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Richard V, Lee K, Kerin MJ. MicroRNAs as Endocrine Modulators of Breast Cancer. Int J Mol Sci 2025; 26:3449. [PMID: 40244378 PMCID: PMC11989600 DOI: 10.3390/ijms26073449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025] Open
Abstract
Breast cancer is an aggressive disease of multiple subtypes with varying phenotypic, hormonal, and clinicopathological features, offering enhanced resistance to conventional therapeutic regimens. There is an unmet need for reliable molecular biomarkers capable of detecting the malignant transformation from the early stages of the disease to enhance diagnosis and treatment outcomes. A subset of small non-coding nucleic acid molecules, micro ribonucleic acids (microRNAs/miRNAs), have emerged as promising biomarkers due to their role in gene regulation and cancer pathogenesis. This review discusses, in detail, the different origins and hormone-like regulatory functionalities of miRNAs localized in tumor tissue and in the circulation, as well as their inherent stability and turnover that determines the utility of miRNAs as biomarkers for disease detection, monitoring, prognosis, and therapeutic targets.
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Affiliation(s)
- Vinitha Richard
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, H91 V4AY Galway, Ireland
| | - Kevin Lee
- School of Medicine, University of Galway, H91 V4AY Galway, Ireland;
| | - Michael Joseph Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, H91 V4AY Galway, Ireland
- School of Medicine, University of Galway, H91 V4AY Galway, Ireland;
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2
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Jigari Asl F, Khordadmehr M, Baradaran B, Baghbani E, Noorolyai S, Rahmani S, Saberivand A. Restoration of miR-451a-5p/miR-34a-5p could suppress the proliferation and migration of human breast cancer cells through Wnt/β- catenin and ERK/P-ERK signaling pathways. ARCHIVES OF RAZI INSTITUTE 2024; 79:367-377. [PMID: 39463723 PMCID: PMC11512187 DOI: 10.32592/ari.2024.79.2.367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2024]
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs with a length of 21-25 nucleotides and play an essential role in the regulation of cancer initiation, development and progression. Breast cancer (BC) is the most commonly detected malignancy in women and one of the leading causes of death worldwide. In this study, the effects of transfection of microRNA-451a-5p and miR-34a-5p (tumor suppressors), individually and in combination on apoptosis, proliferation and migration of breast cancer cells in vitro were investigated. For this study, malignant breast cancer cells (MDA-MB-231) were transfected with the miR-451a-5p and miR-34a-5p mimics. Subsequently cytotoxicity, apoptosis, proliferation, migration protein and gene expression of caspase-3, caspase-8, MMP9, ROCK, vimentin and c-Myc of the cancer cells were analyzed by MTT, flow cytometry, q-RT-PCR (expression level of caspase-3, caspase-8, MMP9, ROCK, vimentin and c-Myc genes), wound healing and Western blot assays. The results showed that miR-34a-5p and miR-451a-5p could additionally induce apoptosis and cell cycle arrest in the sub-G1phase, suppress proliferation and migration in breast cancer cells, and also decrease the expression of β- catenin and ERK/P-ERK proteins . The present data document that restoration of the tumor suppressor miR-451/miR-34 strongly induces programmed cell death in vitro and apparently inhibits cell proliferation and migration in human breast cancer cells. In summary, miR-451a and miR-34a play an important role in breast cancer cell proliferation and migration via the Wnt/β-catenin and ERK/P-ERK signaling pathways. Therefore, the simultaneous restoration of the presented tumor suppressor miRNAs can be proposed as a valuable and potential therapeutic strategy in the treatment of breast cancer. However, further studies should be useful.
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Affiliation(s)
- F Jigari Asl
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - M Khordadmehr
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - B Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - E Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - S Noorolyai
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - S Rahmani
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - A Saberivand
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
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Soares S, Aires F, Monteiro A, Pinto G, Faria I, Sales G, Correa-Duarte MA, Guerreiro S, Fernandes R. Radiotherapy Metastatic Prostate Cancer Cell Lines Treated with Gold Nanorods Modulate miRNA Signatures. Int J Mol Sci 2024; 25:2754. [PMID: 38474003 DOI: 10.3390/ijms25052754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/21/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
MicroRNA (miRNA) modulation has been identified as a promising strategy for improving the response of human prostate cancer (PCa) to radiotherapy (RT). Studies have shown that mimics or inhibitors of miRNAs could modulate the sensitivity of PCa cells to RT. In addition, pegylated gold nanoparticles have been studied as a therapeutic approach to treat PCa cells and/or vehicles for carrying miRNAs to the inside of cells. Therefore, we evaluated the capacity of hypofractionated RT and pegylated gold nanorods (AuNPr-PEG) to modulate the miRNA signature on PCa cells. Thus, RT-qPCR was used to analyze miRNA-95, miRNA-106-5p, miRNA-145-5p, and miRNA-541-3p on three human metastatic prostate cell lines (PC3, DU145, and LNCaP) and one human prostate epithelial cell line (HprEpiC, a non-tumor cell line) with and without treatment. Our results showed that miRNA expression levels depend on cell type and the treatment combination applied using RT and AuNPr-PEG. In addition, cells pre-treated with AuNPr-PEG and submitted to 2.5 Gy per day for 3 days decreased the expression levels of miRNA-95, miRNA-106, miRNA-145, and miRNA-541-3p. In conclusion, PCa patients submitted to hypofractionated RT could receive personalized treatment based on their metastatic cellular miRNA signature, and AuNPr-PEG could be used to increase metastatic cell radiosensitivity.
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Affiliation(s)
- Sílvia Soares
- (i3S), Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal
- FP-I3ID, Instituto de Investigação, Inovação e Desenvolvimento, FP-BHS, Biomedical and Health Sciences, Universidade Fernando Pessoa (UFP), 4249-004 Porto, Portugal
- CECLIN, Centro de Estudos Clínicos, Hospital Escola Fernando Pessoa, 4420-096 Gondomar, Portugal
- Faculty of Chemistry, University of Vigo, 36310 Vigo, Spain
- CEB, Centre of Biological Engineering, Minho University, 4710-057 Braga, Portugal
- Biomark@UC/CEB-Centre of Biological Engineering of Minho University, Department of Chemical Engineering, Faculty of Sciences and Technology, Coimbra University, 3030-790 Coimbra, Portugal
- Radiotherapy Service, São João Hospital Center, 4200-319 Porto, Portugal
| | - Fátima Aires
- Radiotherapy Service, São João Hospital Center, 4200-319 Porto, Portugal
| | - Armanda Monteiro
- Radiotherapy Service, São João Hospital Center, 4200-319 Porto, Portugal
| | - Gabriela Pinto
- Radiotherapy Service, São João Hospital Center, 4200-319 Porto, Portugal
| | - Isabel Faria
- FP-I3ID, Instituto de Investigação, Inovação e Desenvolvimento, FP-BHS, Biomedical and Health Sciences, Universidade Fernando Pessoa (UFP), 4249-004 Porto, Portugal
- CECLIN, Centro de Estudos Clínicos, Hospital Escola Fernando Pessoa, 4420-096 Gondomar, Portugal
| | - Goreti Sales
- CEB, Centre of Biological Engineering, Minho University, 4710-057 Braga, Portugal
- Biomark@UC/CEB-Centre of Biological Engineering of Minho University, Department of Chemical Engineering, Faculty of Sciences and Technology, Coimbra University, 3030-790 Coimbra, Portugal
| | - Miguel A Correa-Duarte
- CINBIO, University of Vigo, 36310 Vigo, Spain
- Southern Galicia Institute of Health Research (IISGS), Biomedical Research Networking Center for Mental Health (CIBERSAM), 36310 Madrid, Spain
| | - Susana Guerreiro
- (i3S), Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto-IPATIMUP, 4200-465 Porto, Portugal
- Department of Biomedicine, Biochemistry Unit, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Faculty of Nutrition and Food Sciences, University of Porto, 4150-180 Porto, Portugal
| | - Rúben Fernandes
- (i3S), Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal
- FP-I3ID, Instituto de Investigação, Inovação e Desenvolvimento, FP-BHS, Biomedical and Health Sciences, Universidade Fernando Pessoa (UFP), 4249-004 Porto, Portugal
- CECLIN, Centro de Estudos Clínicos, Hospital Escola Fernando Pessoa, 4420-096 Gondomar, Portugal
- UFP@RISE, Rede de Investigação em Saúde, Universidade Fernando Pessoa, 4249-004 Porto, Portugal
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Palanisamy H, Manoharan JP, Vidyalakshmi S. Prognostic microRNAs as biomarkers for prostate cancer. J Cancer Res Ther 2024; 20:297-303. [PMID: 38554337 DOI: 10.4103/jcrt.jcrt_1469_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/01/2022] [Indexed: 04/01/2024]
Abstract
OBJECTIVE Prostate cancer is the second largest cancer, most commonly diagnosed in men. Several studies reveal that miRNAs (microRNAs) are involved in various stages of prostate cancer. miRNAs are a family of small non-coding RNA species that have been implicated in the post-transcriptional regulation of gene expression. The present in silico study aims at identifying miRNA biomarkers that are significantly associated with the regulation of genes involved in prostate cancer. METHODS Dataset of miRNA and mRNA of prostate adenocarcinoma patients and controls was downloaded from The Cancer Genome Atlas (TCGA), and differential gene expression analysis was carried out. ROC and Kaplan-Meier survival analyses were performed on differentially expressed miRNAs. Pathway analysis was carried out for significant miRNAs, and protein-protein interaction of involved genes and miRNAs was examined. RESULTS A total of 185 miRNAs were differentially expressed between the patients and the control. ROC and Kaplan-Meier survival analysis showed that the two miRNAs hsa-mir-133b and hsa-mir-17-5p were found to be significantly associated with prostate cancer prognosis. HAS2 and EPHA10 gene targets of identified miRNA were also differentially expressed. A protein-protein interaction (PPI) network was constructed, and the HAS2 gene was found to be interacting with the epidermal growth factor receptor (EGFR). CONCLUSION This study highlights the potential of hsa-mir-133b and hsa-mir-17-5p miRNAs as biomarkers for the prognosis of prostate cancer. However, further experimental studies are required to validate this finding.
