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Hergalant S, Casse JM, Oussalah A, Houlgatte R, Helle D, Rech F, Vallar L, Guéant JL, Vignaud JM, Battaglia-Hsu SF, Gauchotte G. MicroRNAs miR-16 and miR-519 control meningioma cell proliferation via overlapping transcriptomic programs shared with the RNA-binding protein HuR. Front Oncol 2023; 13:1158773. [PMID: 37601663 PMCID: PMC10433742 DOI: 10.3389/fonc.2023.1158773] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 07/14/2023] [Indexed: 08/22/2023] Open
Abstract
Introduction Meningiomas are the most common type of primary central nervous system tumors. In about 80% cases, these tumors are benign and grow very slowly, but the remainder 20% can unlock higher proliferation rates and become malignant. In this study we examined two miRs, miR-16 and miR-519, and evaluated their role in tumorigenesis and cell growth in human meningioma. Methods A cohort of 60 intracranial grade 1 and grade 2 human meningioma plus 20 healthy meningeal tissues was used to quantify miR-16 and miR-519 expressions. Cell growth and dose-response assays were performed in two human meningioma cell lines, Ben-Men-1 (benign) and IOMM-Lee (aggressive). Transcriptomes of IOMM-lee cells were measured after both miR-mimics transfection, followed by integrative bioinformatics to expand on available data. Results In tumoral tissues, we detected decreased levels of miR-16 and miR-519 when compared with arachnoid cells of healthy patients (miR-16: P=8.7e-04; miR-519: P=3.5e-07). When individually overexpressing these miRs in Ben-Men-1 and IOMM-Lee, we observed that each showed reduced growth (P<0.001). In IOMM-Lee cell transcriptomes, downregulated genes, among which ELAVL1/HuR (miR-16: P=6.1e-06; miR-519:P=9.38e-03), were linked to biological processes such as mitotic cell cycle regulation, pre-replicative complex, and brain development (FDR<1e-05). Additionally, we uncovered a specific transcriptomic signature of miR-16/miR-519-dysregulated genes which was highly enriched in HuR targets (>6-fold; 79.6% of target genes). Discussion These results were confirmed on several public transcriptomic and microRNA datasets of human meningiomas, hinting that the putative tumor suppressor effect of these miRs is mediated, at least in part, via HuR direct or indirect inhibition.
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Affiliation(s)
- Sébastien Hergalant
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Jean-Matthieu Casse
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Abderrahim Oussalah
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
- Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France
- Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France
| | - Rémi Houlgatte
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Déborah Helle
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Fabien Rech
- Department of Neurosurgery, University Hospital of Nancy (CHRU), Nancy, France
- CNRS, UMR7039, CRAN - Centre de Recherche en Automatique de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France
| | - Laurent Vallar
- Genomics and Proteomics, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Jean-Louis Guéant
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
- Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France
- Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France
| | - Jean-Michel Vignaud
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
- Department of Biopathology Institut De Cancérologie de Lorraine (CHRU-ICL), University Hospital of Nancy (CHRU), Nancy, France
- Centre de Ressources Biologiques BB-0033-00035, University Hospital of Nancy (CHRU), Nancy, France
| | - Shyue-Fang Battaglia-Hsu
- Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France
- Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France
- CNRS, UMR7039, CRAN - Centre de Recherche en Automatique de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France
| | - Guillaume Gauchotte
- INSERM, U1256, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
- Department of Biopathology Institut De Cancérologie de Lorraine (CHRU-ICL), University Hospital of Nancy (CHRU), Nancy, France
- Centre de Ressources Biologiques BB-0033-00035, University Hospital of Nancy (CHRU), Nancy, France
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Chu X, Wu D, Zhang C, Hu S. Expression pattern of miR-16-2-3p and its prognostic values on pediatric acute lymphoblastic leukemia. Scand J Clin Lab Invest 2023:1-5. [PMID: 37093849 DOI: 10.1080/00365513.2023.2191335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Acute lymphoblastic leukemia (ALL) is a debilitating illness that easily occurs in adolescents. microRNAs (miRNAs) are potential biomarkers for multiple diseases. This paper was to elaborate on the expression of miR-16-2-3p in childhood ALL and its clinical values on ALL diagnosis and prognosis. First, serum miR-16-2-3p expression in ALL children and healthy volunteers was measured using RT-qPCR. Next, diagnostic potential and prognostic values of miR-16-2-3p on ALL were analyzed through receiver operating characteristic (ROC) curve, Kaplan-Meier survival curve, and multivariate Cox regression analysis, respectively. No significant difference was observed in the clinical baseline data between ALL patients and healthy children. ALL patients showed downregulated serum miR-16-2-3p (0.65 ± 0.27) (p < .01), whose area under the ROC curve was 0.837 with a cut-off value of 0.745 (67.92% sensitivity, 96.94% specificity). ALL patients with higher miR-16-2-3p expression had higher survival rates than those with lower miR-16-2-3p expression. Low miR-16-2-3p expression predicted poor prognosis of ALL patients. After adjusting LDH and lymphomyelocyte proportion (p = 0.003, HR = 0.003, 95%CI = 0.000-0.145), miR-16-2-3p was recognized as an independent prognostic factor for ALL patient survival. Briefly, low serum miR-16-2-3p expression in ALL children could aid ALL diagnosis and predict poor prognosis.
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Affiliation(s)
- Xinran Chu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Dong Wu
- Department of Pediatric, Qiyuan People's Hospital, Zibo, China
| | - Chenyue Zhang
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Shaoyan Hu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
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Lipid Handling Protein Gene Expression in Colorectal Cancer: CD36 and Targeting miRNAs. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122127. [PMID: 36556492 PMCID: PMC9786157 DOI: 10.3390/life12122127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Abstract
The reprogramming of lipid metabolism has been highlighted in colorectal cancer (CRC) studies, suggesting a critical role for the scavenger receptor CD36 and fatty acid synthase (FASN) in this malignancy. In this study, we analyzed the gene expression levels of CD36, FASN, the cell surface glypican 4 (GPC4), and the two transporters SLC27A3 and SLC27A4 in 39 paired tumoral and peritumoral tissues from patients with CRC compared with 18 normal colonic mucosae. Moreover, the levels of seven miRNAs targeting CD36 and most of the analyzed genes were evaluated. We found a significant impairment of the expression of all the analyzed genes except GPC4 as well as the differential expression of miR-16-5p, miR-26b-5p, miR-107, miR-195-5p, and miR-27a-3p in the colonic mucosa of CRC patients. Interestingly, CD36 and miR-27a-3p were downregulated and upregulated, respectively, in tumoral tissues compared to peritumoral and control tissues, with a significant negative correlation in the group of patients developing lymph node metastasis. Our results sustain the relationship between CRC and fatty acid metabolism and emphasize the importance of related miRNAs in developing new therapeutic strategies.
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Dohmen J, Semaan A, Kobilay M, Zaleski M, Branchi V, Schlierf A, Hettwer K, Uhlig S, Hartmann G, Kalff JC, Matthaei H, Lingohr P, Holdenrieder S. Diagnostic Potential of Exosomal microRNAs in Colorectal Cancer. Diagnostics (Basel) 2022; 12:diagnostics12061413. [PMID: 35741223 PMCID: PMC9221658 DOI: 10.3390/diagnostics12061413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/01/2022] [Accepted: 05/27/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Despite the significance of colonoscopy for early diagnosis of colorectal adenocarcinoma (CRC), population-wide screening remains challenging, mainly because of low acceptance rates. Herein, exosomal (exo-miR) and free circulating microRNA (c-miR) may be used as liquid biopsies in CRC to identify individuals at risk. Direct comparison of both compartments has shown inconclusive results, which is why we directly compared a panel of 10 microRNAs in this entity. Methods: Exo-miR and c-miR levels were measured using real-time quantitative PCR after isolation from serum specimens in a cohort of 69 patients. Furthermore, results were compared to established tumor markers CEA and CA 19-9. Results: Direct comparison of exo- and c-miR biopsy results showed significantly higher microRNA levels in the exosomal compartment (p < 0.001). Exo-Let7, exo-miR-16 and exo-miR-23 significantly differed between CRC and healthy controls (all p < 0.05), while no c-miR showed this potential. Sensitivity and specificity can be further enhanced using combinations of multiple exosomal miRNAs. Conclusions: Exosomal microRNA should be considered as a promising biomarker in CRC for future studies. Nonetheless, results may show interference with common comorbidities, which must be taken into account in future studies.
