a minimally-invasive diagnosis, based on the identification of sensitive biomarkers in liquid biopsies could therefore facilitate screening among population at risk. METHODS In this study, we aim to develop a novel approach to identify highly sensitive and specific biomarkers by investigating the use of extracellular vesicles (EVs) isolated from the peritoneal lavage as a source of potential miRNA diagnostic biomarkers. We isolated EVs by ultracentrifugation from 25 ascitic fluids and 25 peritoneal lavages from non-cancer and CRC patients, respectively. Analysis of the expression of EV-associated miRNAs was performed using Taqman OpenArray technology through which we could detect 371 miRNAs. RESULTS 210 miRNAs were significantly dysregulated (adjusted p value < 0.05 and abs(logFC) ≥ 1). The top-10 miRNAs, which had the AUC value higher than 0.95, were miRNA-199b-5p, miRNA-150-5p, miRNA-29c-5p, miRNA-218-5p, miRNA-99a-3p, miRNA-383-5p, miRNA-199a-3p, miRNA-193a-5p, miRNA-10b-5p and miRNA-181c-5p. CONCLUSIONS This finding opens the avenue to the use of EV-associated miRNA of peritoneal lavages as an untapped source of biomarkers for CRC.
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Affiliation(s)
- Berta Roman-Canal
- Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain.,Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Jordi Tarragona
- Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain
| | - Cristian Pablo Moiola
- Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain.,Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, CIBERONC, Pg. Vall Hebron 119-129, 08035, Barcelona, Spain
| | - Sònia Gatius
- Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain
| | - Sarah Bonnin
- Centre for Genomic Regulation (CRG), The Barcelona Institute or Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Spain
| | - Maria Ruiz-Miró
- Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain
| | - José Enrique Sierra
- Department of Surgery, Hospital Arnau de Vilanova, Biomedical Research Institute of Lleida (IRBLleida), Lleida, Spain
| | - Maria Rufas
- Department of Surgery, Hospital Arnau de Vilanova, Biomedical Research Institute of Lleida (IRBLleida), Lleida, Spain
| | - Esperanza González
- Exosomes Laboratory and Metabolomics Platform, CIC bioGUNE, CIBEREHD Bizkaia Technology Park, Derio, Spain
| | - José M Porcel
- Pleural Medicine Unit, Arnau de Vilanova University Hospital, IRBLleida, Lleida, Spain
| | - Antonio Gil-Moreno
- Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, CIBERONC, Pg. Vall Hebron 119-129, 08035, Barcelona, Spain.,Gynecological Oncology Department, Vall Hebron University Hospital, CIBERONC, Barcelona, Spain
| | - Juan M Falcón-Pérez
- Exosomes Laboratory and Metabolomics Platform, CIC bioGUNE, CIBEREHD Bizkaia Technology Park, Derio, Spain.,IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain
| | - Julia Ponomarenko
- Centre for Genomic Regulation (CRG), The Barcelona Institute or Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Spain.,University Pompeu Fabra, Barcelona, Spain
| | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics/Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida, CIBERONC, Lleida, Spain. .,Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. .,Oncologic Pathology Group, Department of Medicine UdL, Biomedical Research Institute of Lleida (IrbLleida), Av. Rovira Roure 80, 25198, Lleida, Spain.
| | - Eva Colas
- Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, CIBERONC, Pg. Vall Hebron 119-129, 08035, Barcelona, Spain.
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25
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Gungormez C, Gumushan Aktas H, Dilsiz N, Borazan E. Novel miRNAs as potential biomarkers in stage II colon cancer: microarray analysis. Mol Biol Rep 2019; 46:4175-4183. [PMID: 31123908 DOI: 10.1007/s11033-019-04868-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/09/2019] [Indexed: 01/22/2023]
Abstract
The aim of this study was to determine oncogenic and tumor-suppressing miRNA profiles associated with the development and progression of cancer using tumor tissues from patients with colorectal cancer (stage II) that did not show nodal spread or advanced metastasis to identify potential biomarkers. A microarray system (GeneChip miRNA 4.0 Array chip, Affymetrix) was used to determine the microRNA profiles of five patients with stage II colon cancer based on normal and colon tumor tissues. Of 32 identified miRNAs, an increase in three microRNAs (hsa-miR-4745-5p, hsa-miR-6126, and hsa-miR-1469) was observed in tumor tissues relative to that in control tissues. Additionally, this study demonstrated for the first time that the expression of the 8 miRNAs (hsa-miR-378i, hsa-miR-378a-3p, hsa-miR-378c, hsa-miR-378d, hsa-miR-378e, hsa-miR-378f, hsa-miR-378a-5p, and hsa-miR-378g) from miR-378 members among the differentially expressed miRNAs is reduced. The target genes of these downregulated miRNAs were determined by using DIANA miRPath v3. The effect of identified genes on colon cancer stage II was determined the biological process and biological pathway using Funrich Gene Enrichment. It was revealed that these miRNAs were affected the signaling pathways which control cell proliferation, cell-cell interaction, and apoptosis in stage II colon cancer. In patients with early stage II colon cancer, miR-378 can be used as a biomarker of colorectal cancer. Thus, miR-378 can facilitate treatment with early diagnosis.
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Affiliation(s)
- Cigdem Gungormez
- Central Research Laboratory, Harran University, 63100, Şanlıurfa, Turkey. .,Biology Department, Faculty of Arts and Sciences, Harran University, Şanlıurfa, Turkey.
| | - Hatice Gumushan Aktas
- Biology Department, Faculty of Arts and Sciences, Harran University, Şanlıurfa, Turkey
| | - Nihat Dilsiz
- Molecular Biology and Genetics Department, Faculty of Engineering and Natural Sciences, Medeniyet University, Istanbul, Turkey
| | - Ersin Borazan
- General Surgery Department, Medical Faculty, Gaziantep University, Gaziantep, Turkey
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26
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High-Amylose Maize, Potato, and Butyrylated Starch Modulate Large Intestinal Fermentation, Microbial Composition, and Oncogenic miRNA Expression in Rats Fed A High-Protein Meat Diet. Int J Mol Sci 2019; 20:ijms20092137. [PMID: 31052187 PMCID: PMC6540251 DOI: 10.3390/ijms20092137] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/18/2019] [Accepted: 04/24/2019] [Indexed: 02/07/2023] Open
Abstract
High red meat intake is associated with the risk of colorectal cancer (CRC), whereas dietary fibers, such as resistant starch (RS) seemed to protect against CRC. The aim of this study was to determine whether high-amylose potato starch (HAPS), high-amylose maize starch (HAMS), and butyrylated high-amylose maize starch (HAMSB)—produced by an organocatalytic route—could oppose the negative effects of a high-protein meat diet (HPM), in terms of fermentation pattern, cecal microbial composition, and colonic biomarkers of CRC. Rats were fed a HPM diet or an HPM diet where 10% of the maize starch was substituted with either HAPS, HAMS, or HAMSB, for 4 weeks. Feces, cecum digesta, and colonic tissue were obtained for biochemical, microbial, gene expression (oncogenic microRNA), and immuno-histochemical (O6-methyl-2-deoxyguanosine (O6MeG) adduct) analysis. The HAMS and HAMSB diets shifted the fecal fermentation pattern from protein towards carbohydrate metabolism. The HAMSB diet also substantially increased fecal butyrate concentration and the pool, compared with the other diets. All three RS treatments altered the cecal microbial composition in a diet specific manner. HAPS and HAMSB showed CRC preventive effects, based on the reduced colonic oncogenic miR17-92 cluster miRNA expression, but there was no significant diet-induced differences in the colonic O6MeG adduct levels. Overall, HAMSB consumption showed the most potential for limiting the negative effects of a high-meat diet.