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Affiliation(s)
- Hema Palanisamy
- Department of Biotechnology, PSG College of Technology, Coimbatore Tamil Nadu, India
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5
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Doghish AS, Midan HM, Elbadry AMM, Darwish SF, Rizk NI, Ziada BO, Elbokhomy AS, Elrebehy MA, Elballal MS, El-Husseiny HM, Abdel Mageed SS, Abulsoud AI. The potential role of miRNAs in the pathogenesis of gallbladder cancer - A focus on signaling pathways interplay. Pathol Res Pract 2023; 248:154682. [PMID: 37451195 DOI: 10.1016/j.prp.2023.154682] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
microRNAs (also known as miRNAs or miRs) are a class of small non-coding RNAs that play a critical role in post-transcriptional gene regulation as negative gene regulators by binding complementary sequences in the 3'-UTR of target messenger RNAs (mRNAs) leading to translational repression and/or target degradation a wide range of genes and biological processes, including cell proliferation, invasion, migration, and apoptosis. The development and progression of cancer have been linked to the anomalous expression of miRNAs. According to recent studies, miRNAs have been found to regulate the expression of cancer-related genes through multiple signaling pathways in gallbladder cancer (GBC). Besides, miRNAs are implicated in several modulatory signaling pathways of GBC, including the Notch signaling pathway, JAK/STAT signaling pathway, protein kinase B (AKT), and Hedgehog signaling pathway. This review summarizes our current knowledge of the functions of miRNAs in the mechanisms underlying the pathogenic symptoms of GBC and illustrates their potential significance as treatment targets.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Abdullah M M Elbadry
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Samar F Darwish
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Bassant O Ziada
- Research Department, Utopia Pharmaceuticals, Nasr City 11765, Cairo, Egypt
| | - Amir S Elbokhomy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Hussein M El-Husseiny
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt; Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Sherif S Abdel Mageed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
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6
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Sufian MA, Ilies MA. Lipid-based nucleic acid therapeutics with in vivo efficacy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1856. [PMID: 36180107 PMCID: PMC10023279 DOI: 10.1002/wnan.1856] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/22/2022] [Accepted: 08/30/2022] [Indexed: 03/09/2023]
Abstract
Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP-compliant norms. The approval of Onpattro, a lipid-based siRNA therapeutic, and the proven clinical success of two lipid-based COVID-19 vaccines from Pfizer-BioNTech, and Moderna heralded the specific advantages of lipid-based systems among all other synthetic nucleic acid carriers. Lipid-based systems with diverse payloads-plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)-are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi-component systems. Here, we discuss the main nucleic acid-based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid-based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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Affiliation(s)
- Md Abu Sufian
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - Marc A. Ilies
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
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7
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Xia M, Wang S, Qi Y, Long K, Li E, He L, Pan F, Guo Z, Hu Z. Inhibition of O-GlcNAc transferase sensitizes prostate cancer cells to docetaxel. Front Oncol 2022; 12:993243. [PMID: 36439421 PMCID: PMC9686342 DOI: 10.3389/fonc.2022.993243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 10/26/2022] [Indexed: 08/18/2023] Open
Abstract
The expression of O-GlcNAc transferase (OGT) and its catalytic product, O-GlcNAcylation (O-GlcNAc), are elevated in many types of cancers, including prostate cancer (PC). Inhibition of OGT serves as a potential strategy for PC treatment alone or combinational therapy. PC is the second common cancer type in male worldwide, for which chemotherapy is still the first-line treatment. However, the function of inhibition of OGT on chemotherapeutic response in PC cells is still unknown. In this study, we show that inhibition of OGT by genetic knockdown using shRNA or by chemical inhibition using OGT inhibitors sensitize PC cells to docetaxel, which is the most common chemotherapeutic agent in PC chemotherapy. Furthermore, we identified that microRNA-140 (miR-140) directly binds to OGT mRNA 3' untranslated region and inhibits OGT expression. Moreover, docetaxel treatment stimulates miR-140 expression, whereas represses OGT expression in PC cells. Overexpression of miR-140 enhanced the drug sensitivity of PC cells to docetaxel, which could be reversed by overexpression of OGT. Overall, this study demonstrates miR-140/OGT axis as therapeutic target in PC treatment and provides a promising adjuvant therapeutic strategy for PC therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
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Okusha Y, Guerrero-Gimenez ME, Lang BJ, Borges TJ, Stevenson MA, Truman AW, Calderwood SK. MicroRNA-570 targets the HSP chaperone network, increases proteotoxic stress and inhibits mammary tumor cell migration. Sci Rep 2022; 12:15582. [PMID: 36114410 PMCID: PMC9481609 DOI: 10.1038/s41598-022-19533-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
The dynamic network of chaperone interactions known as the chaperome contributes significantly to the proteotoxic cell response and the malignant phenotype. To bypass the inherent redundancy in the network, we have used a microRNA (mir) approach to target multiple members of the chaperome simultaneously. We identified a potent microRNA, miR-570 that could bind the 3'untranslated regions of multiple HSP mRNAs and inhibit HSP synthesis. Transfection of cells with this miR species reduced expression of multiple HSPs, inhibited the heat shock response and reduced tumor cell growth while acted additively in combination with cytotoxic drugs. As overexpression of miR-570 elicited tumor suppressive effects, we inferred that this miR could play a potential role in inhibiting tumorigenesis and cancer cell growth. In accordance with this hypothesis, we determined a significant role for miR-570 in regulating markers of mammary tumor progression, including cell motility and invasion. Our data provide a proof of the principle that the tumor chaperome can be targeted by microRNAs suggesting a potential therapeutic avenue towards cancer therapy.
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Affiliation(s)
- Yuka Okusha
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. .,JSPS Overseas Research Fellow, Tokyo, 102-0083, Japan.
| | - Martin E. Guerrero-Gimenez
- grid.38142.3c000000041936754XBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 USA ,grid.412108.e0000 0001 2185 5065Institute of Biochemistry and Biotechnology, School of Medicine, National University of Cuyo, 5500 Mendoza, Argentina
| | - Benjamin J. Lang
- grid.38142.3c000000041936754XBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 USA
| | - Thiago J. Borges
- grid.38142.3c000000041936754XCenter for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129 USA
| | - Mary A. Stevenson
- grid.38142.3c000000041936754XBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 USA
| | - Andrew W. Truman
- grid.266859.60000 0000 8598 2218Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC 28223 USA
| | - Stuart K. Calderwood
- grid.38142.3c000000041936754XBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 USA
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9
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Kara G, Arun B, Calin GA, Ozpolat B. miRacle of microRNA-Driven Cancer Nanotherapeutics. Cancers (Basel) 2022; 14:3818. [PMID: 35954481 PMCID: PMC9367393 DOI: 10.3390/cancers14153818] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/28/2022] [Accepted: 08/04/2022] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics have entered human clinical trials with promising results, and they are expected to accelerate the transition of miRNAs from the bench to the bedside in the next decade. Here, we present recent perspectives and the newest developments, describing several engineered natural and synthetic novel miRNA nanocarrier formulations and their key in vivo applications and clinical trials.
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Affiliation(s)
- Goknur Kara
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Chemistry, Biochemistry Division, Ordu University, Ordu 52200, Turkey
| | - Banu Arun
- Department of Breast Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
| | - George A. Calin
- Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
| | - Bulent Ozpolat
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
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10
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Eshkoor SA, Ghodsian N, Akhtari-Zavare M. MicroRNAs influence and longevity. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00316-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
MiRNAs play critical roles in the regulation of cellular function, life span, and the aging process. They can affect longevity positively and negatively through different aging pathways.
Main text
MiRNAs are a group of short non-coding RNAs that regulate gene expressions at post-transcriptional levels. The different types of alterations in miRNAs biogenesis, mRNA expressions, and activities of miRNA-protein complexes can affect the regulation of normal post-transcriptional gene process, which may lead to aging, age-related diseases, and an earlier death. It seems that the influence of deregulation of miRNAs on senescence and age-related diseases occurring by targeting aging molecular pathways can be used for diagnosis and prognosis of them. Therefore, the expression and function of miRNAs should be studied more accurately with new applicable and validated experimental tools. However, the current review wishes to highlight simply a connection among miRNAs, senescence and some age-related diseases.
Conclusion
Despite several research indicating the key roles of miRNAs in aging and longevity, further investigations are still needed to elucidate the essential roles of miRNAs in controlling mRNA regulation, cell proliferation, death and/or protection during stress and health problems. Besides, more research on miRNAs will help to identify new targets for alternative strategies regarding effectively screen, treat, and prevent diseases as well as make slow the aging process.