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Affiliation(s)
- Jonas Dohmen
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Alexander Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Makbule Kobilay
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
| | - Martin Zaleski
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
| | - Vittorio Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Anja Schlierf
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Karina Hettwer
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Steffen Uhlig
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Gunther Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Jörg C. Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Hanno Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Stefan Holdenrieder
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
- Correspondence:
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Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy. Cancer Gene Ther 2022; 29:1105-1116. [PMID: 35082400 DOI: 10.1038/s41417-022-00427-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/11/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are known as promising sources for cancer therapy and can be utilized as vehicles in cancer gene therapy. MSC-derived exosomes are central mediators in the therapeutic functions of MSCs, known as the novel cell-free alternatives to MSC-based cell therapy. MSC-derived exosomes show advantages including higher safety as well as more stability and convenience for storage, transport and administration compared to MSCs transplant therapy. Unmodified MSC-derived exosomes can promote or inhibit tumors while modified MSC-derived exosomes are involved in the suppression of cancer development and progression via the delivery of several therapeutics molecules including chemotherapeutic drugs, miRNAs, anti-miRNAs, specific siRNAs, and suicide gene mRNAs. In most malignancies, dysregulation of miRNAs not only occurs as a consequence of cancer progression but also is directly involved during tumor initiation and development due to their roles as oncogenes (oncomiRs) or tumor suppressors (TS-miRNAs). MiRNA restoration is usually achieved by overexpression of TS-miRNAs using synthetic miRNA mimics and viral vectors or even downregulation of oncomiRs using anti-miRNAs. Similar to other therapeutic molecules, the efficacy of miRNAs restoration in cancer therapy depends on the effectiveness of the delivery system. In the present review, we first provided an overview of the properties and potentials of MSCs in cancer therapy as well as the application of MSC-derived exosomes in cancer therapy. Finally, we specifically focused on harnessing the MSC-derived exosomes for the aim of miRNA delivery in cancer therapy.
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Chen CC, Chang PY, Chang YS, You JF, Chan EC, Chen JS, Tsai WS, Huang YL, Fan CW, Hsu HC, Chiang JM. MicroRNA-based signature for diagnosis and prognosis of colorectal cancer using residuum of fecal immunochemical test. Biomed J 2022; 46:144-153. [PMID: 35074584 PMCID: PMC10104956 DOI: 10.1016/j.bj.2022.01.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/28/2021] [Accepted: 01/13/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is still among the most lethal and prevalent malignancies in the world. Despite continuous efforts, the diagnosis and prognosis of CRC have never been satisfying, especially the non-invasive assays. METHODS Our study comprised three independent cohorts of 835 qualified stool samples. From 46 literature-identified miRNA candidates, four miRNA ratios were selected and developed into a miRNA-based signature after applied to the training and test sets. The clinical performances of this signature were further evaluated in the prospective cohorts. RESULTS Four miRNA ratios with significant alterations and the highest discriminating power between the CRC and control groups in the training set were successfully validated in the test set. In the training dataset, combining these four miRNA ratios using a logistic regression model improved the area under the curve value to 0.821 and obtained a sensitivity of 73.6% and specificity of 78.9%. This miRNA signature showed consistent performances in the other two sample cohorts, with the highest sensitivity of 85.7% in the prospective cohort. Additionally, the higher miRNA signature was associated with worse disease-free survival (hazard ratio = 2.27) and overall survival (hazard ratio = 1.83) of CRC patients. For fecal immunochemical test (FIT)-positive populations, the positive predictive value for CRC detection in miRNA-positive subjects was 3.43-fold higher in the prospective cohort, compared to FIT alone. CONCLUSION This stool miRNA signature is highly associated with poor outcome of CRC and can be added to FIT tests to help identify the most at-risk group to receive prompt colonoscopy examination.
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Kudelova E, Holubekova V, Grendar M, Kolkova Z, Samec M, Vanova B, Mikolajcik P, Smolar M, Kudela E, Laca L, Lasabova Z. Circulating miRNA expression over the course of colorectal cancer treatment. Oncol Lett 2021; 23:18. [PMID: 34868358 PMCID: PMC8630815 DOI: 10.3892/ol.2021.13136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/20/2021] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer (CRC) is the third-most common cancer type in males and the second-most common cancer type in females, and has the second-highest overall mortality rate worldwide. Approximately 50% of patients in stage I–III develop metastases, mostly localized to the liver. All physiological conditions occurring in the organism are also reflected in the levels of circulating microRNAs (miRNAs/miRs) in patients. miRNAs are a class of small, non-coding, single-stranded RNAs consisting of 18–25 nucleotides, which have important roles in various cellular processes. The aim of the present study was to evaluate a panel of seven circulating miRNAs (miR-106a-5p, miR-210-5p, miR-155-5p, miR-21-5p, miR-103a-3p, miR-191-5p and miR-16-5p) as biomarkers for monitoring patients undergoing adjuvant treatment of CRC. Total RNA was extracted from the plasma of patients with CRC prior to surgery, in the early post-operative period (n=60) and 3 months after surgery (n=14). The levels of the selected circulating miRNAs were measured with the miRCURY LNA miRNA PCR system and fold changes were calculated using the standard ∆∆Cq method. DIANA-miRPath analysis was used to evaluate the role of significantly deregulated miRNAs. The results indicated significant upregulation of miR-155-5p, miR-21-5p and miR-191-5p, and downregulation of miR-16-5p directly after the surgery. In paired follow-up samples, the most significant upregulation was detected for miR-106a-5p and miR-16-5p, and the most significant downregulation was for miR-21-5p. Pathway analysis outlined the role of the differentially expressed miRNAs in cancer development, but the same pathways are also involved in wound healing and regeneration of intestinal epithelium. It may be suggested that these processes should also be considered in studies investigating sensitive and easily detectable circulating biomarkers for recurrence in patients.
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Affiliation(s)
- Eva Kudelova
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Veronika Holubekova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marian Grendar
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Zuzana Kolkova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marek Samec
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Barbora Vanova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Peter Mikolajcik
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marek Smolar
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Erik Kudela
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Ludovit Laca
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
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Huang Y, Zou Y, Xiong Q, Zhang C, Sayagués JM, Shelat VG, Wang X. Development of a novel necroptosis-associated miRNA risk signature to evaluate the prognosis of colon cancer patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1800. [PMID: 35071494 PMCID: PMC8756225 DOI: 10.21037/atm-21-6576] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Necroptosis is a recently discovered caspase-independent form of cell death which plays an important role in the occurrence and development of cancer. As an important regulatory factor in necroptosis, microRNAs (miRNAs) are important for the development of colon cancer. This study established a novel necroptosis-related miRNA risk signature to evaluate the prognosis of patients with colon adenocarcinoma (COAD). METHODS The necroptosis-related miRNAs were selected by assessing the differential expression of miRNAs in 459 COAD patient samples and 8 control samples from The Cancer Genome Atlas (TCGA). Selection operator Cox analyses and survival analyses were used to establish the risk signature of 7 miRNAs related to necroptosis. Functional enrichment analysis and nomograms were used to explore the potential effects of necroptosis-related miRNAs on prognosis and metastasis. The target genes of the necroptosis-related miRNAs were predicted using online databases and the genes related to overall survival (OS) were screened. RESULTS The risk signature was based on 7 necroptosis-related miRNAs. Nomograms showed that the risk signature was effective at predicting the prognosis and TNM stage of COAD patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that these miRNAs play an important role in cancer development, metastasis, and prognosis. A total of 38 target genes for these miRNAs were found to be associated with the OS in COAD patients. CONCLUSIONS This study provided novel evidence that necroptosis-related miRNAs are associated with the prognosis of COAD patients. A risk signature established based on these miRNAs could effectively predict the prognosis and metastasis of COAD in patients.
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Affiliation(s)
- Yang Huang
- General Surgery Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanyuan Zou
- General Surgery Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiru Xiong
- General Surgery Department, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chao Zhang
- General Surgery Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - José María Sayagués
- Servicio de Anatomía Patológica, Hospital Clínico Universitario de Salamanca e Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Salamanca, Spain
| | - Vishal G. Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Xingyu Wang
- Emergency Surgery Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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10
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Ourô S, Mourato C, Velho S, Cardador A, Ferreira MP, Albergaria D, Castro RE, Maio R, Rodrigues CMP. Potential of miR-21 to Predict Incomplete Response to Chemoradiotherapy in Rectal Adenocarcinoma. Front Oncol 2020; 10:577653. [PMID: 33194696 PMCID: PMC7653406 DOI: 10.3389/fonc.2020.577653] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/21/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Patients with locally advanced rectal adenocarcinoma (LARC) are treated with neoadjuvant chemoradiotherapy (CRT). However, biomarkers for patient selection are lacking, and the association between miRNA expression and treatment response and oncological outcomes is unclear. Objectives: To investigate miRNAs as predictors of response to neoadjuvant CRT and its association with oncological outcomes. Methods: This retrospective study analyzed miRNA expression (miR-16, miR-21, miR-135b, miR-145, and miR-335) in pre- and post-chemoradiation rectal adenocarcinoma tissue and non-neoplastic mucosa in 91 patients treated with neoadjuvant CRT (50.4 Gy) and proctectomy. Two groups were defined: a pathological complete responders group (tumor regression grade—TRG 0) and a pathological incomplete responders group (TRG 1, 2, and 3). Results: miR-21 and miR-135b were upregulated in tumor tissue of incomplete responders comparing with non-neoplastic tissue (p = 0.008 and p < 0.0001, respectively). Multivariate analysis showed significant association between miR-21 in pre-CRT tumor tissue and response, with a 3.67 odds ratio (OR) of incomplete response in patients with higher miR-21 levels (p = 0.04). Although with no significance, patients treated with 5-fluorouracil (5-FU) presented reduced odds of incomplete response compared with those treated with capecitabine (OR = 0.19; 95% confidence interval (CI) 0.03–1.12, p = 0.05). Moreover, significant differences were seen in overall survival (OS) in relation to clinical TNM stage (p = 0.0004), cT (p = 0.0001), presence of distant disease (p = 0.002), mesorectal tumor deposits (p = 0.003), and tumor regression grade (p = 0.04). Conclusion: miR-21 may predict response to CRT in rectal cancer (RC).