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27
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Zhang K, Yan J, Yi B, Rui Y, Hu H. High KCNQ1OT1 expression might independently predict shorter survival of colon adenocarcinoma. Future Oncol 2019; 15:1085-1095. [PMID: 30932685 DOI: 10.2217/fon-2018-0499] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
AIM To explore the expression profile of KCNQ1OT1 and its prognostic value in colon and rectal adenocarcinoma (COAD and READ) separately. PATIENTS & METHODS clinicopathological, genomic and survival data from The Cancer Genome Atlas and GSE39582 were obtained for a secondary analysis. RESULTS KCNQ1OT1 was significantly up-regulated in both COAD and READ compared with adjacent normal tissues. However, its up-regulation was only independently associated with shorter overall survival (hazard ratio: 2.02; 95% CI: 1.18-3.46; p = 0.01) and recurrence-free survival (hazard ratio: 2.79, 95% CI: 1.54-5.07; p < 0.01) in COAD, but not in READ. CONCLUSION KCNQ1OT1 up-regulation might serve as a valuable independent prognostic indicator of shorter overall survival and recurrence-free survival of COAD, but not READ.
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Affiliation(s)
- Ke Zhang
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, 610041, PR China
| | - Jin Yan
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, 610041, PR China
| | - Bo Yi
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, 610041, PR China
| | - Yuanyi Rui
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, 610041, PR China
| | - Hai Hu
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, 610041, PR China
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28
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Shaker OG, Ali MA, Ahmed TI, Zaki OM, Ali DY, Hassan EA, Hemeda NF, AbdelHafez MN. Association between LINC00657 and miR-106a serum expression levels and susceptibility to colorectal cancer, adenomatous polyposis, and ulcerative colitis in Egyptian population. IUBMB Life 2019; 71:1322-1335. [PMID: 30927333 DOI: 10.1002/iub.2039] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/24/2019] [Accepted: 03/12/2019] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) represented the second cause of mortality among cancer patients. Long noncoding RNAs and microRNAs (miRNAs) serve as noninvasive biomarkers for CRC surveillance and introduce new therapeutic approaches. LINC00657 and miR-106a expression levels play a pivotal role in CRC. This study included 190 Egyptian subjects, and the expression levels of LINC00657 and miR-106a in serum were measured by using quantitative real-time polymerase chain reaction. We found that upregulation of LINC00657 and downregulation of miR-106a are significantly associated with the development of CRC. Also, a positive correlation was detected between their serum levels. In addition, serum LINC00657 can distinguish adenomatous polyposis (AP) patients and/or ulcerative colitis (UC) patients from controls. Also the miRNA-106a expression level discriminates AP but not UC from healthy individuals. Our study cited new diagnostic biomarkers for CRC, AP, and UC among Egyptians in addition to be noninvasive screening tools for CRC in both healthy subjects and those having precancerous lesions. © 2019 IUBMB Life, 71(9):1322-1335, 2019.
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Affiliation(s)
- Olfat G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Marwa A Ali
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Tarek I Ahmed
- Department of Internal Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Othman M Zaki
- Department of Clinical Pathology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Doaa Y Ali
- Department of Clinical Pathology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Essam A Hassan
- Department of Tropical Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Nada F Hemeda
- Department of Genetics, Faculty of Agriculture, Fayoum University, Fayoum, Egypt
| | - Marwa N AbdelHafez
- Department of Medical Oncology, National Cancer Institute, Cairo University, Giza, Egypt
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29
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Moreno EC, Pascual A, Prieto-Cuadra D, Laza VF, Molina-Cerrillo J, Ramos-Muñoz ME, Rodríguez-Serrano EM, Soto JL, Carrato A, García-Bermejo ML, Guillén-Ponce C. Novel Molecular Characterization of Colorectal Primary Tumors Based on miRNAs. Cancers (Basel) 2019; 11:cancers11030346. [PMID: 30862091 PMCID: PMC6468580 DOI: 10.3390/cancers11030346] [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: 01/21/2019] [Revised: 03/05/2019] [Accepted: 03/06/2019] [Indexed: 12/13/2022] Open
Abstract
microRNAs (miRNA) expression in colorectal (CR) primary tumours can facilitate a more precise molecular characterization. We identified and validated a miRNA profile associated with clinical and histopathological features that might be useful for patient stratification. In situ hybridization array using paraffin-embedded biopsies of CR primary tumours were used to screen 1436 miRNAs. 17 miRNAs were selected for validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (n = 192) and were further correlated with clinical and histopathological data. We demonstrated that miRNAs associated to Colorectal Cancer (CRC) diagnosis age (over 50s and 60s) included miR-1-3p, miR-23b-3p, miR-27b-3p, miR-143-3p, miR-145-5p and miR-193b-5p. miR-23b-3p and miR-24-3p discriminated between Lynch Syndrome and sporadic CRC. miR-10a-5p, miR-20a-5p, miR-642b and Let-7a-5p were associated to stroma abundance. miR-642b and Let-7a-5p were associated with to peritumoral inflammation abundance. miR-1-3p, miR-143-3p and miR-145-5p correlated with mucinous component. miR-326 correlated with tumour location (right or left sided). miR-1-3p associated with tumour grade. miR-20a-5p, miR-193b-5p, miR-320a, miR-326 and miR-642b-3p associated to tumour stage and progression. Remarkably, we also demonstrated that miR-1-3p and miR-326 expression significantly associated with patient overall survival (OS). Hierarchical clustering and bioinformatics analysis indicated that selected miRNAs could re-classify the patients and work cooperatively, modulating common target genes involved in colorectal cancer key signalling pathways. In conclusion, molecular characterization of CR primary tumours based on miRNAs could lead to more accurate patient reclassification and may be useful for efficient patient management.