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11
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Sahabi K, Selvarajah GT, Mokrish A, Rasedee A, Kqueen CY. Development and molecular characterization of doxorubicin-resistant canine mammary gland tumour cells. JOURNAL OF APPLIED ANIMAL RESEARCH 2022. [DOI: 10.1080/09712119.2022.2032719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Kabiru Sahabi
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Gayathri T. Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory (CANRES), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| | - Ajat Mokrish
- Department of Veterinary Preclinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Abdullah Rasedee
- Department of Veterinary Diagnostic Laboratory, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Cheah Y. Kqueen
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory (CANRES), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
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12
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Yang L, Yang S, Ren C, Liu S, Zhang X, Sui A. Deciphering the roles of miR-16-5p in Malignant Solid Tumorsmalignant solid tumors. Pharmacotherapy 2022; 148:112703. [PMID: 35149384 DOI: 10.1016/j.biopha.2022.112703] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 11/02/2022]
Abstract
MiR-16-5p, a member of the miR-16 family, has been reported to be abnormal expression in tumor tissues and blood of tumor patients, and also downregulated in most cancer cell lines. Aberrant expression of miR-16-5p promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and can also affect the treatment sensitivity, such as radiotherapy and chemotherapy. Generally, miR-16-5p plays an anti-tumor role and these diverse functions of miR-16-5p in tumors collectively indicate that miR-16-5p may become an attractive target for novel anticancer therapies and a powerful diagnostic and prognostic biomarker for early tumor detection and population risk screening. Herein we review the role and utilization of miR-16-5p in malignant tumor in detail.
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Affiliation(s)
- Liuyi Yang
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of North China University of Science and Technology, Tangshan, Hebei, China
| | - Sen Yang
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of North China University of Science and Technology, Tangshan, Hebei, China
| | - Congcong Ren
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Shihua Liu
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Xiaopei Zhang
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Aixia Sui
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China.
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13
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Kornmueller K, Amri EZ, Scheideler M, Prassl R. Delivery of miRNAs to the adipose organ for metabolic health. Adv Drug Deliv Rev 2022; 181:114110. [PMID: 34995679 DOI: 10.1016/j.addr.2021.114110] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 12/14/2021] [Accepted: 12/30/2021] [Indexed: 11/16/2022]
Abstract
Despite the increasing prevalence of obesity and diabetes, there is no efficient treatment to combat these epidemics. The adipose organ is the main site for energy storage and plays a pivotal role in whole body lipid metabolism and energy homeostasis, including remodeling and dysfunction of adipocytes and adipose tissues in obesity and diabetes. Thus, restoring and balancing metabolic functions in the adipose organ is in demand. MiRNAs represent a novel class of drugs and drug targets, as they are heavily involved in the regulation of many cellular and metabolic processes and diseases, likewise in adipocytes. In this review, we summarize key regulatory activities of miRNAs in the adipose organ, discuss various miRNA replacement and inhibition strategies, promising delivery systems for miRNAs and reflect the future of novel miRNA-based therapeutics to target adipose tissues with the ultimate goal to combat metabolic disorders.
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Affiliation(s)
- Karin Kornmueller
- Department of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | | | - Marcel Scheideler
- Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Ruth Prassl
- Department of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, Austria.
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14
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Ahmadi A, Bayatiani MR, Seif F, Ansari J, Rashidi P, Moghadasi M, Etemadi M. Evaluation of Radiotherapy on miR-374 Gene Expression in Colorectal Cancer Patient Blood Samples. Rep Biochem Mol Biol 2022; 10:614-621. [PMID: 35291612 PMCID: PMC8903365 DOI: 10.52547/rbmb.10.4.614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/24/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Current cancer treatments include surgery, radiotherapy, chemotherapy, and immunotherapy. Despite these treatments, a main issue in cancer treatment is early detection. microRNAs (miRNAs) can be used as markers to diagnose and treat cancers. This study investigated the effect of radiotherapy on miR-374 expression, and APC and GSK-3β, two of its target genes, in the WNT pathway, in peripheral blood samples from radiotherapy-treated colorectal cancer (CRC) patients. METHODS Peripheral blood was collected from 25 patients before and after radiotherapy. RNA was extracted from the blood and cDNA synthesized. miR-374, APC, and GSK-3β expression was determined by real-time polymerase chain reaction (RT-PCR) and the amplicons were sequenced. Finally, the data were statistically evaluated. RESULTS Quantitative RT-PCR revealed significant down-regulation of miR-374 (0.63-fold) and up-regulation of APC (1.12-fold) and GSK-3β (1.22-fold) in CRC patients after five weeks of radiotherapy. Sequencing of PCR-produced amplicons confirmed the conservation of mature and precursor sequences encoding miR-374. miR-374 expression changed with time after radiotherapy treatment and related tumor grading. Increased age and tumor grade positively correlated with decreased miR-374 expression. CONCLUSION miR-374 expression, and that of its two target genes, APC and GSK-3β, changed after radiotherapy. These genes can likely be used as diagnostic radiotherapy markers in CRC.
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Affiliation(s)
- Azam Ahmadi
- Infectious Diseases Research Center (IDRC), Arak University of Medical Sciences, Arak, Iran.
| | - Mohammad Reza Bayatiani
- Department of Medical Physics and Radiotherapy, Arak University of Medical Sciences and Khansari Hospital, Arak, Iran.
| | - Fatemeh Seif
- Department of Medical Physics and Radiotherapy, Arak University of Medical Sciences and Khansari Hospital, Arak, Iran.
| | - Jamshid Ansari
- Department of Medical Physics and Radiotherapy, Arak University of Medical Sciences and Khansari Hospital, Arak, Iran.
| | - Parisa Rashidi
- Department of Medical Physics and Radiotherapy, Arak University of Medical Sciences and Khansari Hospital, Arak, Iran.
| | - Mona Moghadasi
- Students Research Committee, Arak University of Medical Sciences, Arak, Iran.
| | - Mobarakeh Etemadi
- Students Research Committee, Arak University of Medical Sciences, Arak, Iran.
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15
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Van der Mude A. A proposed Information-Based modality for the treatment of cancer. Biosystems 2021; 211:104587. [PMID: 34915101 DOI: 10.1016/j.biosystems.2021.104587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 11/20/2021] [Accepted: 12/01/2021] [Indexed: 11/02/2022]
Abstract
Treatment modalities for cancer involve physical manipulations such as surgery, immunology, radiation, chemotherapy or gene editing. This is a proposal for an information-based modality. This modality does not change the internal state of the cancer cell directly - instead, the cancer cell is manipulated by giving it information to instruct the cell to perform an action. This modality is based on a theory of Structure Encoding in DNA, where information about body part structure controls the epigenetic state of cells in the process of development from pluripotent cells to fully differentiated cells. It has been noted that cancer is often due to errors in morphogenetic differentiation accompanied by associated epigenetic processes. This implies a model of cancer called the Epigenetic Differentiation Model. A major feature of the Structure Encoding Theory is that the characteristics of the differentiated cell are affected by inter-cellular information passed in the tissue microenvironment, which specifies the exact location of a cell in a body part structure. This is done by exosomes that carry fragments of long non-coding RNA and transposons, which convey structure information. In the normal process of epigenetic differentiation, the information passed may lead to apoptosis due to the constraints of a particular body part structure. The proposed treatment involves determining what structure information is being passed in a particular tumor, then adding artificial exosomes that overwhelm the current information with commands for the cells to go into apoptosis.
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16
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Wu K, Guo C, Li Y, Yang J, Zhou Q, Cheng S, Li Y, Nie B, Zeng Y. MicroRNA-18a-5p regulates the Warburg effect by targeting hypoxia-inducible factor 1α in the K562/ADM cell line. Exp Ther Med 2021; 22:1069. [PMID: 34447462 PMCID: PMC8355681 DOI: 10.3892/etm.2021.10503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
The Warburg effect is involved in drug resistance and recurrence of cancer, and poses a challenge for the treatment of chronic myelogenous leukemia (CML). Hypoxia-inducible factor 1α (HIF-1α) plays a key role in the Warburg effect. microRNAs (miRs) targeting HIF-1α have potential of regulating such aberrant metabolic process. The present study demonstrated that miR-18a-5p was expressed at a low level in K562/ADM cells via reverse transcription-quantitative PCR (RT-qPCR). The results of the luciferase reporter assay indicated that miR-18a-5p could specifically bind the 3'-untranslated region of HIF-1α. Through RT-qPCR and western blotting, it was revealed that miR-18a-5p downregulated the expression of HIF-1α. By inhibiting HIF-1α, miR-18a-5p suppressed aerobic glycolysis in K562/ADM cells, according to the results produced by glucose uptake, lactate production, pyruvate level and ATP synthesis measurement, along with the results obtained from extracellular acidification rate and oxygen consumption rate assays. These results provided new evidence that miR-18a-5p may suppress the Warburg effect by targeting HIF-1α. Furthermore, via CCK-8 and flow cytometry assays, cells transfected with miR-18a-5p mimics were more sensitive to Adriamycin (AMD) compared with AMD group. Reversing the Warburg effect by miR-30a-5p might provide a potential therapeutic strategy for CML.
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Affiliation(s)
- Kun Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Innovation Team of Clinical Laboratory and Diagnosis, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Chong Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Innovation Team of Clinical Laboratory and Diagnosis, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yixun Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Innovation Team of Clinical Laboratory and Diagnosis, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Jinrong Yang
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Qiang Zhou
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Shenju Cheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Innovation Team of Clinical Laboratory and Diagnosis, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yanhong Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Yunnan Innovation Team of Clinical Laboratory and Diagnosis, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Bo Nie
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yun Zeng
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.,Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
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17
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Soares S, Guerreiro SG, Cruz-Martins N, Faria I, Baylina P, Sales MG, Correa-Duarte MA, Fernandes R. The Influence of miRNAs on Radiotherapy Treatment in Prostate Cancer - A Systematic Review. Front Oncol 2021; 11:704664. [PMID: 34414113 PMCID: PMC8369466 DOI: 10.3389/fonc.2021.704664] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/06/2021] [Indexed: 11/21/2022] Open
Abstract
In the last years, extensive investigation on miRNomics have shown to have great advantages in cancer personalized medicine regarding diagnosis, treatment and even clinical outcomes. Prostate cancer (PCa) is the second most common male cancer and about 50% of all PCa patients received radiotherapy (RT), despite some of them develop radioresistance. Here, we aim to provide an overview on the mechanisms of miRNA biogenesis and to discuss the functional impact of miRNAs on PCa under radiation response. As main findings, 23 miRNAs were already identified as being involved in genetic regulation of PCa cell response to RT. The mechanisms of radioresistance are still poorly understood, despite it has been suggested that miRNAs play an important role in cell signaling pathways. Identification of miRNAs panel can be thus considered an upcoming and potentially useful strategy in PCa diagnosis, given that radioresistance biomarkers, in both prognosis and therapy still remains a challenge.