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Affiliation(s)
- Susana Ourô
- Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal.,NOVA Medical School, Lisbon, Portugal
| | - Cláudia Mourato
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Sónia Velho
- Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - André Cardador
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | | | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Rui Maio
- Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal.,NOVA Medical School, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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11
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Tian Y, Cui L, Lin C, Wang Y, Liu Z, Miao X. LncRNA CDKN2B-AS1 relieved inflammation of ulcerative colitis via sponging miR-16 and miR-195. Int Immunopharmacol 2020; 88:106970. [PMID: 33182065 DOI: 10.1016/j.intimp.2020.106970] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/13/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study was aimed to explore the differential expression of lncRNA CDKN2B-AS1-miR-195-5p/miR-16-5p axis in ulcerative colitis (UC) and its role in regulating UC pathogenesis. METHODS One hundred and eighty-seven UC patients and one hundred and fifty-two healthy volunteers were recruited, and their blood samples were collected. Inflammatory cytokines in serum were determined with ELISA, and lncRNA CDKN2B-AS1, miR-195-5p and miR-16-5p levels were detected with RT-PCR. Then pcDNA3.1-CDKN2B-AS1, si-CDKN2B-AS1, miR-195-5p mimic, miR-195-5p inhibitor, miR-16-5p mimic and miR-16-5p inhibitor were transfected into HT29 cells, and proliferation and apoptosis of the cells were assessed. Dual-luciferase reporter gene assay was implemented to identify the sponging relationship between lncRNA CDKN2B-AS1 and miR-195-5p/miR-16-5p. RESULTS CDKN2B-AS1 level was negatively correlated with levels of inflammatory cytokines, including TNF-α, IL-6 and sIL-2R, yet miR-16-5p and miR-195-5p levels were negatively correlated with the CDKN2B-AS1 level. The CDKN2B-AS1 combined with miR-16-5p and miR-195-5p also achieved an optimum efficacy in differentiating between light and medium UC, light and severe UC, as well as medium and heavy UC. Furthermore, pcDNA3.1-CDKN2B-AS1 depressed expressions of IFN-γ, IL-8, IL-1β and TNF-α in HT29 cells (P < 0.05), and strengthened proliferation of the cells (P < 0.05). CDKN2B-AS1 also sponged and regulated miR-16-5p and miR-195-5p in HT29 cells, and miR-16-5p and miR-195-5p could reverse the effect of CDKN2B-AS1 on inflammatory cytokine production, barrier function and apoptosis of HT29 cells (P < 0.05). CONCLUSION LncRNA CDKN2B-AS1 regulated inflammation of UC by sponging miR-195-5p and miR-16-5p, providing an alternative for diagnosis and treatment of UC.
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Affiliation(s)
- Yuanyuan Tian
- Department of Gastroenterology, Hainan General Hospital & Hainan Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province 570311, China
| | - Lujia Cui
- Department of Gastroenterology, Hainan General Hospital & Hainan Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province 570311, China
| | - Cheng Lin
- Department of Gastroenterology, Hainan General Hospital & Hainan Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province 570311, China
| | - Yuxuan Wang
- Department of Gastroenterology, Hainan General Hospital & Hainan Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province 570311, China
| | - Zhanju Liu
- Department of Pathology, Haikou Hospital of Traditional Chinese Medicine, Haikou City, Hainan Province 570216, China
| | - Xinpu Miao
- Department of Gastroenterology, Hainan General Hospital & Hainan Affiliated Hospital of Hainan Medical University, Haikou City, Hainan Province 570311, China.
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12
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Han J, Sun W, Liu R, Zhou Z, Zhang H, Chen X, Ba Y. Plasma Exosomal miRNA Expression Profile as Oxaliplatin-Based Chemoresistant Biomarkers in Colorectal Adenocarcinoma. Front Oncol 2020; 10:1495. [PMID: 33072545 PMCID: PMC7531016 DOI: 10.3389/fonc.2020.01495] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 07/13/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Chemotherapy is one of the most common therapies used in the treatment of colorectal cancer (CRC), but chemoresistance inevitably occurs. It is challenging to obtain an immediate and accurate diagnosis of chemoresistance. The potential of circulating exosomal miRNAs as oxaliplatin-based chemoresistant biomarkers in CRC patients was investigated in this study. Methods: Plasma exosomal miRNAs in sensitive and resistant patients were analyzed by miRNA microarray analysis, followed by verification with a quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay in two independent cohorts. The diagnostic accuracy was determined by ROC curve analysis. Logistic regression analysis and Spearman's rank correlation test were also performed. Finally, bioinformatics was used to preliminarily explore the potential molecular mechanism of the selected miRNAs in chemoresistance. Results: miRNA microarray analysis identified four upregulated miRNAs and 20 downregulated miRNAs in chemoresistant patients compared to chemosensitive patients. Twelve markedly dysregulated miRNAs were selected for further investigation, of which six (miR-100, miR-92a, miR-16, miR-30e, miR-144-5p, and let-7i) were verified to be significantly and consistently dysregulated (>1.5-fold, P < 0.05). The combination of the six miRNAs had the highest AUC (0.825, 95% CI, 0.753–0.897). The expression level of these 6 miRNAs was not correlated with tumor location, stage, or chemotherapy program. Only miR-100 was significantly upregulated in low histological grade. GO analysis and KEGG pathway analysis showed that miRNAs were related to RNA polymerase II transcription and enriched in the PI3K-AKT signaling pathway, AMPK signaling pathway, and FoxO signaling pathway. Conclusions: We identified a panel of plasma exosomal miRNAs, containing miR-100, miR-92a, miR-16, miR-30e, miR-144-5p, and let-7i, that could significantly distinguish chemoresistant patients from chemosensitive patients. The detection of circulating exosomal miRNAs may serve as an effective way to monitor CRC patient responses to chemotherapy. Targeting these miRNAs may also be a promising strategy for CRC treatment.
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Affiliation(s)
- Jiayi Han
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Wu Sun
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Rui Liu
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Zhen Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University Advanced Institute for Life Sciences (NAILS), Nanjing University, Nanjing, China
| | - Haiyang Zhang
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Xi Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University Advanced Institute for Life Sciences (NAILS), Nanjing University, Nanjing, China
| | - Yi Ba
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
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13
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Association of the Expression Level of miR-16 with Prognosis of Solid Cancer Patients: A Meta-Analysis and Bioinformatic Analysis. DISEASE MARKERS 2020; 2020:8815270. [PMID: 32774515 PMCID: PMC7397416 DOI: 10.1155/2020/8815270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/19/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
Objective To assess the association between the expression level of miR-16 and prognosis of solid cancer patients by meta-analysis and bioinformatic analysis. Methods PubMed, Web of Science, and Embase databases were searched until October 31, 2019, to identify eligible studies reporting the association of the miR-16 status with the prognosis of solid cancer patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled, and a heterogeneity test was conducted. Sensitivity analysis and a publication bias test were also carried out. Furthermore, the miRpower database was used to validate the association. Results Thirteen articles with 2303 solid cancer patients were included in the meta-analysis. Solid cancer patients with low expression level of miR-16 had shorter survival time (I2 = 84.0%, HR = 1.47, 95% CI: 1.13-1.91, P = 0.004). In the subgroup analyses of cancer sites, low miR-16 expression level was associated with poor prognosis in the reproductive system cancers (I2 = 33.3%, HR = 1.24, 95% CI: 1.06-1.45, P = 0.008). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Begg's test and Egger's test revealed no publication bias in the meta-analysis. In bioinformatic analysis, the significant association between miR-16 level and prognosis of patients with reproductive system cancers was further confirmed (HR = 1.21, 95% CI: 1.03-1.42, P = 0.017). Conclusion Low expression level of miR-16 is an indicator for poor prognosis of solid cancer patients, particularly in reproductive system cancers.
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14
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Development of MicroRNAs as Potential Therapeutics against Cancer. JOURNAL OF ONCOLOGY 2020; 2020:8029721. [PMID: 32733559 PMCID: PMC7378626 DOI: 10.1155/2020/8029721] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/25/2020] [Indexed: 12/24/2022]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that function at the posttranscriptional level in the cellular regulation process. miRNA expression exerts vital effects on cell growth such as cell proliferation and survival. In cancers, miRNAs have been shown to initiate carcinogenesis, where overexpression of oncogenic miRNAs (oncomiRs) or reduced expression of tumor suppressor miRNAs has been reported. In this review, we discuss the involvement of miRNAs in tumorigenesis, the role of synthetic miRNAs as either mimics or antagomirs to overcome cancer growth, miRNA delivery, and approaches to enhance their therapeutic potentials.