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Affiliation(s)
- Elisa Conde Moreno
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | - Alejandro Pascual
- Pathology Department, Ramon y Cajal Research Institute, University Hospital, 28034 Madrid, Spain.
| | - Daniel Prieto-Cuadra
- SynlabPathology, Pathology Department, Virgen de la Victoria, University Hospital, 29010 Málaga, Spain.
| | - Val F Laza
- Microbiology Department and Bioinformatics Core Facility, IRYCIS, 28034 Madrid, Spain.
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, 28034 Madrid, Spain.
| | - Miren Edurne Ramos-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | | | - José Luis Soto
- Hereditary Cancer Program Valencian Region, Molecular Genetics Laboratory, Elche University Hospital, Elche, 03202 Alicante, Spain.
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, Alcala University, 28034 Ciberonc, Spain.
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | - Carmen Guillén-Ponce
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, 28034 Madrid, Spain.
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30
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Mjelle R, Sjursen W, Thommesen L, Sætrom P, Hofsli E. Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location. BMC Cancer 2019; 19:161. [PMID: 30786859 PMCID: PMC6381638 DOI: 10.1186/s12885-019-5330-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 01/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNA) and other small RNAs are frequently dysregulated in cancer and are promising biomarkers for colon cancer. Here we profile human, virus and bacteria small RNAs in normal and tumor tissue from early stage colon cancer and correlate the expression with clinical parameters. METHODS Small RNAs from colon cancer tissue and adjacent normal mucosa of 48 patients were sequenced using Illumina high-throughput sequencing. Clinical parameters were correlated with the small RNA expression data using linear models. We performed a meta-analysis by comparing publicly available small RNA sequencing datasets with our original sequencing data to confirm the main findings. RESULTS We identified 331 differentially expressed miRNAs between tumor and normal samples. We found that the major changes in miRNA expression between left and right colon are due to miRNAs located within the Hox-developmental genes, including miR-10b, miR-196b and miR-615. Further, we identified new miRNAs associated with microsatellite instability (MSI), including miR-335, miR-26 and miR-625. We performed a meta-analysis on all publicly available miRNA-seq datasets and identified 117 common miRNAs that were differentially expressed between tumor and normal tissue. The miRNAs miR-135b and miR-31 were the most significant upregulated miRNA in tumor across all datasets. The miRNA miR-133a was the most strongly downregulated miRNA in our dataset and also showed consistent downregulation in the other datasets. The miRNAs associated with MSI and tumor location in our data showed similar changes in the other datasets. Finally, we show that small RNAs from Epstein-Barr virus and Fusobacterium nucleatum are differentially expressed between tumor and normal adjacent tissue. CONCLUSIONS Small RNA profiling in colon cancer tissue revealed novel RNAs associated with MSI and tumor location. We show that Fusobacterium nucleatum are detectable at the RNA-level in colon tissue, and that both Fusobacterium nucleatum and Epstein-Barr virus separate tumor and normal tissue.
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Affiliation(s)
- Robin Mjelle
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.
| | - Wenche Sjursen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Medical Genetics, St Olavs Hospital, Trondheim Norway, Erling Skjalgssons gt 1, 7030, Trondheim, Norway
| | - Liv Thommesen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Biomedical Laboratory Science, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Computer and Information Science, Norwegian University of Science and Technology, NTNU, Sem Sælandsvei 9, 7491, Trondheim, Norway.,Bioinformatics core facility-BioCore, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway.,K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, NTNU, 7491, Trondheim, Norway
| | - Eva Hofsli
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,The Cancer Clinic, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
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31
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Li B, Wang S, Wang S. MiR-195 suppresses colon cancer proliferation and metastasis by targeting WNT3A. Mol Genet Genomics 2018; 293:1245-1253. [PMID: 29948330 DOI: 10.1007/s00438-018-1457-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 06/04/2018] [Indexed: 11/30/2022]
Abstract
MicroRNAs (miRNAs) are a novel class of diagnostic and therapeutic target in cancer. Here, we aimed to explore the effects and mechanism of miR-195 regulation in colon cancer. The expressions of several putative miRNAs in colon tumors, compared to those in normal tissues, were investigated by bioinformatical analysis of a Gene Expression Omnibus database. Quantitative real-time PCR analysis (qRT-PCR) was used to validate the identified changes in normal tissues, primary tumors, and metastatic tumors. MTT, soft agar colony formation, and transwell assays were used to evaluate the effects of miR-195 overexpression or inhibition on cell viability, proliferation, migration, and invasion. Targets of miR-195 were identified by TargetScan, and subsequently verified by qRT-PCR and Western blot. The role of miR-195 in the β-catenin pathway was also studied using RT-PCR and Western blot. MiR-195 expression was downregulated in colon carcinoma tissues and negatively correlated with the metastatic potential. While transfecting miR-195 mimics decreased the proliferation, migration, and invasion of colon cancer cells, miR-195 inhibition exerted opposing effects. WNT3A was identified as a direct target of miR-195. β-catenin was also downregulated by miR-195 in colon cancers. MiR-195 downregulation is associated with the enhanced proliferation, migration, and invasion of colon cancer. MiR-195 directly downregulates WNT3A. Our results indicate that miR-195 is a potential diagnostic marker and therapeutic target for improving the clinical management of colon cancer.
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Affiliation(s)
- Baoyu Li
- General Surgery Department, Yidu Central Hospital of Weifang, 4138 Linglongshan Nanlu, Qingzhou, 262500, Shandong, China.