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Affiliation(s)
- Sílvia Soares
- BioMark@ISEP, School of Engineering, Polytechnic Institute of Porto, Porto, Portugal.,LaBMI - Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology & Innovation Center (PORTIC), P.PORTO - Polytechnic Institute of Porto, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), Porto, Portugal.,Faculty of Chemistry, University of Vigo, Vigo, Spain.,CEB, Centre of Biological Engineering of Minho University, Braga, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Susana G Guerreiro
- Institute for Research and Innovation in Health (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto-IPATIMUP, Porto, Portugal.,Department of Biomedicine, Biochemistry Unit, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Natália Cruz-Martins
- Institute for Research and Innovation in Health (i3S), Porto, Portugal.,Department of Biomedicine, Biochemistry Unit, Faculty of Medicine, University of Porto, Porto, Portugal.,Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Gandra, Portugal
| | - Isabel Faria
- School of Health, Polytechnic of Porto, Porto, Portugal
| | - Pilar Baylina
- LaBMI - Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology & Innovation Center (PORTIC), P.PORTO - Polytechnic Institute of Porto, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), Porto, Portugal.,School of Health, Polytechnic of Porto, Porto, Portugal
| | - Maria Goreti Sales
- BioMark@ISEP, School of Engineering, Polytechnic Institute of Porto, Porto, Portugal.,CEB, Centre of Biological Engineering of Minho University, Braga, Portugal.,Biomark@UC, Department of Chemical Engineering, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Miguel A Correa-Duarte
- Faculty of Chemistry, University of Vigo, Vigo, Spain.,CINBIO, University of Vigo, Vigo, Spain.,Southern Galicia Institute of Health Research (IISGS), and Biomedical Research Networking Center for Mental Health (CIBERSAM), Vigo, Spain
| | - Rúben Fernandes
- LaBMI - Laboratory of Medical & Industrial Biotechnology, Porto Research, Technology & Innovation Center (PORTIC), P.PORTO - Polytechnic Institute of Porto, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), Porto, Portugal.,School of Health, Polytechnic of Porto, Porto, Portugal
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18
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Romano G, Acunzo M, Nana-Sinkam P. microRNAs as Novel Therapeutics in Cancer. Cancers (Basel) 2021; 13:1526. [PMID: 33810332 PMCID: PMC8037786 DOI: 10.3390/cancers13071526] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the basic hallmarks of cancer, including apoptosis, proliferation, migration, and invasion. Despite the substantial progress made in identifying the molecular mechanisms driving the deregulation of miRNAs in cancer, the clinical translation of these important molecules to therapy remains in its infancy. The paucity of vehicles available for the safe and efficient delivery of miRNAs and ongoing concerns for toxicity remain major obstacles to clinical application. Novel formulations and the development of new vectors have significantly improved the stability of oligonucleotides, increasing the effectiveness of therapy. Furthermore, the use of specific moieties for delivery in target tissues or cells has increased the specificity of treatment. The use of new technologies has allowed small but important steps toward more specific therapeutic delivery in tumor tissues and cells. Although a long road remains, the path ahead holds great potential. Currently, a few miRNA drugs are under investigation in human clinical trials with promising results ahead.
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Affiliation(s)
| | | | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (G.R.); (M.A.)
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19
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Bayatiani MR, Ahmadi A, Aghabozorgi R, Seif F. Concomitant Up-Regulation of Hsa- Mir-374 and Down-Regulation of Its Targets, GSK-3β and APC, in Tissue Samples of Colorectal Cancer. Rep Biochem Mol Biol 2021; 9:408-416. [PMID: 33969134 PMCID: PMC8068448 DOI: 10.52547/rbmb.9.4.408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 06/28/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND The WNT-pathway is involved in several cancers, including colorectal cancer (CRC). Many cell signaling components and pathways are controlled by microRNAs. The main purpose of the present study was to investigate the expression of hsa-miR-374, and its two target genes of the Wnt-pathway in CRC clinical samples. METHODS In this study, we predicted the miRNAs targeting key genes of WNT-pathway using bioinformatics algorithms. The expression levels of hsa-miR-374, APC and GSK-3β on 48 pairs of Formalin-Fixed Paraffin-Embedded (FFPE) CRC tumors and marginal-tumors were evaluated using real time-PCR. Additionally, the hsa-miR-374a-5p precursor sequence was amplified by whole-blood DNA as a template. This amplicon was cloned into pEGFP-c1 expression vector and transfected into SW742 cells. Aside from this, MTT assay was performed to evaluate the effect of miR-374 on cell viability. RESULTS The bioinformatics analysis indicated that hsa-miR-374 binds to the regulatory region the key components of WNT-pathway, including APC and GSK-3β considering the recognition elements and mirSVR scores. Our results revealed significant down-regulation of GSK-3β (0.94 times, p= 0.0098) and APC (0.96 times, p= 0.03) and up-regulation of miR-374 (1.22 times, p= 0.0071) on tumor samples compared with their normal pairs. Meanwhile, the results of the over-expression of miR-374 showed down-regulation of APC and GSK-3β. MTT-assay also indicated that the miR-374 increased cell survival. CONCLUSION The results of our study indicated a concomitant change in the expression of miR-374 and its two related target genes, in clinical samples of CRC. Hsa-miR-374 might be as a helpful biomarker or therapeutic target in CRC.
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Affiliation(s)
- Mohammad Reza Bayatiani
- Department of Radiotherapy and Medical Physics, Arak University of Medical Sciences, Arak, Iran.
| | - Azam Ahmadi
- Infectious Diseases Research Center (IDRC), Arak University of Medical Sciences, Arak, Iran.
| | - Reza Aghabozorgi
- Khansari Hospital and Department of Internal Medicine, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Fatemeh Seif
- Department of Radiotherapy and Medical Physics, Arak University of Medical Sciences, Arak, Iran.
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20
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Lin T, Yang Y, Ye X, Yao J, Zhou H. Low expression of miR-99b promotes progression of clear cell renal cell carcinoma by up-regulating IGF1R/Akt/mTOR signaling. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:3083-3091. [PMID: 33425108 PMCID: PMC7791382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/12/2020] [Indexed: 06/12/2023]
Abstract
OBJECTIVE Dysfunctions of microRNAs have been implicated in the progression of clear cell renal cell carcinoma (ccRCC). Here, we investigated the roles of miR-99b and miR-99b* in ccRCC development. METHODS The expression levels of miR-99b and miR-99b* in tumor and tumor-adjacent tissues from ccRCC patients were quantified by quantitative Real-Time PCR (qRT-PCR). MicroRNA mimics and inhibitors were employed to evaluate the functions of miR-99b and miR-99b*. The effects of miR-99b on the proliferation and migration of ccRCC cells were analyzed by MTT and wound-healing assays, respectively. The effect of miR-99b on the expression of its target gene IGF1R and mTOR was determined by western blotting and qRT-PCR. RESULTS The abundances of miR-99b and miR-99b* were lower in ccRCC tissues than in the tumor-adjacent tissues from patients. Similarly, the expression of these two microRNAs was higher in the normal kidney HK-2 cells than in the ccRCC cell lines. Moreover, miR-99b and miR-99b* inhibited the proliferation and migration of ccRCC cells. MiR-99b was found to down-regulate IGF1R and mTOR expression, likely through targeting their mRNAs to induce degradation. Consistently, the mRNA levels of IGF1R and mTOR were higher in ccRCC tissues than in the tumor-adjacent tissues, and Akt, a downstream factor of IGF1R, was highly activated correspondingly in ccRCC tissues. CONCLUSION The low expression of miR-99b and miR-99b* contributes to ccRCC development and miR-99b acts as an onco-suppressor by suppressing IGF1R and mTOR expression to down-regulate IGF1R/AKT/mTOR signaling.
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Affiliation(s)
- Tianqi Lin
- Department of Urology, Zhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhou, Fujian, China
| | - Yun Yang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, High Throughput Drug Screening Platform, Xiamen UniversityXiamen, Fujian, China
| | - Xiaohong Ye
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, High Throughput Drug Screening Platform, Xiamen UniversityXiamen, Fujian, China
| | - Jiayue Yao
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, High Throughput Drug Screening Platform, Xiamen UniversityXiamen, Fujian, China
| | - Hu Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, High Throughput Drug Screening Platform, Xiamen UniversityXiamen, Fujian, China
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21
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Wang Y, Chen J, Wang X, Wang K. miR-140-3p inhibits bladder cancer cell proliferation and invasion by targeting FOXQ1. Aging (Albany NY) 2020; 12:20366-20379. [PMID: 33098639 PMCID: PMC7655201 DOI: 10.18632/aging.103828] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
Upregulation of the forkhead box protein Q1 (FOXQ1) promotes bladder cancer (BCa) cell growth and metastasis. Factors affecting FOXQ1 expression at the post-transcriptional level have not yet been identified. We performed cell proliferation, cell invasion, and tumorigenesis experiments to characterize the relationship between FOXQ1 and miR-140-3p. We found that FOXQ1 was significantly upregulated and miR-140-3p was significantly downregulated in BCa tissues. We also identified an inverse correlation between miR-140-3p and FOXQ1 expression in BCa tissues. Overexpression of miR-140-3p reduced FOXQ1 expression, suppressing BCa cell proliferation and invasion. A luciferase assay confirmed that miR-140-3p bound to the 3’-UTR of FOXQ1 mRNA and decreased its expression. In addition, we used a mouse xenograft model to demonstrate that miR-140-3p suppressed tumor cell growth in vivo. Our findings suggest that miR-140-3p suppresses BCa cell proliferation and invasion by directly decreasing FOXQ1 expression.