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15
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Ye S, Yu C, Zhang G, Shi F, Chen Y, Yang J, Wu W, Zhou Y. Downregulation of microRNA-126 is inversely correlated with insulin receptor substrate-1 protein expression in colorectal cancer and is associated with advanced stages of disease. Oncol Lett 2020; 20:2411-2419. [PMID: 32782558 PMCID: PMC7400408 DOI: 10.3892/ol.2020.11796] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/28/2020] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is a common human malignant tumor, and the fourth most common cause of cancer-associated mortality in China. However, the pathogenesis of CRC is not yet fully understood. The present study aimed to investigate the expression and clinical significance of microRNA (miR)-126 and insulin receptor substrate-1 (IRS-1), as well as the role of miR-126 in the prognosis of patients with CRC. A total of 86 colorectal tissue specimens, including 40 CRC and adjacent normal tissue, 26 colorectal adenoma tissue and 20 normal colorectal tissue samples, were collected for the present study. Reverse transcription-quantitative PCR analysis was performed to determine miR-126 and IRS-1 mRNA expression levels, while western blotting and immunohistochemistry (IHC) analyses were performed to determine IRS-1 protein expression levels. The correlation between miR-126 and IRS-1 expression, as well as the association between altered miR-126 and IRS-1 expression levels and clinicopathological characteristics, and the overall survival time of patients with CRC were assessed. The results demonstrated that miR-126 expression was significantly downregulated, while IRS-1 protein expression was upregulated in CRC tissues compared with that in adjacent normal tissues, colorectal adenoma tissues and normal colorectal tissues, respectively. IHC analysis exhibited strong positive staining of IRS-1 protein in CRC tissues, while absent or weak staining of IRS-1 protein was detected in adjacent normal tissues, colorectal adenoma tissues and normal colorectal tissues. miR-126 expression was inversely correlated with IRS-1 protein expression in CRC tissues (r=−0.420; P<0.05). Furthermore, downregulated miR-126 expression was associated with advanced clinicopathological characteristics of the disease and a shorter overall survival time in patients with CRC. Taken together, the results of the present study suggest that miR-126 downregulation may be a candidate molecular marker predictive of poor prognosis of patients with CRC.
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Affiliation(s)
- Shicai Ye
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Caiyuan Yu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Guixia Zhang
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Feixiong Shi
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Yongze Chen
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Jianyun Yang
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Weiyun Wu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Yu Zhou
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
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16
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Yang Y, Zhao F. MicroRNA-16 inhibits the growth and metastasis of human glioma cells via modulation of PI3K/AKT/mTOR signalling pathway. Arch Med Sci 2020; 20:839-846. [PMID: 39050153 PMCID: PMC11264078 DOI: 10.5114/aoms.2020.95653] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 01/18/2020] [Indexed: 07/27/2024] Open
Abstract
Introduction Gliomas are lethal cancers accounting for significant human mortality across the globe. MicroRNAs (miRs) have shown potential to act as therapeutic targets for the treatment of cancer. Herein the role and therapeutic implications of miR-16 in glioma were investigated. Material and methods Expression analysis was carried out by qRT-PCR. Cell-Titer-Glo assay (Promega) was used for the determination of cell proliferation. DAPI, AO/EB, and annexin V/PI assays were used to detect apoptosis. Wound healing and Transwell assays were used for cell migration and invasion, respectively. Western blot analysis was used for the determination of protein expression. Results The study revealed that miR-16 was significantly suppressed in the human glioma cells. Ectopic expression of miR-16 in U118 MG cells inhibited the proliferation via induction of apoptosis. The apoptosis induction was also accompanied by an upsurge of Bax and depletion of Bcl-2. The overexpression of miR-16 also inhibited the migration and invasion of the glioma U118 MG cells, as evident from the wound healing and transwell assays, which were accompanied by the inhibition of metalloproteinase-2 and -9 (MMP-2 and MMP-9). The effects of miR-16 overexpression were also examined on the PI3K/AKT/mTOR signalling pathway. The results showed that miR-16 overexpression inhibited the phosphorylation of the p70S6K, AKT, and mTOR at Ser473, Ser2448, and Thr389, respectively, with no apparent effects on the total PI3K and AKT. Conclusions miR-16 acts as tumour suppressor in glioma and may severe as therapeutic target for glioma treatment.
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Affiliation(s)
- Yan Yang
- Department of Clinical Pharmacy, No. 1 People’s Hospital, Jining, Shandong, China
| | - Feng Zhao
- Department of Neurosurgery, Jining No. 1 People’s Hospital, Jining, Shandong, China
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17
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Farace C, Pisano A, Griñan-Lison C, Solinas G, Jiménez G, Serra M, Carrillo E, Scognamillo F, Attene F, Montella A, Marchal JA, Madeddu R. Deregulation of cancer-stem-cell-associated miRNAs in tissues and sera of colorectal cancer patients. Oncotarget 2020; 11:116-130. [PMID: 32010426 PMCID: PMC6968784 DOI: 10.18632/oncotarget.27411] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is a deadly tumour in Western countries characterized by high cellular/molecular heterogeneity. Cancer stem cells (CSC) act in cancer recurrence, drug-resistance and in metastatic epithelial-to-mesenchymal transition. microRNAs (miRNAs) contribute to cancer is increasing, and miRNA roles in CSC phenotype and fate and their utility as CRC biomarkers have also been reported. Here, we investigated miR-21, miR-221, miR-18a, miR-210, miR-31, miR-34a, miR-10b and miR-16 expression in experimental ALDH+ and CD44+/CD326+ colorectal CSCs obtained from the human CRC cell lines HCT-116, HT-29 and T-84. Then, we moved our analysis in cancer tissue (CT), healthy tissue (HT) and serum (S) of adult CRC patients (n=12), determining relationships with clinical parameters (age, sex, metastasis, biochemical serum markers). Specific miRNA patterns were evident in vitro (normal, monolayers and CSCs) and in patients’ samples stratified by TNM stage (LOW vs HIGH) or metastasis (Met vs no-Met). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the CSCs phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in CT ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of LOW/HIGH grade and no-Met patients. Our results identify miRNAs useful as colorectal CSC biomarker and that miR-21, miR-210, miR-10b and miR-31b are promising markers of CRC. A specific role of miR-18a as metastatic CRC serum biomarker in adult patients was also highlighted.
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Affiliation(s)
- Cristiano Farace
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,National Institute of Biostructures and Biosystems, Rome, Italy
| | - Andrea Pisano
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Carmen Griñan-Lison
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain
| | - Giuliana Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Gema Jiménez
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Bio-Health Research Foundation of Eastern Andalusia - Alejandro Otero (FIBAO), Granada, Spain
| | - Marina Serra
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Esmeralda Carrillo
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | | | - Federico Attene
- O.U. of Surgery I (Surgical Pathology), A.O.U. Sassari, Sassari, Italy
| | - Andrea Montella
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Roberto Madeddu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,National Institute of Biostructures and Biosystems, Rome, Italy
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18
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Liu Y, Zhou J, Wang S, Song Y, Zhou J, Ren F. Long non-coding RNA SNHG12 promotes proliferation and invasion of colorectal cancer cells by acting as a molecular sponge of microRNA-16. Exp Ther Med 2019; 18:1212-1220. [PMID: 31316616 PMCID: PMC6601377 DOI: 10.3892/etm.2019.7650] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 04/18/2019] [Indexed: 12/11/2022] Open
Abstract
Long non-coding (lnc)RNA small nucleolar RNA host gene 12 (SNHG12) has an oncogenic role in various common human cancer types, including colorectal cancer (CRC). However, the detailed regulatory mechanisms of SNHG12 in CRC cells have remained largely elusive, and the investigation thereof was the purpose of the present study. Polymerase chain reaction analysis was performed to examine the expression of lncRNA and microRNA (miR). Cell Counting Kit-8 and Transwell assays were used to assess cell proliferation and invasion. A luciferase reporter assay was performed to confirm a predicted targeting association between lncRNA and miR. It was observed that SNHG12 was markedly upregulated in CRC tissues when compared with that in adjacent non-tumour tissues, and its high expression was associated with CRC progression, as well as poor prognosis of patients. In addition, the expression of SNHG12 was higher in CRC cell lines when compared with that in a normal intestinal epithelial cell line. Knockdown of SNHG12 significantly inhibited CRC cell proliferation and invasion, while ectopic overexpression of SNHG12 had the opposite effect. A Bioinformatics analysis predicted that SNHG12 and miR-16 have complementary binding sites, which was confirmed by a luciferase reporter gene assay. The expression levels of miR-16 were markedly decreased in CRC tissues and cell lines compared with those in normal tissues or cells, and were inversely correlated with the expression levels of SNHG12 in CRC tissues. Furthermore, silencing of miR-16 eliminated the suppressive effects of SNHG12 knockdown on CRC cell proliferation and invasion. In conclusion, the present study demonstrated that SNHG12 promotes CRC cell proliferation and invasion, at least in part, by acting as a molecular sponge of miR-16, suggesting that SNHG12 may be a promising therapeutic target for CRC.