| | - Shunsheng Wang
- General Surgery Department, Yidu Central Hospital of Weifang, 4138 Linglongshan Nanlu, Qingzhou, 262500, Shandong, China
| | - Shumei Wang
- General Surgery Department, Yidu Central Hospital of Weifang, 4138 Linglongshan Nanlu, Qingzhou, 262500, Shandong, China
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32
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Jin WH, Hoffe SE, Shridhar R, Strom T, Venkat P, Springett GM, Hodul PJ, Pimiento JM, Meredith KL, Malafa MP, Frakes JM. Adjuvant radiation provides survival benefit for resected pancreatic adenocarcinomas of the tail. J Gastrointest Oncol 2018; 9:487-494. [PMID: 29998014 PMCID: PMC6006031 DOI: 10.21037/jgo.2018.02.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 01/15/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The appropriate adjuvant treatment for resected pancreatic cancer remains a controversy. We sought to determine the effect of adjuvant treatment on overall survival (OS) in patients with pancreatic tail adenocarcinoma. METHODS Retrospective review of patients with upfront surgically resected pancreatic tail cancer treated at our institution between 2000-2012 was performed to determine outcomes of patients treated with and without adjuvant radiation therapy (RT). Survival curves were calculated according to the Kaplan-Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the Cox proportional hazards model. RESULTS Thirty-four patients met inclusion criteria. 79% received adjuvant chemotherapy, either concurrent with RT or alone. The groups were well matched, with the only significant difference being patient sex. On both UVA and MVA there was significantly worse survival in patients with a post-op CA19-9 >90 [hazard ratio (HR) 5.55; 95% confidence interval (CI): 1.20-25.7, P=0.03] and improved survival in patients treated with adjuvant RT (HR 0.15; 95% CI: 0.04-0.58, P=0.006). The median and 2-year OS were 21.6 months and 47% for patients treated with adjuvant RT compared with 11.3 months and 21% for those treated without RT. CONCLUSIONS Although few in patient numbers, this data suggests integration of adjuvant RT in resected pancreatic tail adenocarcinoma may improve OS.
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Affiliation(s)
- William H. Jin
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Sarah E. Hoffe
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Ravi Shridhar
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Tobin Strom
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Puja Venkat
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Pamela J. Hodul
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jose M. Pimiento
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Mokenge P. Malafa
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jessica M. Frakes
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
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33
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Coebergh van den Braak RRJ, Sieuwerts AM, Lalmahomed ZS, Smid M, Wilting SM, Bril SI, Xiang S, van der Vlugt-Daane M, de Weerd V, van Galen A, Biermann K, van Krieken JHJM, Kloosterman WP, Foekens JA, Martens JWM, IJzermans JNM. Confirmation of a metastasis-specific microRNA signature in primary colon cancer. Sci Rep 2018; 8:5242. [PMID: 29588449 PMCID: PMC5869672 DOI: 10.1038/s41598-018-22532-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 02/21/2018] [Indexed: 12/16/2022] Open
Abstract
The identification of patients with high-risk stage II colon cancer who may benefit from adjuvant therapy may allow the clinical approach to be tailored for these patients based on an understanding of tumour biology. MicroRNAs have been proposed as markers of the prognosis or treatment response in colorectal cancer. Recently, a 2-microRNA signature (let-7i and miR-10b) was proposed to identify colorectal cancer patients at risk of developing distant metastasis. We assessed the prognostic value of this signature and additional candidate microRNAs in an independent, clinically well-defined, prospectively collected cohort of primary colon cancer patients including stage I-II colon cancer without and stage III colon cancer with adjuvant treatment. The 2-microRNA signature specifically predicted hepatic recurrence in the stage I-II group, but not the overall ability to develop distant metastasis. The addition of miR-30b to the 2-microRNA signature allowed the prediction of both distant metastasis and hepatic recurrence in patients with stage I-II colon cancer who did not receive adjuvant chemotherapy. Available gene expression data allowed us to associate miR-30b expression with axon guidance and let-7i expression with cell adhesion, migration, and motility.
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Affiliation(s)
| | - Anieta M Sieuwerts
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.,Cancer Genomics Center Netherlands, Amsterdam, The Netherlands
| | - Zarina S Lalmahomed
- Department of Surgery, Erasmus MC Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - Marcel Smid
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Saskia M Wilting
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Sandra I Bril
- Department of Surgery, Erasmus MC Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.,Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Shanshan Xiang
- Department of Surgery, Erasmus MC Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.,Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michelle van der Vlugt-Daane
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Vanja de Weerd
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Anne van Galen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Katharina Biermann
- Department of Pathology, Erasmus MC Medical Center, Rotterdam, The Netherlands
| | - J Han J M van Krieken
- Department of Pathology, Radboud UMC, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands
| | - Wigard P Kloosterman
- Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - John A Foekens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - John W M Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.,Cancer Genomics Center Netherlands, Amsterdam, The Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus MC Medical Center, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
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34
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Mullany LE, Herrick JS, Wolff RK, Stevens JR, Samowitz W, Slattery ML. MicroRNA-transcription factor interactions and their combined effect on target gene expression in colon cancer cases. Genes Chromosomes Cancer 2017; 57:192-202. [PMID: 29226599 PMCID: PMC5807123 DOI: 10.1002/gcc.22520] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 12/05/2017] [Accepted: 12/06/2017] [Indexed: 12/11/2022] Open
Abstract
Transcription factors (TFs) and microRNAs (miRNAs) regulate gene expression: TFs by influencing messenger RNA (mRNA) transcription and miRNAs by influencing mRNA translation and transcript degradation. Additionally, miRNAs and TFs alter each other's expression, making it difficult to ascertain the effect either one has on target gene (TG) expression. In this investigation, we use a two‐way interaction model with the TF and miRNA as independent variables to investigate whether miRNAs and TFs work together to influence TG expression levels in colon cancer subjects. We used known TF binding sites and validated miRNA targets to determine potential miRNA‐TF‐TG interactions, restricting interactions to those with a TF previously associated with altered risk of colorectal cancer death. We analyzed interactions using normal colonic mucosa expression as well as differential expression, which is measured as colonic carcinoma expression minus normal colonic mucosa expression. We analyzed 3518 miRNA‐TF‐TG triplets using normal mucosa expression and 617 triplets using differential expression. Normal colonic RNA‐Seq data were available for 168 individuals; of these, 159 also had carcinoma RNA‐Seq data. Thirteen unique miRNA‐TF‐TG interactions, comprising six miRNAs, four TFs, and 11 TGs, were statistically significant after adjustment for multiple comparisons in normal colonic mucosa, and 14 unique miRNA‐TF‐TG interactions, comprising two miRNAs, two TFs, and 13 TGs, were found for carcinoma‐normal differential expression. Our results show that TG expression is influenced by both miRNAs as well as TFs, and the influence of one regulator impacts the effect of the other on the shared TG expression.