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Affiliation(s)
- Yuan Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Junwen Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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22
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Akoto T, Bhagirath D, Saini S. MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3:804-818. [PMID: 33426506 PMCID: PMC7793563 DOI: 10.20517/cdr.2020.30] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Prostate cancer is a condition commonly associated with men worldwide. Androgen deprivation therapy remains one of the targeted therapies. However, after some years, there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer (CRPC). CRPC cases are treated with second-line androgen deprivation therapy, after which, these CRPCs transdifferentiate to form neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. NEPC arises via a reversible transdifferentiation process, known as neuroendocrine differentiation (NED), which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2, chromogranin A and synaptophysin. The etiological factors and molecular basis for NED are poorly understood, contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy. Therefore, there is a need to fully understand the underlying molecular basis for this cancer. Recent studies have shown that microRNAs (miRNAs) play a key epigenetic role in driving therapy-induced NED in prostate cancer. In this review, we briefly describe the role of miRNAs in prostate cancer and CRPCs, discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC. This understanding will contribute to better clinical management of the disease.
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Affiliation(s)
- Theresa Akoto
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA
| | - Divya Bhagirath
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
| | - Sharanjot Saini
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
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Salah Z, Abd El Azeem EM, Youssef HF, Gamal-Eldeen AM, Farrag AR, El-Meliegy E, Soliman B, Elhefnawi M. Effect of Tumor Suppressor MiR-34a Loaded on ZSM-5 Nanozeolite in Hepatocellular Carcinoma: In Vitro and In Vivo Approach. Curr Gene Ther 2020; 19:342-354. [PMID: 31701846 DOI: 10.2174/1566523219666191108103739] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 10/16/2019] [Accepted: 11/01/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge. OBJECTIVE We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo. METHODS In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo. RESULTS ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo. CONCLUSION Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery.
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Affiliation(s)
- Zeinab Salah
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, Informatics and System Dept, National Research Centre (NRC), Cairo, Egypt
| | - Eman M Abd El Azeem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hanan F Youssef
- Refractories, Ceramics and Building Materials Department, National Research Centre (NRC), Dokki, Cairo 12622, Egypt
| | - Amira M Gamal-Eldeen
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taif University, Al Mutamarat Rd, Al Mathnah, At Taif 26521, Saudi Arabia
| | - Abdel R Farrag
- Pathology Department Medical Division Research, National Research Centre, Cairo, 12622, Dokki, Egypt
| | - Emad El-Meliegy
- Department of Biomaterials, National Research Centre, Cairo, Egypt
| | - Bangly Soliman
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, Informatics and System Dept, National Research Centre (NRC), Cairo, Egypt
| | - Mahmoud Elhefnawi
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, Informatics and System Dept, National Research Centre (NRC), Cairo, Egypt
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24
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Mei H, Wen Y. MicroRNAs for Diagnosis and Treatment of Colorectal Cancer. Endocr Metab Immune Disord Drug Targets 2020; 21:47-55. [PMID: 32819240 DOI: 10.2174/1871530320999200818134339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 05/28/2020] [Accepted: 07/15/2020] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, with high morbidity and mortality rates. The diagnosis and treatment of CRC have the most significant value for disease- free survival. Early diagnosis and early surgical resection are generally considered to be the most effective ways to reduce CRC mortality. In the past few years, many researchers have focused on the role of microRNAs in different tumors, making the functions of microRNAs gradually clear. The present study reviews the role of microRNAs in the diagnosis and treatment of colorectal cancer. Compared with the usual diagnosis methods and biomarker, circulating microRNAs can be promising new effective biomarkers for CRC diagnosis and treatment.
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Affiliation(s)
- Haitao Mei
- Shanghai General Hospital, Department of general surgery, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yugang Wen
- Shanghai General Hospital, Department of general surgery, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Yang L, Kong D, He M, Gong J, Nie Y, Tai S, Teng CB. MiR-7 mediates mitochondrial impairment to trigger apoptosis and necroptosis in Rhabdomyosarcoma. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118826. [PMID: 32810522 DOI: 10.1016/j.bbamcr.2020.118826] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 07/25/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Rhabdomyosarcoma (RMS) is a pediatric cancer with rhabdomyoblastic phenotype and mitochondria act as pivotal regulators of its growth and progression. While miR-7-5p (miR-7) is reported to have a tumor-suppressive role, little is yet known about its antitumor activity in RMS. METHODS The effects of miR-7 on RMS were analyzed both in vitro and in vivo. Cell death modalities induced by miR-7 were identified. Influence on mitochondria was evaluated through RNA sequencing data, morphological observation and mitochondrial functional assays, including outer membrane permeability, bioenergetics and redox balance. Dual-luciferase assay and phenotype validation after transient gene silencing were performed to identify miR-7 targets in RMS. RESULTS MiR-7 executed anti-tumor effect in RMS beyond proliferation inhibition. Morphologic features and molecular characteristics with apoptosis and necroptosis were found in miR-7-transfected RMS cells. Chemical inhibitors of apoptosis and necroptosis were able to prevent miR-7-induced cell death. Further, we identified that mitochondrial impairment mainly contributed to these phenomena and mitochondrial proteins SLC25A37 and TIMM50 were crucial targets for miR-7 to induce cell death in RMS. CONCLUSION Our results extended the mechanism of miR-7 antitumor role in rhabdomyosarcoma cancer, and provided potential implications for its therapy.
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Affiliation(s)
- Lin Yang
- Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China
| | - Delin Kong
- Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China
| | - Mei He
- Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China
| | - Jiawei Gong
- Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China
| | - Yuzhe Nie
- Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China
| | - Sheng Tai
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Chun-Bo Teng
- Key Laboratory of Saline-alkali Vegetation Ecology Restoration, College of Life Science, Northeast Forestry University, Harbin, China.
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26
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Khordadmehr M, Shahbazi R, Baradaran B, Sadreddini S, Shanebandi D, Hajiasgharzadeh K. Restoring of miR-193a-5p Sensitizes Breast Cancer Cells to Paclitaxel through P53 Pathway. Adv Pharm Bull 2020; 10:595-601. [PMID: 33072537 PMCID: PMC7539307 DOI: 10.34172/apb.2020.071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/11/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose: Recent evidence presented the important role of microRNAs in health and disease particularly in human cancers. Among those, miR-193 family contributes as a tumor suppressor in different benign and malignant cancers like breast cancer (BC) via interaction with specific targets. On the other hand, it was stated that miR-193 is able to modulate some targets in chemoresistant cancer cells. Therefore, the aim of this study was to evaluate the potential function of miR-193a-5p and paclitaxel in the apoptosis induction by targeting P53 in BC cells. Methods: At first, miR-193a-5p mimics were transfected to MDA-MB-231 BC cell line which indicated the lower expression level of miR-193a-5p. Subsequently, the transfected cells were treated with paclitaxel. Then, cell viability, apoptosis, and migration were evaluated by MTT, flow cytometry and DAPI staining, and scratch-wound motility assays, respectively. Moreover, the expression levels of P53 was evaluated by qRT-PCR. Results: The expression level of miR-193a-5p was restored in MDA-MB-231 cells which profoundly inhibited the proliferation (P<0.0001), induced apoptosis (P <0.0001) and harnessed migration (P <0.0001) in the BC cells and more effectiveness was observed in combination with paclitaxel. Interestingly, increased miR-193a-5p expression led to a reduction in P53 mRNA, offering that it can be a potential target of miR-193a. Conclusion: Taken together, it is concluded that the combination of miR-193a-5p restoration and paclitaxel could be potentially considered as an effective therapeutic strategy to get over chemoresistance during paclitaxel chemotherapy
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Dariush Shanebandi
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Khalil Hajiasgharzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
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27
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Lin YW, Wen YC, Chu CY, Tung MC, Yang YC, Hua KT, Pan KF, Hsiao M, Lee WJ, Chien MH. Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer. Cell Death Dis 2020; 11:591. [PMID: 32719332 PMCID: PMC7385149 DOI: 10.1038/s41419-020-02786-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 12/28/2022]
Abstract
N-α-Acetyltransferase 10 protein (Naa10p) was reported to be an oncoprotein in androgen-dependent prostate cancer (PCa; ADPC) through binding and increasing transcriptional activity of the androgen receptor (AR). PCa usually progresses from an androgen-dependent to an androgen-independent stage, leading to an increase in the metastatic potential and an incurable malignancy. At present, the role of Naa10p in androgen-independent prostate cancer (AIPC) remains unclear. In this study, in silico and immunohistochemistry analyses showed that Naa10 transcripts or the Naa10p protein were more highly expressed in primary and metastatic PCa cancer tissues compared to adjacent normal tissues and non-metastatic cancer tissues, respectively. Knockdown and overexpression of Naa10p in AIPC cells (DU145 and PC-3M), respectively, led to decreased and increased cell clonogenic and invasive abilities in vitro as well as tumor growth and metastasis in AIPC xenografts. From the protease array screening, we identified a disintegrin and metalloprotease 9 (ADAM9) as a potential target of Naa10p, which was responsible for the Naa10p-induced invasion of AIPC cells. Naa10p can form a complex with ADAM9 to maintain ADAM9 protein stability and promote AIPC's invasive ability which were independent of its acetyltransferase activity. In contrast to the Naa10p-ADAM9 axis, ADAM9 exerted positive feedback regulation on Naa10p to modulate progression of AIPC in vitro and in vivo. Taken together, for the first time, our results reveal a novel cross-talk between Naa10p and ADAM9 in regulating the progression of AIPC. Disruption of Naa10p-ADAM9 interactions may be a potential intervention for AIPC therapy.