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Affiliation(s)
- Yuehua Liu
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Jingyu Zhou
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Shalong Wang
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yuliang Song
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Jianping Zhou
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Feng Ren
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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19
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Madadi S, Soleimani M. Comparison of miR-16 and cel-miR-39 as reference controls for serum miRNA normalization in colorectal cancer. J Cell Biochem 2019; 120:4802-4803. [PMID: 30609138 DOI: 10.1002/jcb.28174] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Soheil Madadi
- Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Meysam Soleimani
- Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
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Hasáková K, Bezakova J, Vician M, Reis R, Zeman M, Herichova I. Gender-dependent expression of leading and passenger strand of miR-21 and miR-16 in human colorectal cancer and adjacent colonic tissues. Physiol Res 2018; 66:S575-S582. [PMID: 29355387 DOI: 10.33549/physiolres.933808] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
miRNAs are small regulatory RNA molecules involved in posttranscriptional gene silencing. Their biosynthesis results in the formation of duplex consisting of a leading and a passenger strand of mature miRNA. The leading strand exhibits the main activity but recent findings indicate a certain role of the passenger strand as well. Deregulated levels of miRNA were found in many types of cancers including colorectal cancer. miR-21 and miR-16 were indicated as possible markers of colorectal cancer, however, small attention to gender differences in their expression was paid so far. Therefore, the aim of our study was to investigate the expression of miR-21-5p, miR-21-3p, miR-16-5p and miR-16-3p in human colorectal cancer tissue and compare it to the adjacent tissues taken during surgery in men and women separately. Our results showed an up-regulation of all measured miRNAs in tumor tissue compared to adjacent tissues. As expected, tumors and adjacent tissues exhibited a significantly higher expression of leading miRNAs compared to passenger strand of miR-21 and miR-16. The expression of leading and passenger strand of miR-21 and miR-16 positively correlated exhibiting the highest correlation coefficient in the distal tissue. The expression pattern showed gender-dependent differences, with higher levels of miRNA in men than in women. Our findings indicate a gender-related expression pattern of miRNA, which should be considered as an important factor in generating new prognostic or diagnostic biomarkers.
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Affiliation(s)
- K Hasáková
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, Slovak Republic.
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21
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Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of microRNAs in colorectal cancer: a meta-analysis. Cancer Manag Res 2018; 10:907-929. [PMID: 29750053 PMCID: PMC5935085 DOI: 10.2147/cmar.s157493] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have shown that miRNA levels are closely related to the survival time of patients with colon, rectal, or colorectal cancer (CRC). However, the outcomes of different investigations have been inconsistent. Accordingly, a meta-analysis was conducted to study associations among the three types of cancers. Materials and methods Studies published in English that estimated the expression levels of miRNAs with survival curves in CRC were identified until May 20, 2017 by online searches in PubMed, Embase, Web of Science, and the Cochrane Library by two independent authors. Pooled HRs with 95% CIs were used to estimate the correlation between miRNA expression and overall survival. Results A total of 63 relevant articles regarding 13 different miRNAs, with 10,254 patients were ultimately included. CRC patients with high expression of blood miR141 (HR 2.52, 95% CI 1.68-3.77), tissue miR21 (HR 1.31, 95% CI 1.12-1.53), miR181a (HR 1.52, 95% CI 1.26-1.83), or miR224 (HR 2.12, 95% CI 1.04-4.34), or low expression of tissue miR126 (HR 1.55, 95% CI 1.24-1.93) had significantly poor overall survival (P<0.05). Conclusion In general, blood miR141 and tissue miR21, miR181a, miR224, and miR126 had significant prognostic value. Among these, blood miR141 and tissue miR224 were strong biomarkers of prognosis for CRC.
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Affiliation(s)
- Song Gao
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Zhi-Ying Zhao
- School of Computer Science and Engineering, Northeastern University, Shenyang
| | - Rong Wu
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Yue Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen-Yong Zhang
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
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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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Eldeib MG, Kandil YI, Abdelghany TM, Mansour OA, El-Zahabi MM. Alterations of microRNAs expression in response to 5-Fluorouracil, Oxaliplatin, and Irinotecan treatment of colorectal cancer cells. GENE REPORTS 2017. [DOI: 10.1016/j.genrep.2017.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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24
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Wu LY, Ma XP, Shi Y, Bao CH, Jin XM, Lu Y, Zhao JM, Zhou CL, Chen D, Liu HR. Alterations in microRNA expression profiles in inflamed and noninflamed ascending colon mucosae of patients with active Crohn's disease. J Gastroenterol Hepatol 2017; 32:1706-1715. [PMID: 28261881 DOI: 10.1111/jgh.13778] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/30/2017] [Accepted: 02/17/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM The microRNA (miRNA) expression profiles of the terminal ileum, sigmoid colon, and rectal mucosa of adult patients with active Crohn's disease (CD) have been previously reported. The purpose of this study was to identify dysregulated miRNAs in the mucosa of the ascending colon. METHODS Biopsy tissue samples were taken from the mucosae of inflammatory (iCD) or noninflammatory (niCD) areas of the ascending colons of adult patients with active CD. miRNA and mRNA expression profiles were detected using microarray analyses. miRNAs and messenger RNAs (mRNAs) demonstrating significant differences were validated via quantitative real-time polymerase chain reaction. Luciferase reporter genes were used to measure two miRNAs inhibition of potential target genes in human 293T cells in vitro. RESULTS Compared with the healthy control group, the ascending colon miRNA expression profiles revealed that 43 miRNAs were significantly upregulated and 35 were downregulated in the iCD group. The mRNA expression profiles indicated that 3370 transcripts were significantly differentially expressed in the ascending colon, with 2169 upregulated and 1201 downregulated mRNAs in the iCD group, and only 20 miRNAs demonstrated significant differential expression in the niCD group. In contrast, nearly 100 miRNAs significantly varied between the iCD and niCD groups. Finally, luciferase reporter gene assays showed that hsa-miR-16-1 directly regulated the human C10orf54 gene and that they were negatively correlated. CONCLUSIONS Our results indicated that the differentially expressed miRNAs and mRNAs were related to immune inflammation and intestinal flora. The data provide preliminary evidence that the occurrence of CD involves the inhibition of C10orf54 expression by hsa-miR-16-1.
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Affiliation(s)
- Lu Yi Wu
- Qigong Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao Peng Ma
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yin Shi
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chun Hui Bao
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao Ming Jin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yuan Lu
- Department of Mechanics and Engineering Science, Fudan University, Shanghai, China
| | - Ji Meng Zhao
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ci Li Zhou
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dai Chen
- Novel Bioinformatics Company, Ltd., Shanghai, China
| | - Hui Rong Liu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Yang J, Liu R, Deng Y, Qian J, Lu Z, Wang Y, Zhang D, Luo F, Chu Y. MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8+ T cells through targeting mTOR. Int J Cancer 2017; 141:2082-2092. [PMID: 28758198 DOI: 10.1002/ijc.30912] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 07/04/2017] [Accepted: 07/19/2017] [Indexed: 12/17/2022]
Abstract
MiR-15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor-infiltrating immune cells. In our study, using an orthotropic GL261 mouse glioma model, we found that miR-15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor-infiltrating CD8+ T cells. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells. Also, our in vitro experiments further confirmed that miR-15a/16-/- CD8+ T displayed higher active phenotypes, more cytokines secretion and faster expansion, compared to WT CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR-15a/16 to negatively regulate the activation of CD8+ T cells. Taken together, these data suggest that miR-15a/16 deficiency resists the exhaustion and maintains the activation of glioma-infiltrating CD8+ T cells to alleviate glioma progression via targeting mTOR. Our findings provide evidence for the potential immunotherapy through targeting miR-15a/16 in tumor-infiltrating immune cells.