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Affiliation(s)
- Lila E Mullany
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Division of Epidemiology, University of Utah, Salt Lake City, Utah
| | - Jennifer S Herrick
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Division of Epidemiology, University of Utah, Salt Lake City, Utah
| | - Roger K Wolff
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Division of Epidemiology, University of Utah, Salt Lake City, Utah
| | - John R Stevens
- Department of Mathematics and Statistics, Utah State University, Logan, Utah
| | - Wade Samowitz
- Department of Pathology, University of Utah School, Salt Lake City, Utah
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Division of Epidemiology, University of Utah, Salt Lake City, Utah
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35
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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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36
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miRNA-495 suppresses proliferation and migration of colorectal cancer cells by targeting FAM83D. Biomed Pharmacother 2017; 96:974-981. [DOI: 10.1016/j.biopha.2017.11.138] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 11/22/2017] [Accepted: 11/27/2017] [Indexed: 01/23/2023] Open
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37
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Dai H, Hou K, Cai Z, Zhou Q, Zhu S. Low-level miR-646 in colorectal cancer inhibits cell proliferation and migration by targeting NOB1 expression. Oncol Lett 2017; 14:6708-6714. [PMID: 29391877 PMCID: PMC5770607 DOI: 10.3892/ol.2017.7032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 08/03/2017] [Indexed: 12/16/2022] Open
Abstract
Aberrant expression of microRNA (miRNA) is important in the progression of various human cancers, however further investigation is required in order to fully elucidate mechanisms of and validate actions of endogenous non-coding RNAs. The present study demonstrated that the expression of miR-646 was downregulated in colorectal cancer tissues and cell lines. Notably, it was observed that miR-646, a tumor suppressor, inhibited colorectal cancer cell progression through directly targeting Nin one binding protein (NOB1) expression, which possesses anti-tumor properties in colorectal cancer. Furthermore, knockdown of NOB1 expression was responsible for the tumor-suppressive effect of miR-646. The findings suggest that miR-646 may act as a therapeutic target for the treatment of colorectal cancer.
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Affiliation(s)
- Huajia Dai
- The First Department of General Surgery, Shidong Hospital, Shanghai 200438, P.R. China
| | - Kezhu Hou
- The First Department of General Surgery, Shidong Hospital, Shanghai 200438, P.R. China
| | - Zujin Cai
- The First Department of General Surgery, Shidong Hospital, Shanghai 200438, P.R. China
| | - Qi Zhou
- The First Department of General Surgery, Shidong Hospital, Shanghai 200438, P.R. China
| | - Song Zhu
- The First Department of General Surgery, Shidong Hospital, Shanghai 200438, P.R. China
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38
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Wang Y, Xue J, Kuang H, Zhou X, Liao L, Yin F. microRNA-1297 Inhibits the Growth and Metastasis of Colorectal Cancer by Suppressing Cyclin D2 Expression. DNA Cell Biol 2017; 36:991-999. [PMID: 28933597 DOI: 10.1089/dna.2017.3829] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
microRNAs (miR) can potentially be used for categorizing the various subtypes of colorectal cancer (CRC) and predicting a patient's response to treatment with traditional anti-CRC therapies. We investigated how miR-1297 and its potential target molecule cyclin D2 (CCND2) might affect the progression of CRC. Thirty-two pairs of CRC specimens and corresponding samples of para-tumor tissue were collected and examined for their levels of miR-1297 and CCND2 expression. We also examined miR-1297 and CCND2 expression in cultured SW480 cells. The effects of modulated levels of miR-1297 and CCND2 on cell viability, anchorage-independent growth ability, proliferation, apoptosis, cell cycle distribution, migration, and invasion were detected using specific techniques. The possible regulatory effect of miR-1297 on CCND2 was investigated using dual luciferase assays. Our results showed that miR-1297 expression was downregulated in clinical CRC specimens, and such downregulation was associated with upregulated levels of CCND2 expression. Upregulation of miR-1297 and downregulation of CCND2 reduced the proliferation and metastasis potential of SW480 cells, but did not affect the apoptotic process. In addition, miR-1297 regulated CCND2 function by directly binding to the promoter sequence of the CCND2 gene, which would block CCND2-related signaling at the transcription level. Our findings validate the anti-CRC function of miR-1297 and pro-CRC function of CCND2. Our findings may assist in developing miR-based therapies against CRC.
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Affiliation(s)
- Yanan Wang
- 1 Department of Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University , Zhuhai, China
| | - Jinfang Xue
- 1 Department of Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University , Zhuhai, China
| | - Haoyu Kuang
- 1 Department of Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University , Zhuhai, China
| | - Xiaojun Zhou
- 2 Department of Gastroenterology, The Fifth Affiliated Hospital, Sun Yat-sen University , Zhuhai, China
| | - Liya Liao
- 1 Department of Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University , Zhuhai, China
| | - Fang Yin
- 3 Department of General Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University , Zhuhai, China
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Chen YX, Huang KJ, Niu KX. Recent advances in signal amplification strategy based on oligonucleotide and nanomaterials for microRNA detection-a review. Biosens Bioelectron 2017; 99:612-624. [PMID: 28837925 DOI: 10.1016/j.bios.2017.08.036] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 08/13/2017] [Accepted: 08/14/2017] [Indexed: 01/01/2023]
Abstract
MicroRNAs (MiRNAs) play multiple crucial regulating roles in cell which can regulate one third of protein-coding genes. MiRNAs participate in the developmental and physiological processes of human body, while their aberrant adjustment will be more likely to trigger diseases such as cancers, kidney disease, central nervous system diseases, cardiovascular diseases, diabetes, viral infections and so on. What's worse, for the detection of miRNAs, their small size, high sequence similarity, low abundance and difficult extraction from cells impose great challenges in the analysis. Hence, it's necessary to fabricate accurate and sensitive biosensing platform for miRNAs detection. Up to now, researchers have developed many signal-amplification strategies for miRNAs detection, including hybridization chain reaction, nuclease amplification, rolling circle amplification, catalyzed hairpin assembly amplification and nanomaterials based amplification. These methods are typical, feasible and frequently used. In this review, we retrospect recent advances in signal amplification strategies for detecting miRNAs and point out the pros and cons of them. Furthermore, further prospects and promising developments of the signal-amplification strategies for detecting miRNAs are proposed.
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Affiliation(s)
- Ying-Xu Chen
- College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000, China; Henan Province Key Laboratory of Utilization of Non-metallic Mineral in the South of Henan, Xinyang Normal University, Xinyang 464000, China
| | - Ke-Jing Huang
- College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000, China; Henan Province Key Laboratory of Utilization of Non-metallic Mineral in the South of Henan, Xinyang Normal University, Xinyang 464000, China.