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Affiliation(s)
- Yung-Wei Lin
- Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan.,Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Ching Wen
- Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan.,Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Ying Chu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Min-Che Tung
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan
| | - Yi-Chieh Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Medical Research, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Kuo-Tai Hua
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ke-Fan Pan
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Wei-Jiunn Lee
- TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan. .,Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. .,Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. .,Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. .,Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
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28
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Sheetz T, Mills J, Tessari A, Pawlikowski M, Braddom AE, Posid T, Zynger DL, James C, Embrione V, Parbhoo K, Foray C, Coppola V, Croce CM, Palmieri D. NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs. Cancers (Basel) 2020; 12:1861. [PMID: 32664322 PMCID: PMC7408652 DOI: 10.3390/cancers12071861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/05/2020] [Accepted: 07/06/2020] [Indexed: 11/16/2022] Open
Abstract
Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.
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Affiliation(s)
- Tyler Sheetz
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Joseph Mills
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Anna Tessari
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Megan Pawlikowski
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Ashley E. Braddom
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Tasha Posid
- Department of Urology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Debra L. Zynger
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Cindy James
- Mass Spectroscopy and Proteomics Facility, The Ohio State University, Columbus, OH 43210, USA;
| | - Valerio Embrione
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Kareesma Parbhoo
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Claudia Foray
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
| | - Vincenzo Coppola
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Carlo M. Croce
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Dario Palmieri
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.S.); (J.M.); (A.T.); (M.P.); (A.E.B.); (V.E.); (K.P.); (C.F.); (V.C.); (C.M.C.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
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29
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Yang Y, Li D, Li Y, Jiang Q, Sun R, Liu J, Wu F, Miao J, Ni L, Shi X, Huang C. Low-Temperature Plasma Suppresses Proliferation and Induces Apoptosis in Lung Cancer Cells by Regulating the miR-203a/BIRC5 Axis. Onco Targets Ther 2020; 13:5145-5153. [PMID: 32606735 PMCID: PMC7292489 DOI: 10.2147/ott.s244853] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 04/09/2020] [Indexed: 12/11/2022] Open
Abstract
Aim Low-temperature plasma (LTP) has potential applications in cancer therapy. Herein, we explored the molecular mechanisms of proliferation inhibition induced by LTP. Methods LTP was generated by a helium atmospheric-pressure plasma jet and used to treat A549 and H1299 cells. CCK-8 and cell apoptosis assays were performed to evaluate the effects of LTP treatment on A549 and H1299 cells. The qRT-PCR was performed to measure the expression of miR-203a after treating with LTP. CCK-8, colony formation, cell apoptosis assays, and Western blotting were performed to analyse the function of miR-203a in the development of lung cancer. Dual-luciferase assay and Western blotting were used to probe the relationship between miR-203a and BIRC5, and gene silencing using si-BIRC5 was carried out to explore the effect of knocking down BIRC5 on lung cancer cells. Results We found that LTP significantly suppressed proliferation and promoted apoptosis in A549 and H1299 cells. The miR-203a expression was increased after cells were treated with LTP. The miR-203a expression was downregulated among lung cancer tissue samples, and overexpression of miR-203a suppressed cell growth and induced apoptosis in lung cancer cells. We showed that miR-203a targeted BIRC5. Moreover, silencing of BIRC5 caused proliferation inhibition and induced apoptosis in lung cancer cells. Conclusion Our study revealed that LTP inhibited proliferation and induced apoptosis in A549 and H1299 cells through the miR-203a/BIRC5 axis. These findings showed that LTP could potentially be used to treat lung cancer.
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Affiliation(s)
- Yang Yang
- Department of Toxicology and Sanitary Analysis, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, People's Republic of China
| | - Dan Li
- Department of Clinical Medicine, Medical College of Yan'an University, Yan'an 716000, Shanxi Province, People's Republic of China
| | - Yulong Li
- Department of Gastroenterology, Shaanxi Provincial People's Hospital, Xi'an 710068, People's Republic of China
| | - Qiuyu Jiang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Ruifang Sun
- Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Jinren Liu
- Department of Toxicology and Sanitary Analysis, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, People's Republic of China
| | - Fei Wu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Jiyu Miao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Lei Ni
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
| | - Xingmin Shi
- Department of Toxicology and Sanitary Analysis, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, People's Republic of China
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China
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30
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Urinary microRNAs expression in prostate cancer diagnosis: a systematic review. Clin Transl Oncol 2020; 22:2061-2073. [PMID: 32323148 DOI: 10.1007/s12094-020-02349-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/25/2020] [Indexed: 01/09/2023]
Abstract
PURPOSE Circulating microRNAs (miRNAs) have been shown to have the potential as noninvasive diagnosis biomarkers in several types of cancers, including prostate cancer (PCa). Urine-based miRNA biomarkers have been researched as an alternative tool in PCa diagnosis. However, few studies have performed miRNA detection in urine samples from PCa patients, as well as low numbers of miRNAs have been assayed, and there is a lack of standard strategies for validation. In this context, we conducted an in-depth literature review focusing on miRNAs isolated from urine samples that may contribute to the diagnosis of PCa. METHODS A systematic review was performed searching the PubMed, Lilacs and Cochrane Library databases for articles focused on the value of significantly deregulated miRNAs as biomarkers in PCa patients. RESULTS Only 18 primary manuscripts were included in this review, according to the search criteria. Our results suggest that miR-21-5p, miR-141-3p, miR-375 and miR-574-3p should be considered as potential urinary biomarkers for the diagnosis of PCa. CONCLUSION These results suggested that large-scale prospective studies are still needed to validate our findings, using standardized protocols for analysis.
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31
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Elhefnawi M, Salah Z, Soliman B. The Promise of miRNA Replacement Therapy for Hepatocellular Carcinoma. Curr Gene Ther 2019; 19:290-304. [DOI: 10.2174/1566523219666191023101433] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/25/2019] [Accepted: 10/09/2019] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma is a devastating tumor which accounts for death mortality rate
94% globally, and about 780,000 new cases each year. Tumor suppressor miRNAs represent a class of
noncoding RNAs, which exhibit decreased or inhibited expression in the case of carcinogenesis.
Therefore, the replacement of these molecules leads to post-transcriptional regulation of tens to hundreds
of oncogenic targets and limiting the tumor. Interestingly, there is a group of tumor silencer
miRNAs that have been highlighted in HCC and herein, our review will discuss the prominent examples
of these miRs in terms of their efficient delivery using vectors, nano-delivery systems, their successful
models either in vitro or in vivo and pre-clinical trials. Collectively, tumor suppressor miRNAs
can act as novel therapeutics for HCC and more studies should be directed towards these promising
therapeutics.
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Affiliation(s)
- Mahmoud Elhefnawi
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
| | - Zeinab Salah
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
| | - Bangly Soliman
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
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32
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Dastmalchi N, Safaralizadeh R, Baradaran B, Hosseinpourfeizi M, Baghbanzadeh A. An update review of deregulated tumor suppressive microRNAs and their contribution in various molecular subtypes of breast cancer. Gene 2019; 729:144301. [PMID: 31884105 DOI: 10.1016/j.gene.2019.144301] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/10/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Breast cancer (BC) is histologically classified into hormone-receptor+ (ER+, PR + ), human epidermal growth factor receptor-2+ (Her2 + ), and triple-negative breast cancer (TNBC) types. The important contribution of tumor-suppressive (TS) microRNAs (miRs) in BC development and treatment have been well-acknowledged in the literature. OBJECTIVE The present review focused on the contribution of recently examined TS miRs in the progression and treatment of various histological subtypes of BC. RESULTS In summary, various miRs have tumor-suppressive roles in BC, so that their aberrant expression leads to the abnormality in the cellular processes such as enhanced cell growth, decreased apoptosis, cell migration and metastasis, and decreased sensitivity to chemotherapy through deregulated expression of oncogene targets of TS miRs. CONCLUSION TS miRs could be regarded as a proper molecular target for target therapy of BC. However, further in vitro and in vivo investigations are required to confirm the exact molecular functions of TS miRs in BC cells to offer more efficient targeted therapies.
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Affiliation(s)
- Narges Dastmalchi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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33
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Scheideler M, Vidakovic I, Prassl R. Lipid nanocarriers for microRNA delivery. Chem Phys Lipids 2019; 226:104837. [PMID: 31689410 DOI: 10.1016/j.chemphyslip.2019.104837] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/12/2019] [Accepted: 10/15/2019] [Indexed: 02/06/2023]
Abstract
Non-coding RNAs (ncRNAs) like microRNAs (miRNAs) or small interference RNAs (siRNAs) with their power to selectively silence any gene of interest enable the targeting of so far 'undruggable' proteins and diseases. Such RNA molecules have gained much attention from biotech and pharmaceutical companies, which led to the first Food and Drug Administration (FDA) approved ncRNA therapeutic in 2018. However, the main barrier in clinical practice of ncRNAs is the lack of an effective delivery system that can protect the RNA molecules from nuclease degradation, deliver them to specific tissues and cell types, and release them into the cytoplasm of the targeted cells, all without inducing adverse effects. For that reason, drug delivery approaches, formulations, technologies and systems for transporting pharmacological ncRNA compounds to achieve a diagnostic or therapeutic effect in the human body are in demand. Here, we review the development of therapeutic lipid-based nanoparticles for delivery of miRNAs, one class of endogenous ncRNAs with specific regulatory functions. We outline challenges and opportunities for advanced miRNA-based therapies, and discuss the complexity associated with the delivery of functional miRNAs. Novel strategies are addressed how to deal with the most critical points in miRNA delivery, such as toxicity, specific targeting of disease sites, proper cellular uptake and endosomal escape of miRNAs. Current fields of application and various preclinical settings involving miRNA therapeutics are discussed, providing an outlook to future clinical approaches. Following the current trends and technological developments in nanomedicine exciting new delivery systems for ncRNA-based therapeutics can be expected in upcoming years.