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Affiliation(s)
- Jiao Yang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
| | - Ronghua Liu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuting Deng
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
| | - Jiawen Qian
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
| | - Zhou Lu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuedi Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
| | - Dan Zhang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
| | - Feifei Luo
- Biotherapy Research Center, Fudan University, Shanghai, China.,Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
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26
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Zhan XH, Xu QY, Tian R, Yan H, Zhang M, Wu J, Wang W, He J. MicroRNA16 regulates glioma cell proliferation, apoptosis and invasion by targeting Wip1-ATM-p53 feedback loop. Oncotarget 2017; 8:54788-54798. [PMID: 28903382 PMCID: PMC5589621 DOI: 10.18632/oncotarget.18510] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 05/27/2017] [Indexed: 01/05/2023] Open
Abstract
The present study aimed to investigate the role and underlying mechanisms of microRNA16 (miR-16) on proliferation, apoptosis and invasion of glioma cells. The cell models of miR-16 upregulation and Negative control group (NC group) were built. The cell functions of different groups were detected by colony formation assay, transwell chamber assay, proliferation, apoptosis and cycle experiments. The intracranial orthotopic transplantation animal models were built to different groups: miR-16 agomir group, miR-16 antagomir group and their NC group. The expressions of miR-16, Wip1, ATM and p53 were measured by qRT-PCR, western blot and immunohistochemistry. As a result, miR-16 overexpressed groups had lower cloning formation rate and proliferation rate, less invasive cells, higher early apoptosis rate than the control groups. G1 phase was significantly smaller compared miR-16 overexpressed groups with the control groups, and S phase significantly lesser. Cell growth was retardated. Differences were statistically significant (P <0.05). Compared with miR-16 overexpressed groups and NC groups, the Wip1 gene and protein expression were downregulated, while ATM and p53 genes, p-ATM and p-p53 proteins were upregulated. The differences were statistically significant (P <0.05). Taken together, our findings demonstrated that miR-16 suppressed glioma cell proliferation and invasion, promoted apoptosis and inhibited cell cycle by targeting Wip1-ATM-p53 signaling pathway.
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Affiliation(s)
- Xiao-Hong Zhan
- 1 School of Medicine, Shandong University, Jinan 250012, Shangdong Province, P.R. China
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
- 3 Department of Pathology, The Affiliated Central Hospital of Qingdao University, Qingdao 266000, Shandong Province, P.R. China
| | - Qiu-Yan Xu
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
| | - Rui Tian
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
| | - Hong Yan
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
| | - Min Zhang
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
| | - Jing Wu
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
| | - Wei Wang
- 4 Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, Anhui Province, P.R. China
| | - Jie He
- 1 School of Medicine, Shandong University, Jinan 250012, Shangdong Province, P.R. China
- 2 Department of Pathology, Anhui Provincial Cancer Hospital; Anhui Provincial Hospital, Anhui Medical University, Hefei 230031, Anhui Province, P.R. China
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Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:183-204. [PMID: 27573901 DOI: 10.1007/978-3-319-42059-2_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC.
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28
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Zheng Q, Chen C, Guan H, Kang W, Yu C. Prognostic role of microRNAs in human gastrointestinal cancer: A systematic review and meta-analysis. Oncotarget 2017; 8:46611-46623. [PMID: 28402940 PMCID: PMC5542297 DOI: 10.18632/oncotarget.16679] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 03/09/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastrointestinal cancers (GICs) mainly including esophageal, gastric and colorectal cancer, are the most common cause of cancer-related death and lead into high mortality worldwide. We performed this systematic review and meta-analysis to elucidate relationship between multiple microRNAs (miRs) expression and survival of GIC patients. METHODS We searched a wide range of database. Fixed-effects and random-effects models were used to calculate the pooled hazard ratio values of overall survival and disease free survival. In addition, funnel plots were used to qualitatively analyze the publication bias and verified by Begg's test while it seems asymmetry. RESULTS 60 studies involving a total of 6225 patients (1271 with esophageal cancer, 3467 with gastric cancer and 1517 with colorectal cancer) were included in our meta-analysis. The pooled hazard ratio values of overall survival related to different miRs expression in esophageal, gastric, colorectal and gastrointestinal cancer were 2.10 (1.78-2.49), 2.02 (1.83-2.23), 2.54 (2.14-3.02) and 2.15 (1.99-2.31), respectively. We have identified a total of 59 miRs including 23 significantly up-regulated expression miRs (miR-214, miR-17, miR-20a, miR-200c, miR-107, miR-27a, etc.) and 36 significantly down-regulated expression miRs (miR-433, let-7g, miR-125a-5p, miR-760, miR-206, miR-26a, miR-200b, miR-185, etc.) correlated with poor prognosis in GIC patients. Moreover, 35 of them revealed mechanisms. CONCLUSION Overall, specific miRs are significantly associated with the prognosis of GIC patients and potentially eligible for the prediction of patients survival. It also provides a potential value for clinical decision-making development and may serve as a promising miR-based target therapy waiting for further elucidation.
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Affiliation(s)
- Qiang Zheng
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Changyu Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Traditional Medical University, Hefei, China
| | - Haiyang Guan
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Weibiao Kang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Changjun Yu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
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Moridikia A, Mirzaei H, Sahebkar A, Salimian J. MicroRNAs: Potential candidates for diagnosis and treatment of colorectal cancer. J Cell Physiol 2017; 233:901-913. [PMID: 28092102 DOI: 10.1002/jcp.25801] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is known as the third common cancer worldwide and an important public health problem in different populations. Several genetics and environmental risk factors are involved in the development and progression of CRC including chromosomal abnormalities, epigenetic alterations, and unhealthy lifestyle. Identification of risk factors and biomarkers could lead to a better understanding of molecular pathways involved in CRC pathogenesis. MicroRNAs (miRNAs) are important regulatory molecules which could affect a variety of cellular and molecular targets in CRC. A large number of studies have indicated deregulations of some known tissue-specific miRNAs, for example, miR-21, miR-9, miR-155, miR-17, miR-19, let-7, and miR-24 as well as circulating miRNAs, for example, miR-181b, miR-21, miR-183, let-7g, miR-17, and miR-126, in patients with CRC. In the current review, we focus on the findings of preclinical and clinical studies performed on tissue-specific and circulating miRNAs as diagnostic biomarkers and therapeutic targets for the detection of patients at various stages of CRC.
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Affiliation(s)
- Abdullah Moridikia
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Mashhad University of Medical Science, Mashhad, Iran
| | - Jafar Salimian
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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30
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Diamantopoulos MA, Kontos CK, Kerimis D, Papadopoulos IN, Scorilas A. Upregulated miR-16 expression is an independent indicator of relapse and poor overall survival of colorectal adenocarcinoma patients. Clin Chem Lab Med 2017; 55:737-747. [PMID: 27930363 DOI: 10.1515/cclm-2016-0756] [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] [Received: 08/26/2016] [Accepted: 10/31/2016] [Indexed: 02/01/2023]
Abstract
BACKGROUND Colorectal adenocarcinoma is one of the most common malignant tumors of the gastrointestinal tract and the second leading cause of cancer-related deaths among adults in Western countries. miR-16 is heavily involved in cancer progression. In this study, we examined the potential diagnostic and prognostic utility of miR-16 expression in colorectal adenocarcinoma. METHODS Total RNA was extracted from 182 colorectal adenocarcinoma specimens and 86 non-cancerous colorectal mucosae. After polyadenylation of 2 μg total RNA by poly(A) polymerase and subsequent reverse transcription with an oligo-dT adapter primer, miR-16 expression was determined using an in-house developed reverse transcription quantitative real-time PCR method, based on SYBR Green chemistry. SNORD43 (RNU43) and SNORD48 (RNU48) were used as reference genes. Next, we performed extensive biostatistical analysis. RESULTS miR-16 was shown to be significantly upregulated in colorectal adenocarcinoma specimens compared to non-cancerous colorectal mucosae, suggesting its potential exploitation for diagnostic purposes. Moreover, high miR-16 expression predicts poor disease-free survival (DFS) and overall survival (OS) of colorectal adenocarcinoma patients. Multivariate Cox regression analysis confirmed that miR-16 overexpression is a significant unfavorable prognosticator in colorectal adenocarcinoma, independent of other established prognostic factors, radiotherapy, and chemotherapy. Interestingly, miR-16 overexpression retains its unfavorable prognostic value in patients with advanced yet locally restricted colorectal adenocarcinoma that has not grown through the wall of the colon or rectum (T3) and in those without distant metastasis (M0). CONCLUSIONS Overexpression of the cancer-associated miR-16 predicts poor DFS and OS of colorectal adenocarcinoma patients, independently of clinicopathological factors that are currently used for prognostic purposes.
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Affiliation(s)
- Marios A Diamantopoulos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens
| | - Christos K Kontos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens
| | - Dimitrios Kerimis
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens
| | - Iordanis N Papadopoulos
- Fourth Surgery Department, National and Kapodistrian University of Athens, University General Hospital "Attikon", Athens
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701 Athens
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Manne U, Jadhav T, Putcha BDK, Samuel T, Soni S, Shanmugam C, Suswam EA. Molecular Biomarkers of Colorectal Cancer and Cancer Disparities: Current Status and Perspective. CURRENT COLORECTAL CANCER REPORTS 2016. [PMID: 28626361 DOI: 10.1007/s11888-016-0338-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
This review provides updates on the efforts for the development of prognostic and predictive markers in colorectal cancer based on the race/ethnicity of patients. Since the clinical consequences of genetic and molecular alterations differ with patient race and ethnicity, the usefulness of these molecular alterations as biomarkers needs to be evaluated in different racial/ethnic groups. To accomplish personalized patient care, a combined analysis of multiple molecular alterations in DNA, RNA, microRNAs (miRNAs), metabolites, and proteins in a single test is required to assess disease status in a precise way. Therefore, a special emphasis is placed on issues related to utility of recently identified genetic and molecular alterations in genes, miRNAs, and various "-omes" (e.g., proteomes, kinomes, metabolomes, exomes, methylomes) as candidate molecular markers to determine cancer progression (disease recurrence/relapse and metastasis) and to assess the efficacy of therapy in colorectal cancer in relation to patient race and ethnicity. This review will be useful for oncologists, pathologists, and basic and translational researchers.