| | - Ke-Xin Niu
- College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000, China; Henan Province Key Laboratory of Utilization of Non-metallic Mineral in the South of Henan, Xinyang Normal University, Xinyang 464000, China
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40
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Lin J, Chuang CC, Zuo L. Potential roles of microRNAs and ROS in colorectal cancer: diagnostic biomarkers and therapeutic targets. Oncotarget 2017; 8:17328-17346. [PMID: 28061475 PMCID: PMC5370044 DOI: 10.18632/oncotarget.14461] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 12/16/2016] [Indexed: 02/06/2023] Open
Abstract
As one of the most commonly diagnosed cancers worldwide, colorectal adenocarcinoma often occurs sporadically in individuals aged 50 or above and there is an increase among younger patients under 50. Routine screenings are recommended for this age group to improve early detection. The multifactorial etiology of colorectal cancer consists of both genetic and epigenetic factors. Recently, studies have shown that the development and progression of colorectal cancer can be attributed to aberrant expression of microRNA. Reactive oxygen species (ROS) that play a key role in cancer cell survival, can also lead to carcinogenesis and cancer exacerbations. Given the rapid accumulating knowledge in the field, an updated review regarding microRNA and ROS in colorectal cancer is necessary. An extensive literature search has been conducted in PubMed/Medline databases to review the roles of microRNAs and ROS in colorectal cancer. Unique microRNA expression in tumor tissue, peripheral blood, and fecal samples from patients with colorectal cancer is outlined. Therapeutic approaches focusing on microRNA and ROS in colorectal cancer treatment is also delineated. This review aims to summarize the newest knowledge on the pathogenesis of colorectal cancer in the hopes of discovering novel diagnostic biomarkers and therapeutic techniques.
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Affiliation(s)
- Jingmei Lin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chia-Chen Chuang
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, Columbus, OH, USA.,Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Li Zuo
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, Columbus, OH, USA.,Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA
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41
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Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7354260. [PMID: 28573140 PMCID: PMC5442347 DOI: 10.1155/2017/7354260] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer.
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42
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Ling Q, Xu X, Ye P, Xie H, Gao F, Hu Q, Liu Z, Wei X, Röder C, Trauzold A, Kalthoff H, Zheng S. The prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma. Oncotarget 2017; 8:15159-15167. [PMID: 28122349 PMCID: PMC5362475 DOI: 10.18632/oncotarget.14768] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 01/10/2017] [Indexed: 12/12/2022] Open
Abstract
Different clinical presentations and prognoses have been implied between pancreatic head and body/tail cancers. We aimed to identify the prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). Thirty-two pairs of patients with strictly matched early stage (II) pancreatic head and body/tail cancers were enrolled. The molecular feature of the two subtypes of PDAC was assessed on the level of miRNA expression. Out of the 64 patients, 34 (53.1%) had tumor recurrence after radical resection during the follow-up period (2.3 ± 0.8 years). Both overall and tumor-free survival were significantly higher in the patients with pancreatic body/tail cancer compared with those with pancreatic head cancer. Patient age and tumor location were the independent prognostic factors for tumor recurrence. A remarkably lower expression of miR-501-3p and higher expression of miR-375 were found and were further verified in pancreatic body/tail cancer tissues compared with pancreatic head cancer tissues. The low expression of miR-501-3p was significantly associated with a low risk of tumor recurrence. Both, subcutaneous and orthotopic PDAC mouse models presented highly invasive tumor phenotypes upon up-regulated miR-501-3p expression. An in vitro study showed that miR-501-3p promoted the invasiveness of PDAC cells possibly via suppressing E-cadherin. In summary, at resectable early stage, pancreatic body/tail cancer presents a less malignant phenotype associated with deregulation of miR-501-3p compared with pancreatic head cancer.
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MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Cadherins/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- Neoplasm Invasiveness
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Neoplasm Staging
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/surgery
- Prognosis
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Qi Ling
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Xiao Xu
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Panpan Ye
- The Ophthalmology Center, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Haiyang Xie
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Feng Gao
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Qichao Hu
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Zhikun Liu
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Xuyong Wei
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Christian Röder
- Institute for Experimental Cancer Research, Comprehensive Cancer Center North, CAU, Kiel, Germany
| | - Anna Trauzold
- Institute for Experimental Cancer Research, Comprehensive Cancer Center North, CAU, Kiel, Germany
| | - Holger Kalthoff
- Institute for Experimental Cancer Research, Comprehensive Cancer Center North, CAU, Kiel, Germany
| | - Shusen Zheng
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, China
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43
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Taborda MI, Ramírez S, Bernal G. Circular RNAs in colorectal cancer: Possible roles in regulation of cancer cells. World J Gastrointest Oncol 2017; 9:62-69. [PMID: 28255427 PMCID: PMC5314202 DOI: 10.4251/wjgo.v9.i2.62] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 11/05/2016] [Accepted: 12/13/2016] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world and the fourth principal cause of cancer deaths worldwide. Currently, there is a lack of low cost and noninvasive screening tests for CRC, becoming a serious health problem. In this context, a potential biomarker for the early detection of CRC has recently gained attention. Circular RNAs (circRNA), a re-discovered, abundant RNA specie, is a type of noncoding covalent closed RNAs formed from both exonic and intronic sequences. These circular molecules are widely expressed in cells, exceeding the abundance of the traditional linear mRNA transcript. They can regulate gene expression, acting as real sponges for miRNAs and also regulate alternative splicing or act as transcriptional factors and inclusive encoding for proteins. However, little is known about circRNA and its relationship with CRC. In this review, we focus on the biogenesis, function and role of these circRNAs in relation to CRC, including their potential as a new biomarker.
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44
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Li D, Li P, Guo Z, Wang H, Pan W. Downregulation of miR-382 by propranolol inhibits the progression of infantile hemangioma via the PTEN-mediated AKT/mTOR pathway. Int J Mol Med 2017; 39:757-763. [PMID: 28112362 DOI: 10.3892/ijmm.2017.2863] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 12/28/2016] [Indexed: 11/06/2022] Open
Abstract
Approximately 10% of infantile hemangiomas (IHs) are the most common vascular tumors affecting children and are characterized by rapid growth, and can have destructive, disfiguring and even life-threatening consequences. Currently, propranolol is considered to be a safe and effective treatment option for problematic proliferating IHs. Recent studies have also revealed that microRNAs (miRNAs or miRs) play important roles in the regulation of angiogenesis. In this study, XPTS‑1 cells were used as a hemangioma-derived endothelial cell line constructed in our laboratory. Through a series of experiments, we discovered that miR‑382 is a novel miRNA associated with IHs, which was overexpressed in XPTS‑1 cells and was conversely downregulated by treatment with propranolol. In addition, we found that miR‑382 contributes to the progression of IHs. Our results revealed that propranolol inhibited XPTS‑1 cell migration and proliferation, and promoted apoptosis, and these effects were reversed by the restoration of miR‑382 expression by transfection of the cells with an miR‑382 overexpression vector. Further experiments revealed that the above-mentioned effects were associated with the phosphatase and tensin homolog (PTEN)-mediated AKT/mammalian target of rapamycin (mTOR) signaling pathway. The expression of PTEN was upregulated, while that of p-AKT, p-mTOR and p-p70S6K was downregulated by propranolol; these effects were partly reversed by the overexpression of miR‑382. On the whole, our study identified that the downregulation of miR‑382 by propranolol inhibits the progression of IHs via the PTEN-mediated AKT/mTOR pathway.