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Affiliation(s)
- Marcel Scheideler
- Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Ivan Vidakovic
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Biophysics, Medical University of Graz, Neue Stiftingtalstraße 6/IV, 8010 Graz, Austria.
| | - Ruth Prassl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Biophysics, Medical University of Graz, Neue Stiftingtalstraße 6/IV, 8010 Graz, Austria.
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34
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Cao MX, Tang YL, Zhang WL, Tang YJ, Liang XH. Non-coding RNAs as Regulators of Lymphangiogenesis in Lymphatic Development, Inflammation, and Cancer Metastasis. Front Oncol 2019; 9:916. [PMID: 31616631 PMCID: PMC6763613 DOI: 10.3389/fonc.2019.00916] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 09/03/2019] [Indexed: 02/05/2023] Open
Abstract
Non-coding RNAs (ncRNAs), which do not encode proteins, have pivotal roles in manipulating gene expression in development, physiology, and pathology. Emerging data have shown that ncRNAs can regulate lymphangiogenesis, which refers to lymphatics deriving from preexisting vessels, becomes established during embryogenesis, and has a close relationship with pathological conditions such as lymphatic developmental diseases, inflammation, and cancer. This review summarizes the molecular mechanisms of lymphangiogenesis in lymphatic development, inflammation and cancer metastasis, and discusses ncRNAs' regulatory effects on them. Therapeutic targets with regard to lymphangiogenesis are also discussed.
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Affiliation(s)
- Ming-Xin Cao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wei-Long Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.,Hubei Key Laboratory of Industrial Microbiology, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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35
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Shen Y, Pu K, Zheng K, Ma X, Qin J, Jiang L, Li J. Differentially Expressed microRNAs in MIA PaCa-2 and PANC-1 Pancreas Ductal Adenocarcinoma Cell Lines are Involved in Cancer Stem Cell Regulation. Int J Mol Sci 2019; 20:E4473. [PMID: 31510100 PMCID: PMC6770012 DOI: 10.3390/ijms20184473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 09/07/2019] [Accepted: 09/09/2019] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and thus better understanding of its molecular pathology is crucial for us to devise more effective treatment of this deadly disease. As cancer cell line remains a convenient starting point for discovery and proof-of-concept studies, here we report the miRNA expression characteristics of two cell lines, MIA PaCa-2 and PANC-1, and discovered three miRNAs (miR-7-5p, let-7d, and miR-135b-5p) that are involved in cancer stem cells (CSCs) suppression. After transfection of each miRNA's mimic into PANC-1 cells which exhibits higher stemness feature than MIA-PaCa-2 cells, partial reduction of CSC surface markers and inhibition of tumor sphere formation were observed. These results enlighten us to consider miRNAs as potential therapeutic agents for pancreatic cancer patients via specific and effective inhibition of CSCs.
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Affiliation(s)
- Ye Shen
- Key Laboratory for Nano-Bio Interface Research, Nano-Bio-Chem Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Kefeng Pu
- Key Laboratory for Nano-Bio Interface Research, Nano-Bio-Chem Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Kexiao Zheng
- Key Laboratory for Nano-Bio Interface Research, Nano-Bio-Chem Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Xiaochuan Ma
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Jingyi Qin
- Key Laboratory for Nano-Bio Interface Research, Nano-Bio-Chem Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Li Jiang
- Key Laboratory for Nano-Bio Interface Research, Nano-Bio-Chem Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Jiong Li
- Key Laboratory for Nano-Bio Interface Research, Nano-Bio-Chem Centre, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
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36
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Jin Y, Cheng H, Cao J, Shen W. MicroRNA 32 promotes cell proliferation, migration, and suppresses apoptosis in colon cancer cells by targeting OTU domain containing 3. J Cell Biochem 2019; 120:18629-18639. [PMID: 31338872 DOI: 10.1002/jcb.28874] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/01/2019] [Accepted: 03/15/2019] [Indexed: 12/14/2022]
Abstract
Colorectal cancer is considered as the fourth leading reason of cancer-linked deaths worldwide. However, our knowledge about its pathogenic mechanism remains inadequate. MicroRNA 32 (miR-32), a member of small noncoding RNAs, has been found vital roles in tumorigenesis. This study studied its functions and underlying mechanism in colorectal cancer. The experiment revealed the obvious upregulation of miR-32 in colorectal cancer tissues and six cancer cell lines, compared with normal tissues and cells. Moreover, miR-32 upregulation reduced cell apoptosis and promoted cell proliferation and migration, while its downregulation displayed opposite effects. Dual luciferase reporter assays proved that miR-32 bound to the 3'-untranslated region (3'-UTR) of OTU domain containing 3 (OTUD3), suggesting that miR-32 directly targeted OTUD3. Further experiments demonstrated that overexpression of miR-32 could reduce the expression level of OTUD3. Furthermore, OTUD3 silence promoted proliferation and motility and decreased apoptosis for HCT116 cells and restored partly miR-32-mediated cell proliferation, migration, and antiapoptosis for colon cancer. Therefore, our study indicated that miR-32 enhanced cell proliferation and motility abilities, and inhibited apoptosis by directly targeting OTUD3 in colon cancer cells, which implied that miR-32 was hopeful to be a biomarker or target used for diagnosis and therapy of colon cancer.
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Affiliation(s)
- Yanzhao Jin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
| | - Hua Cheng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
| | - Jiaqing Cao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
| | - Wei Shen
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
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Nguyen TA, Park J, Dang TL, Choi YG, Kim VN. Microprocessor depends on hemin to recognize the apical loop of primary microRNA. Nucleic Acids Res 2019; 46:5726-5736. [PMID: 29750274 PMCID: PMC6009577 DOI: 10.1093/nar/gky248] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/03/2018] [Indexed: 01/14/2023] Open
Abstract
Microprocessor, which consists of a ribonuclease III DROSHA and its cofactor DGCR8, initiates microRNA (miRNA) maturation by cleaving primary miRNA transcripts (pri-miRNAs). We recently demonstrated that the DGCR8 dimer recognizes the apical elements of pri-miRNAs, including the UGU motif, to accurately locate and orient Microprocessor on pri-miRNAs. However, the mechanism underlying the selective RNA binding remains unknown. In this study, we find that hemin, a ferric ion-containing porphyrin, enhances the specific interaction between the apical UGU motif and the DGCR8 dimer, allowing Microprocessor to achieve high efficiency and fidelity of pri-miRNA processing in vitro. Furthermore, by generating a DGCR8 mutant cell line and carrying out rescue experiments, we discover that hemin preferentially stimulates the expression of miRNAs possessing the UGU motif, thereby conferring differential regulation of miRNA maturation. Our findings reveal the molecular action mechanism of hemin in pri-miRNA processing and establish a novel function of hemin in inducing specific RNA-protein interaction.
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Affiliation(s)
- Tuan Anh Nguyen
- Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China
| | - Joha Park
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea.,Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea
| | - Thi Lieu Dang
- Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China
| | - Yeon-Gil Choi
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea.,Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea
| | - V Narry Kim
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea.,Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea
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38
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Sandomenico A, Ruvo M. Targeting Nodal and Cripto-1: Perspectives Inside Dual Potential Theranostic Cancer Biomarkers. Curr Med Chem 2019; 26:1994-2050. [PMID: 30207211 DOI: 10.2174/0929867325666180912104707] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/13/2018] [Accepted: 07/17/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents. OBJECTIVE To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC). RESULTS We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate. CONCLUSION Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.