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Affiliation(s)
- Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, Wallace Tumor Institute, University of Alabama at Birmingham, Room # 420A, 1530 3rd Avenue South, Birmingham, AL 35294, USA
| | - Trafina Jadhav
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Wallace Tumor Institute, University of Alabama at Birmingham, Room # 430A, 1530 3rd Avenue South, Birmingham, AL 35294, USA.,Present address: Division of Cardiovascular Medicine, Vanderbilt University, 1215 21st Avenue South, Medical Center East, Suite 5050, Nashville, TN 37232-8802, USA
| | - Balananda-Dhurjati Kumar Putcha
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Wallace Tumor Institute, University of Alabama at Birmingham, Room # 430A, 1530 3rd Avenue South, Birmingham, AL 35294, USA.,Present address: 2502 East Woodlands, Saint Joseph, MO 64506, USA
| | - Temesgen Samuel
- Department of Pathobiology, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088, USA
| | - Shivani Soni
- Department of Biological Sciences, Alabama State University, Room # 325, Life Science Building, 1627, Hall Street, Montgomery, AL 36104, USA
| | - Chandrakumar Shanmugam
- Wallace Tumor Institute, University of Alabama at Birmingham, Room # 430A, 1530 3rd Avenue South, Birmingham, AL 35294, USA.,Present address: Department of Pathology, ESIC Medical College and Hospital, Sanathnagar, Hyderabad, Telangana 500 038, India
| | - Esther A Suswam
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Pathology, Wallace Tumor Institute, University of Alabama at Birmingham, 1720 2nd Avenue South, # 410C, Birmingham, AL 35294-3300, USA
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A gene browser of colorectal cancer with literature evidence and pre-computed regulatory information to identify key tumor suppressors and oncogenes. Sci Rep 2016; 6:30624. [PMID: 27477450 PMCID: PMC4967895 DOI: 10.1038/srep30624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a cancer of growing incidence that associates with a high mortality rate worldwide. There is a poor understanding of the heterogeneity of CRC with regard to causative genetic mutations and gene regulatory mechanisms. Previous studies have identified several susceptibility genes in small-scale experiments. However, the information has not been comprehensively and systematically compiled and interpreted. In this study, we constructed the gbCRC, the first literature-based gene resource for investigating CRC-related human genes. The features of our database include: (i) manual curation of experimentally-verified genes reported in the literature; (ii) comprehensive integration of five reliable data sources; and (iii) pre-computed regulatory patterns involving transcription factors, microRNAs and long non-coding RNAs. In total, 2067 genes associating with 2819 PubMed abstracts were compiled. Comprehensive functional annotations associated with all the genes, including gene expression profiles, homologous genes in other model species, protein-protein interactions, somatic mutations, and potential methylation sites. These comprehensive annotations and this pre-computed regulatory information highlighted the importance of the gbCRC with regard to the unexplored regulatory network of CRC. This information is available in a plain text format that is free to download.
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Abstract
Since their first discovery in chronic lymphocytic leukemia, miR-15a and miR-16 have been reported to act as tumor suppressors or potential oncomiRs in different types of cancer. This review summarizes the history, biological properties and the important functions of these two miRNAs in cancer. It also introduces their roles as regulators of immune responses and angiogenesis, endogenous controls as well as potential targets and hallmarks of cancer.
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Affiliation(s)
- Enyu Huang
- Department of Immunology, Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Ronghua Liu
- Department of Immunology, Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yiwei Chu
- Department of Immunology, Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.,Biotherapy Research Center, Fudan University, Shanghai 200032, People's Republic of China
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Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored. Trends Mol Med 2016; 22:274-289. [PMID: 26970951 DOI: 10.1016/j.molmed.2016.02.003] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 02/16/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) remains one of the most prevalent cancers worldwide. In sporadic CRC, mutations frequently occur in the DNA mismatch repair (MMR) pathway. In addition, germline MMR mutations have been linked to Lynch syndrome, the most common form of hereditary CRC. Although genetic mutations, diet, inflammation, and the gut microbiota can influence CRC, it is unclear how MMR deficiency relates to these factors to modulate disease. In this review, the association of MMR to the etiology of CRC is examined, particularly in the context of microRNAs (miRNAs), inflammation, and the microbiome. We also discuss the most current targeted therapies, methods of prevention, and molecular biomarkers against MMR-deficient CRC, all of which are encouraging advancements in the field.
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Hollis M, Nair K, Vyas A, Chaturvedi LS, Gambhir S, Vyas D. MicroRNAs potential utility in colon cancer: Early detection, prognosis, and chemosensitivity. World J Gastroenterol 2015; 21:8284-8292. [PMID: 26217080 PMCID: PMC4507098 DOI: 10.3748/wjg.v21.i27.8284] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/24/2015] [Accepted: 05/27/2015] [Indexed: 02/06/2023] Open
Abstract
Over the past decade, research has shown that aberrant expression of microRNA (miRNA) is involved in colorectal cancer development and progression. MicroRNAs are small sequences of non-coding RNA that regulate expression of genes involved in important cellular functions, such as cell differentiation, multiplication, and apoptosis. A specific miRNA may display the effects of a tumor suppressor or oncogene. Altered miRNA expression is found in colorectal cancer (CRC) and patterns of miRNA expression correlate with CRC detection and outcome. Studies also have examined the use of circulating serum miRNA and fecal miRNA expression as non-invasive markers for early detection. Here, we review recent evidence demonstrating the potential role of miRNA in CRC and the implications of its use in the diagnosis, prognosis, and management of CRC.
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Tarallo S, Pardini B, Mancuso G, Rosa F, Di Gaetano C, Rosina F, Vineis P, Naccarati A. MicroRNA expression in relation to different dietary habits: a comparison in stool and plasma samples. Mutagenesis 2015; 29:385-91. [PMID: 25150024 DOI: 10.1093/mutage/geu028] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
MicroRNAs (miRNAs), a class of small non-coding RNAs, are fundamental for the post-transcriptional regulation of gene expression. Altered expression of miRNAs has been detected in cancers, not only in primary tissue but also in easily obtainable specimens like plasma and stools. miRNA expression is known to be modulated by diet (micro and macronutrients, phytochemicals) and possibly by other lifestyle factors; however, such influence has not yet been exhaustively explored in humans. In the present study, we analysed the expression levels of a panel of seven human miRNAs in plasma and stool samples of a group of 24 healthy individuals characterised by different dietary habits (eight vegans, eight vegetarians and eight subjects with omnivorous diet, all groups with similar age and sex distribution). The dual aim of the study was to identify possible differences in miRNA expression due to diet (or other lifestyle factors recorded from questionnaires) and to compare results in both types of specimens. miR-92a was differentially expressed in both plasma and stool samples and with the same trend, among the three groups with different diets (P = 0.0002 and P = 0.02, respectively, with expression levels of vegans>vegetarians>omnivores). miR-92a was also associated with low body mass index (P = 0.04 and P = 0.05, respectively) in both types of specimens, and with several dietary factors. Other analysed miRNAs (miR-16, miR-21, mir-34a and miR-222) were associated with dietary and lifestyle factors, but not consistently in both stool and plasma. Our pilot study provides the first evidence of miRNA modulation by diet and other factors, that can be detected consistently in both plasma and stools samples.