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Affiliation(s)
- Dongfan Li
- Department of Respiratory Medicine, The Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Peng Li
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Zhengtuan Guo
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Huaijie Wang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Weikang Pan
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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45
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Moustafa AA, Ziada M, Elshaikh A, Datta A, Kim H, Moroz K, Srivastav S, Thomas R, Silberstein JL, Moparty K, Salem FEH, El-Habit OH, Abdel-Mageed AB. Identification of microRNA signature and potential pathway targets in prostate cancer. Exp Biol Med (Maywood) 2016; 242:536-546. [PMID: 27903835 DOI: 10.1177/1535370216681554] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PC) is the most common and the second leading cause of cancer-related death among American men. Early diagnosis is a prerequisite to improving therapeutic benefits. However, the current clinical biomarkers for PC do not reliably decipher indolent PC from other urogenital disorders. Thus, effective clinical intervention necessitates development of new biomarkers for early detection of PC. The present study aimed to identify the miRNA signature in organ-confined (Gleason Score 6) prostate tumors. MicroRNA (miRNA/miR) array analysis identified 118 upregulated and 73 downregulated miRNAs in microdissected tumors in comparison to matched neighboring normal prostate epithelium. The miRs-Plus-A1083, -92b-5p, -18a-3p, -19a-3p, -639, -3622b-3p, -3189-3p, -155-3p, -410, -1179, 548b-5p, and -4469 are predominantly expressed (7-11-fold), whereas miRs-595, 4490, -3120-5p, -1299, -21-5p, -3677-3, -let-7b-5p, -5189, 3-121-5p, -4518, -200a-5p, -3682-5p, -3689d, -3149 represent the most downregulated (12-113-fold) miRNAs in microdissected prostate tumors. The array expression profile of selected miRNA signature and their potential mRNA targets was validated by qRT-PCR analysis in PC cell lines. Integrated in silico and computational prediction analyses demonstrated that the dysregulated miRNA signature map to key regulatory factors involved in tumorigenesis, including cell cycle, apoptosis, and p53 pathways. The newly identified miRNA signature has potential clinical utility as biomarkers, prognostic indicators, and therapeutic targets for early detection of PC. Further studies are needed to assess the functional significance and clinical usefulness of the identified miRNAs. Impact Statement To our knowledge his is the first study of identifying miRNA signatures in microdissected indolent (Gleason score 6) prostate cancer in comparison to matched normal prostate epithelium. By employing in silico and computational prediction analysis, the study provides a landscape of potential miRNA targets and key cellular pathways involved in prostate tumorigenesis. Identification if miRNAs and their relevant targets and pathways pave the way for underpinning their mechanistic role of miRNAs in human prostate tumorigenesis, and possibly other human cancers. Importantly, the outcome of the study has important clinical implications for the management of prostate cancer, including the use of miRNA(s) as biomarkers for early detection of prostate cancer.
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Affiliation(s)
- Ahmed A Moustafa
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA.,2 Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo 11790, Egypt
| | - Mohammed Ziada
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Abubaker Elshaikh
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Amrita Datta
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hogyoung Kim
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Krzysztof Moroz
- 3 Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.,4 Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Sudesh Srivastav
- 5 Department of Biostatistics, Tulane University School of Tropical Medicine, New Orleans, LA 70112, USA
| | - Raju Thomas
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA.,4 Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Jonathan L Silberstein
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Krishnarao Moparty
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Fatma Elzahraa H Salem
- 2 Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo 11790, Egypt
| | - Ola H El-Habit
- 2 Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo 11790, Egypt
| | - Asim B Abdel-Mageed
- 1 Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA.,4 Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
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46
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Vymetalkova V, Pardini B, Rosa F, Jiraskova K, Di Gaetano C, Bendova P, Levy M, Veskrnova V, Buchler T, Vodickova L, Naccarati A, Vodicka P. Polymorphisms in microRNA binding sites of mucin genes as predictors of clinical outcome in colorectal cancer patients. Carcinogenesis 2016; 38:28-39. [PMID: 27803053 DOI: 10.1093/carcin/bgw114] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 09/20/2016] [Accepted: 10/31/2016] [Indexed: 12/13/2022] Open
Abstract
Polymorphisms in microRNA (miRNA) binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and susceptibility to common diseases. Mucins have been identified as markers of adverse prognosis. We hypothesized that genetic variations in miRNA binding sites located in mucin genes may modulate signaling response and the maintenance of genomic stability ultimately affecting cancer susceptibility, efficacy of chemotherapy and survival. In this study, we analyzed the association of single nucleotide polymorphisms in predicted miRNA target sites (miRSNPs) of mucin genes with colorectal cancer (CRC) risk and clinical outcome. Thirteen miRSNPs in 9 genes were assessed in 1111 cases and 1469 controls. No strongly significant associations were observed in the case-control study. Patients carrying the CC genotype of rs886403 in MUC21 displayed a shorter survival and higher recurrence risk when compared with TT carriers [overall survival (OS): hazard ratios (HR) 1.69; 95% confidence intervals (CI) 1.13-2.46; P = 0.01 and event-free survival (EFS): HR 1.99; 95% CI 1.38-2.84; P = 0.0002, respectively]. The observed associations were more striking after stratification for tumor site (in patients with colon cancer, OS: HR 2.63; 95% CI 1.69-4.10; P < 0.0001 and EFS: HR 2.65; 95% CI 1.72-4.07; P < 0.0001). In contrast, rectal cancer cases carrying the CC genotype of rs4729655 in MUC17 displayed a longer survival (OS: HR 0.27; 95% CI 0.14-0.54; P = 0.0002) than those with the most common genotype. To our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to mucin genes and revealing their impact on CRC susceptibility or patient's survival.