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Affiliation(s)
- Sonia Tarallo
- Human Genetics Foundation, via Nizza 52, 10126 Turin, Italy
| | - Barbara Pardini
- Human Genetics Foundation, via Nizza 52, 10126 Turin, Italy, Department of Medical Sciences, University of Turin, via Santena 19, 10126 Turin, Italy
| | | | - Fabio Rosa
- Human Genetics Foundation, via Nizza 52, 10126 Turin, Italy, Department of Medical Sciences, University of Turin, via Santena 19, 10126 Turin, Italy
| | - Cornelia Di Gaetano
- Human Genetics Foundation, via Nizza 52, 10126 Turin, Italy, Department of Medical Sciences, University of Turin, via Santena 19, 10126 Turin, Italy
| | - Floriano Rosina
- Division of Gastro-Hepatology, Ospedale Gradenigo, Corso Regina Margherita 8, 10153 Turin, Italy and
| | - Paolo Vineis
- Human Genetics Foundation, via Nizza 52, 10126 Turin, Italy, School of Public Health, Imperial College, Norfolk Place, London W2 1PG, UK
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Pallante P, Sepe R, Puca F, Fusco A. High mobility group a proteins as tumor markers. Front Med (Lausanne) 2015; 2:15. [PMID: 25859543 PMCID: PMC4373383 DOI: 10.3389/fmed.2015.00015] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 03/07/2015] [Indexed: 01/24/2023] Open
Abstract
Almost 30 years ago, overexpression of HMGA proteins was associated with malignant phenotype of rat thyroid cells transformed with murine retroviruses. Thereafter, several studies have analyzed HMGA expression in a wide range of human neoplasias. Here, we summarize all these results that, in the large majority of the cases, confirm the association of HMGA overexpression with high malignant phenotype as outlined by chemoresistance, spreading of metastases, and a global poor survival. Even though HMGA proteins’ overexpression indicates a poor prognosis in almost all malignancies, their detection may be particularly useful in determining the prognosis of breast, lung, and colon carcinomas, suggesting for the treatment a more aggressive therapy. In particular, the expression of HMGA2 in lung carcinomas is frequently associated with the presence of metastases. Moreover, recent data revealed that often the cause for the high HMGA proteins levels detected in human malignancies is a deregulated expression of non-coding RNA. Therefore, the HMGA proteins represent tumor markers whose detection can be a valid tool for the diagnosis and prognosis of neoplastic diseases.
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Affiliation(s)
- Pierlorenzo Pallante
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II , Naples , Italy
| | - Romina Sepe
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II , Naples , Italy
| | - Francesca Puca
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II , Naples , Italy
| | - Alfredo Fusco
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II , Naples , Italy ; Instituto Nacional de Câncer , Rio de Janeiro , Brazil
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Aberrant Expression of MicroRNA-15a and MicroRNA-16 Synergistically Associates with Tumor Progression and Prognosis in Patients with Colorectal Cancer. Gastroenterol Res Pract 2014; 2014:364549. [PMID: 25435873 PMCID: PMC4236961 DOI: 10.1155/2014/364549] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 09/19/2014] [Accepted: 09/20/2014] [Indexed: 12/19/2022] Open
Abstract
The aim of this study was to reveal the associations of microRNA miR-15a and miR-16 dysregulation with clinicopathological characteristics and prognosis in patients with colorectal cancer. As a result, we found that miR-15a and miR-16 expression, detected by quantitative real time-PCR, were both significantly downregulated in colorectal cancer tissues compared with adjacent colorectal mucosa (both P < 0.001). Particularly, the expression levels of miR-15a in colorectal cancer tissues were positively correlated with those of miR-16 significantly (Spearman correlation coefficient r = 0.652, P < 0.001). In addition, miR-15a and/or miR-16 downregulation were all significantly associated with advanced TNM stage (all P < 0.05), poorly histological grade (all P < 0.05), and positive lymph node metastasis (all P < 0.05). Moreover, the survival analysis identified miR-15a expression, miR-16 expression, and miR-15a/miR-16 combination as independent predictors of both unfavorable overall survival and disease-free survival. Interestingly, the prognostic value of miR-15a/miR-16 combination was more significant than miR-15a or miR-16 expression alone. Collectively, the aberrant expression of miR-15a and miR-16 could be used to stratify patients with aggressive tumor progression of colorectal cancer. The combined pattern of miR-15a and miR-16 downregulation has a significant value for distinguishing patients with a worse prognosis of colorectal cancer after surgery.
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Dong Y, Yu J, Ng SS. MicroRNA dysregulation as a prognostic biomarker in colorectal cancer. Cancer Manag Res 2014; 6:405-22. [PMID: 25342918 PMCID: PMC4206254 DOI: 10.2147/cmar.s35164] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor–node–metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtypes and predict clinical outcomes. In this review, we summarize recent findings concerning the prognostic potential of microRNAs (miRNAs) in CRC. We first discuss the prognostic value of three tissue miRNAs (miR-21-5p, miR-29-3p, miR-148-3p) that have been examined in multiple studies. We also summarize the dysregulation of miRNA processing machinery DICER in CRC and its association with risk for mortality. We also reviewe the potential application of miRNA-associated single-nucleotide polymorphisms as prognostic biomarkers for CRC, especially the miRNA-associated polymorphism in the KRAS gene. Last but not least, we discuss the microsatellite instability-related miRNA candidates. Among all these candidates, miR-21-5p is the most promising prognostic marker, yet further prospective validation studies are required before it can go into clinical usage.
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Affiliation(s)
- Yujuan Dong
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong ; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Simon Sm Ng
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong ; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
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Abstract
The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53’s tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.
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Affiliation(s)
- Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Huihui Li
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Longchang Jiang
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
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Jinushi T, Shibayama Y, Kinoshita I, Oizumi S, Jinushi M, Aota T, Takahashi T, Horita S, Dosaka-Akita H, Iseki K. Low expression levels of microRNA-124-5p correlated with poor prognosis in colorectal cancer via targeting of SMC4. Cancer Med 2014; 3:1544-52. [PMID: 25081869 PMCID: PMC4298381 DOI: 10.1002/cam4.309] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 06/14/2014] [Accepted: 06/22/2014] [Indexed: 12/22/2022] Open
Abstract
A component of polycomb repressor complex 2, enhancer of zeste homolog 2 (EZH2), plays an important role in tumor malignancy and metastasis, while milk fat globule-epidermal growth factor-factor 8 (MFGE8) plays a key role in tumor progression and prognosis. MicroRNAs (miRs) are also critically involved in various physiological and pathological processes. We here evaluated the relationship between overall survival (OS) in colorectal cancer patients and the expression of onco-miRs and miRs, which may target EZH2 and MFGE8. Plasma and formalin-fixed paraffin-embedded (FFPE) samples were obtained from 71 colorectal cancer patients. The expression levels of miRs complementary to EZH2 and MFGE8 mRNA and cancer malignancies were evaluated. The miRs analyzed were as follows: miR-16, miR-21, miR-26a, miR-34a, miR-98, miR-101-3p, miR-101-5p, miR-124-5p (also known as miR-124*), miR-126-3p, miR-126-5p, miR-210, miR-217, and miR-630. The plasma expression levels of MFGE8 in completely resected patients were significantly lower than those in unresectable patients. Lower miR-26a expression levels were correlated with a higher probability of OS. Higher miR-124-5p expression levels in plasma and FFPE samples were correlated with a higher probability of OS. The transfection of mimic miR-124-5p into WiDr and COLO201 cells inhibited the expression of structural maintenance of chromosomes 4 (SMC4) mRNA. Our results indicate that miR-124-5p may target the tumorigenesis gene, SMC4, which suggests that expression levels of miR-124-5p in plasma and FFPE samples; therefore, the expression of MFGE8, miR-26a, and miR-124-5p in plasma may be used as biomarkers to determine the prognosis of colorectal cancer patients.
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Affiliation(s)
- Takafumi Jinushi
- Graduate School of Pharmaceutical Sciences, Clinical Pharmaceutics and Therapeutics, Hokkaido University, Sapporo, Japan; Hokkaido Gastroenterology Hospital, Sapporo, Japan
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Kim JH, Choi PR, Park SJ, Park MI, Moon W, Kim SE, Lee GW. Prognostic factors for metastatic colorectal cancer after first-line chemotherapy with FOLFOX-4 or FOLFIRI regimen. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2014; 63:209-215. [PMID: 24755745 DOI: 10.4166/kjg.2014.63.4.209] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Abstract
BACKGROUND/AIMS Information on prognostic factors for metastatic colorectal cancer is an important basis for planning the treatment and predicting the outcomes of the patients; however, it has not been well established. The aim of this study was to identify factors that predict results of chemotherapy and to establish a plan for treatment of patients whose tumors are inoperable due to metastatic colorectal cancer. METHODS We conducted a retrospective review of records from 75 patients treated for colorectal cancer in Kosin University Gospel Hospital, from October 2004 to September 2008. Patients with inoperable tumors due to metastasis at the time of diagnosis who were treated with oxaliplatin or irinotecan as the first-line treatment were included in this study. We investigated the factors that might have an effect on overall survival. RESULTS A total of 75 patients were included in this study. Results of univariate analysis showed that hemoglobin (Hb) ≥10 g/dL at the time of diagnosis, no increase in CEA on the follow-up examination after chemotherapy, chemotherapy plus surgery, and better response to chemotherapy were significant prognostic factors. Results of multivariate analysis showed that Hb ≥10 g/dL at the time of diagnosis (p<0.001), surgery after chemotherapy (p=0.001), and better response to chemotherapy (p=0.014) were significant prognostic factors. CONCLUSIONS In this study, Hb ≥10 g/dL at the time of diagnosis, surgery after chemotherapy, and better response to chemotherapy were significant prognostic factors for metastatic colorectal cancer.
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Affiliation(s)
- Jae Hyun Kim
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
| | - Pyoung Rak Choi
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
| | - Seun Ja Park
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
| | - Moo In Park
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
| | - Won Moon
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
| | - Sung Eun Kim
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
| | - Gyu Won Lee
- Department of Gastroenterology, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
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