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Affiliation(s)
- Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic, .,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic
| | | | - Fabio Rosa
- Human Genetics Foundation, 10126 Turin, Italy
| | - Katerina Jiraskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic
| | - Cornelia Di Gaetano
- Human Genetics Foundation, 10126 Turin, Italy.,Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Petra Bendova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic
| | - Miloslav Levy
- Department of Surgery, First Faculty of Medicine, Charles University and Thomayer University Hospital, 14200 Prague, Czech Republic and
| | - Veronika Veskrnova
- Department of Oncology, Thomayer Hospital and First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, Thomayer Hospital and First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic
| | - Alessio Naccarati
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.,Human Genetics Foundation, 10126 Turin, Italy
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.,Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic
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47
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Gopalan V, Islam F, Pillai S, Tang JCO, Tong DKH, Law S, Chan KW, Lam AKY. Overexpression of microRNA-1288 in oesophageal squamous cell carcinoma. Exp Cell Res 2016; 348:146-154. [DOI: 10.1016/j.yexcr.2016.09.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 09/14/2016] [Accepted: 09/16/2016] [Indexed: 12/17/2022]
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48
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Mullany LE, Herrick JS, Wolff RK, Stevens JR, Slattery ML. Association of cigarette smoking and microRNA expression in rectal cancer: Insight into tumor phenotype. Cancer Epidemiol 2016; 45:98-107. [PMID: 27780077 DOI: 10.1016/j.canep.2016.10.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/27/2016] [Accepted: 10/17/2016] [Indexed: 02/08/2023]
Abstract
Smoking is known to influence messenger RNA (mRNA) expression in colorectal cancer (CRC) cases. As microRNAs (miRNAs) are known repressors of mRNAs, we hypothesize that smoking may influence miRNA expression, thus altering mRNA expression. Our sample consisted of 1447 CRC cases that had normal colorectal mucosa and carcinoma miRNA data and lifestyle data. We examined current smoking, current versus never and former versus never (C/F/N) smoking1, and pack-years smoked with miRNA expression in normal mucosa as well as differential miRNA expression between paired normal and carcinoma tissue for colon and rectal tissue to determine associations between smoking and miRNA expression. We adjusted for multiple comparisons using the Benjamini Hochberg false discovery rate (FDR). Significant associations were seen for rectal differential miRNA expression only. We analyzed miRNAs significantly associated with smoking with CIMP and MSI status, using a polytomous logistic regression. Two hundred and thirty-one miRNAs were differentially expressed with current smoking, 172 with C/F/N, and 206 with pack-years smoked; 111 were associated with all three. Forty-three miRNAs were unique to current smoking, 14 were unique to C/F/N and 57 were unique to pack years smoked. Of the 306 unique miRNAs associated with cigarette smoking, 41 were inversely associated and 200 were directly associated with CIMP high or MSI tumor molecular phenotype for either colon or rectal cancer. Our results suggest that cigarette smoking can alter miRNA expression and, given associations with CIMP high and MSI tumor molecular phenotype, it is possible that smoking influences tumor phenotype through altered miRNA expression.
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Affiliation(s)
- Lila E Mullany
- Department of Internal Medicine, University of Utah, 383 Colorow Bldg., Salt Lake City, UT 84108, USA.
| | - Jennifer S Herrick
- Department of Internal Medicine, University of Utah, 383 Colorow Bldg., Salt Lake City, UT 84108, USA.
| | - Roger K Wolff
- Department of Internal Medicine, University of Utah, 383 Colorow Bldg., Salt Lake City, UT 84108, USA.
| | - John R Stevens
- Department of Mathematics and Statistics, Utah State University, 3900 Old Main Hill, Logan, UT 84322, USA.
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, 383 Colorow Bldg., Salt Lake City, UT 84108, USA.
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49
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Mohammadi A, Mansoori B, Baradaran B. The role of microRNAs in colorectal cancer. Biomed Pharmacother 2016; 84:705-713. [PMID: 27701052 DOI: 10.1016/j.biopha.2016.09.099] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/25/2016] [Accepted: 09/26/2016] [Indexed: 01/30/2023] Open
Abstract
Colorectal cancer (CRC) is still the third most common cancer in the world. Mechanism of CRC tumorigenesis has been widely studied at the molecular levels, and has been recently entered the area of microRNAs. MicroRNAs are small 19 to 22 nucleotides of RNA that engage in the regulation of cell differentiation, apoptosis, and cell cycle progression. MicroRNAs are similar to small interfering RNA (siRNA), that post-transcriptionally regulate gene expression and control various cellular mechanisms. They are important factors in the carcinogenesis of CRC, one of the most important factors includes microRNA. MicroRNAs have been linked to CRC development, and these molecules have been recently studied as new potential biomarkers in diagnosis and treatment of CRC. Specific microRNA expression patterns help distinguish CRC from other colon related disease, and may be used as a prognostication factor in patients after treatment with different chemotherapy drugs. More over the newest molecular therapy via tumor suppressor micro RNA replacement can be new insight in molecular therapy of CRC. This review summarizes the potential roles of microRNAs as potential biomarkers for CRC diagnosis, and treatment.
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Affiliation(s)
- Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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50
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Pelossof R, Chow OS, Fairchild L, Smith JJ, Setty M, Chen CT, Chen Z, Egawa F, Avila K, Leslie CS, Garcia-Aguilar J. Integrated genomic profiling identifies microRNA-92a regulation of IQGAP2 in locally advanced rectal cancer. Genes Chromosomes Cancer 2016; 55:311-321. [PMID: 26865277 DOI: 10.1002/gcc.22329] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 10/19/2015] [Accepted: 10/20/2015] [Indexed: 01/24/2023] Open
Abstract
Locally advanced rectal cancer (LARC) is treated with chemoradiation prior to surgical excision, leaving residual tumors altered or completely absent. Integrating layers of genomic profiling might identify regulatory pathways relevant to rectal tumorigenesis and inform therapeutic decisions and further research. We utilized formalin-fixed, paraffin-embedded pre-treatment LARC biopsies (n=138) and compared copy number, mRNA, and miRNA expression with matched normal rectal mucosa. An integrative model was used to predict regulatory interactions to explain gene expression changes. These predictions were evaluated in vitro using multiple colorectal cancer cell lines. The Cancer Genome Atlas (TCGA) was also used as an external cohort to validate our genomic profiling and predictions. We found differentially expressed mRNAs and miRNAs that characterize LARC. Our integrative model predicted the upregulation of miR-92a, miR-182, and miR-221 expression to be associated with downregulation of their target genes after adjusting for the effect of copy number alterations. Cell line studies using miR-92a mimics and inhibitors demonstrate that miR-92a expression regulates IQGAP2 expression. We show that endogenous miR-92a expression is inversely associated with endogenous KLF4 expression in multiple cell lines, and that this relationship is also present in rectal cancers of TCGA. Our integrative model predicted regulators of gene expression change in LARC using pre-treatment FFPE tissues. Our methodology implicated multiple regulatory interactions, some of which are corroborated by independent lines of study, while others indicate new opportunities for investigation.
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Affiliation(s)
- Raphael Pelossof
- Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Oliver S Chow
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lauren Fairchild
- Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - J Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Manu Setty
- Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chin-Tung Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Fumiko Egawa
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Karin Avila
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Christina S Leslie
- Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
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