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Affiliation(s)
- Annamaria Sandomenico
- Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (IBB-CNR), via Mezzocannone, 16, 80134, Napoli, Italy
| | - Menotti Ruvo
- Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (IBB-CNR), via Mezzocannone, 16, 80134, Napoli, Italy
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39
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Khordadmehr M, Jigari-Asl F, Ezzati H, Shahbazi R, Sadreddini S, Safaei S, Baradaran B. A comprehensive review on miR-451: A promising cancer biomarker with therapeutic potential. J Cell Physiol 2019; 234:21716-21731. [PMID: 31140618 DOI: 10.1002/jcp.28888] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are proposed as a family of short noncoding molecules able to manage and control the expression of the gene targets at the posttranscriptional level. They contribute in several fundamental physiological mechanisms as well as a verity of human and animal diseases such as cancer progression. Among these tiny RNAs, miR-451 placed on chromosome 17 at 17q11.2 presents an essential role in many biological processes in health condition and also in pathogenesis of different diseases. Besides, it has been recently considered as a valuable biomarker for cancer detection, prognosis and treatment. Therefore, this review will provide the critical functions of miR-451 on biological mechanisms including cell cycle and proliferation, cell survival and apoptosis, differentiation and development as well as disease initiation and progression such as tumor formation, migration, invasion, and metastasis.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Farinaz Jigari-Asl
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hamed Ezzati
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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40
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Ahmadi A, Aghabozorgi R, Anoushirvani AA, Bayatiani M, Arjomandzadegan M, Eslah S, Sobhani Y. Evaluation of Splicing on X-box Binding Protein Transcript in Tissue Samples of Colorectal Cancer. Cureus 2019; 11:e4500. [PMID: 31249762 PMCID: PMC6584302 DOI: 10.7759/cureus.4500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 04/18/2019] [Indexed: 11/05/2022] Open
Abstract
Background The genetic etiology of colorectal cancer (CRC) is the occurrence of mutation in the genes involved in signal transduction pathways including that of cellular responses to endoplasmic reticulum (ER) stress. This study examines alterations of pre-messenger ribonucleic acid (pre-mRNA) splicing in X-box binding protein (XBP) transcripts related to the ER stress pathway in CRC. Materials and methods In this study, samples were deparaffinized and underwent RNA extraction. A total of 30 synthesized complementary deoxyribonucleic acid (cDNA) templates from the extracted RNAs related to tumor and non-tumor CRC samples, collected over three years and containing pathological data, were subjected to semi-quantitative reverse transcriptase polymerase chain reaction (sqRT-PCR). These cDNA templates were amplified in reaction tubes with specific primers for both spliced and non-spliced isoforms of XBP. Results with P< .05 were considered statistically significant. Results Microscopic assessment represented lymphocyte-rich effusion in tumor samples. sqRT-PCR electrophoresis results showed spliced and non-spliced forms of XBP messenger RNA in the studied samples. In addition, our data showed there were more than 7.8 times the total number of spliced variants in the marginal tumor samples than in the tumor tissue samples (P<.05). Conclusion Alterations of expression in genes involved in stress signaling pathways in cancer have been identified previously. Our results showed an inverse relationship between XBP splicing and CRC tumor tissue, possibly lead to the inactivation of apoptosis in the downstream response to ER stress. However, we propose that the remaining genes in this pathway should undergo gene expression analysis using a greater number of samples.
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Affiliation(s)
- Azam Ahmadi
- Genetics, Arak University of Medical Sciences, Arak, IRN
| | - Reza Aghabozorgi
- Internal Medicine, Arak University of Medical Sciences, Arak, IRN
| | | | | | | | - Saeedeh Eslah
- Radiotherapy and Medical Physics, Arak University of Medical Sciences, Arak, IRN
| | - Yasaman Sobhani
- Radiotherapy and Medical Physics, Arak University of Medical Sciences, Arak, IRN
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41
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Baruah MM, Sharma N. In silico identification of key genes and signaling pathways targeted by a panel of signature microRNAs in prostate cancer. Med Oncol 2019; 36:43. [PMID: 30937635 DOI: 10.1007/s12032-019-1268-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 03/27/2019] [Indexed: 12/12/2022]
Abstract
Accumulating evidence have suggested that some microRNAs are aberrantly expressed in prostate cancer. In our previous work, we had identified a panel of four differentially expressed microRNAs in prostate cancer. In the present study, we have investigated common molecular targets of this panel of miRNAs (DEMs) and key hub genes that can serve as potential candidate biomarkers in the pathogenesis and progression of prostate cancer. A joint bioinformatics approach was employed to identify differentially expressed genes (DEGs) in prostate cancer. Gene enrichment analysis followed by the protein-protein interaction (PPI) network construction and selection of hub genes was further performed using String and Cytoscape, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the identified hub genes was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. In total, 496 genes were identified to be common targets of DEMs in prostate cancer and 13 key hub genes were identified from three modules of the PPI network of the DEGs. Further top five genes viz Rhoa, PI3KCA, CDC42, MAPK3, TP53 were used for Enrichment analysis which revealed their association with vital cellular and functional pathways in prostate cancer indicating their potential as candidate biomarkers in prostate cancer.
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Affiliation(s)
- Meghna M Baruah
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Lavale, Mulshi, Pune, 412115, India
| | - Neeti Sharma
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Lavale, Mulshi, Pune, 412115, India.
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Khordadmehr M, Shahbazi R, Sadreddini S, Baradaran B. miR-193: A new weapon against cancer. J Cell Physiol 2019; 234:16861-16872. [PMID: 30779342 DOI: 10.1002/jcp.28368] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 02/06/2019] [Indexed: 12/12/2022]
Abstract
microRNAs (miRNAs) are known as a large group of short noncoding RNAs, which structurally consist of 19-22 nucleotides in length and functionally act as one of the main regulators of gene expression in important biological and physiological contexts like cell growth, apoptosis, proliferation, differentiation, movement (cell motility), and angiogenesis as well as disease formation and progression importantly in cancer cell invasion, migration, and metastasis. Among these notable tiny molecules, many studies recently presented the important role of the miR-193 family comprising miR-193a-3p, miR-193a-5p, miR-193b-3p, and miR-193b-5p in health and disease biological processes by interaction with special targeting and signaling, which mainly contribute as a tumor suppressor. Therefore, in the present paper, we review the functional role of this miRNA family in both health and disease conditions focusing on various tumor developments, diagnoses, prognoses, and treatment.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Roy S, Hooiveld GJ, Seehawer M, Caruso S, Heinzmann F, Schneider AT, Frank AK, Cardenas DV, Sonntag R, Luedde M, Trautwein C, Stein I, Pikarsky E, Loosen S, Tacke F, Ringelhan M, Avsaroglu SK, Goga A, Buendia MA, Vucur M, Heikenwalder M, Zucman-Rossi J, Zender L, Roderburg C, Luedde T. microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-Associated Protein 1 to Suppress Hepatocarcinogenesis. Gastroenterology 2018; 155:1951-1966.e26. [PMID: 30165047 PMCID: PMC6279541 DOI: 10.1053/j.gastro.2018.08.032] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 08/15/2018] [Accepted: 08/18/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS We performed an integrated analysis to identify microRNAs (miRNAs) and messenger RNAs (mRNAs) with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues. METHODS We analyzed miRNA and mRNA expression profiles of liver tissues from mice with diethylnitrosamine-induced hepatocarcinogenesis, conditional expression of lymphotoxin alpha and lymphotoxin beta, or inducible expression of a Myc transgene (Tet-O-Myc mice), as well as male C57BL/6 mice (controls). miRNA mimics were expressed and miRNAs and mRNAs were knocked down in human (Huh7, Hep3B, JHH2) hepatoma cell lines; cells were analyzed for viability, proliferation, apoptosis, migration, and invasion. Cells were grown as xenograft tumors in nude mice and analyzed. We combined in silico target gene prediction with mRNA profiles from all 3 mouse models. We quantified miRNA levels in 146 fresh-frozen tissues from patients (125 HCCs, 17 matched nontumor tissues, and 4 liver samples from patients without cancer) and published human data sets and tested correlations with patient survival times using Kaplan-Meier curves and the log-rank test. Levels of NUSAP1 mRNA were quantified in 237 HCCs and 5 nontumor liver samples using the TaqMan assay. RESULTS Levels of the miRNA 193a-5p (MIR193A-5p) were reduced in liver tumors from all 3 mouse tumor models and in human HCC samples, compared with nontumor liver tissues. Expression of a MIR193A-5p mimic in hepatoma cells reduced proliferation, survival, migration, and invasion and their growth as xenograft tumors in nude mice. We found nucleolar and spindle-associated protein 1 (NUSAP1) to be a target of MIR193A-5p; HCC cells and tissues with low levels of MIR193A-5p had increased expression of NUSAP1. Increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Knockdown of NUSAP1 in Huh7 cells reduced proliferation, survival, migration, and growth as xenograft tumors in nude mice. Hydrodynamic tail-vein injections of a small hairpin RNA against NUSAP1 reduced growth of Akt1-Myc-induced tumors in mice. CONCLUSIONS MIR193A-5p appears to prevent liver tumorigenesis by reducing levels of NUSAP1. Levels of MIR193A-5p are reduced in mouse and human HCC cells and tissues, leading to increased levels of NUSAP1, associated with shorter survival times of patients. Integrated analyses of miRNAs and mRNAs in tumors from mouse models can lead to identification of therapeutic targets in humans. The currently reported miRNA and mRNA profiling data have been submitted to the Gene Expression Omnibus (super-series accession number GSE102418).
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Affiliation(s)
- Sanchari Roy
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology,Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany
| | - Guido J. Hooiveld
- Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, Netherlands
| | - Marco Seehawer
- Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany,Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Stefano Caruso
- Inserm UMR-1162, Functional Genomics of Solid Tumors, University Paris Descartes, University University Paris Diderot, University Paris 13, Labex Immuno-Oncology, Paris, France
| | - Florian Heinzmann
- Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany,Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | | | - Anna K. Frank
- Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany
| | | | - Roland Sonntag
- Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany
| | - Mark Luedde
- Department of Cardiology, University Hospital Kiel, 25105 Kiel, Germany
| | | | - Ilan Stein
- Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
| | - Eli Pikarsky
- Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
| | - Sven Loosen
- Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany
| | - Marc Ringelhan
- Technische Universität München, Ismaningerstr. 22, 81675 München
| | - Seda Kilinc Avsaroglu
- Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143-0452
| | - Andrei Goga
- Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143-0452
| | - Marie-Annick Buendia
- Inserm Unit U1193, University Paris-Sud, Paul Brousse Hospital, Villejuif, France
| | - Mihael Vucur
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Germany
| | - Jessica Zucman-Rossi
- Inserm UMR-1162, Functional Genomics of Solid Tumors, University Paris Descartes, University University Paris Diderot, University Paris 13, Labex Immuno-Oncology, Paris, France
| | - Lars Zender
- Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany,Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany,Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | | | - Tom Luedde
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, Aachen Germany; Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany.
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44
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Khordadmehr M, Shahbazi R, Ezzati H, Jigari-Asl F, Sadreddini S, Baradaran B. Key microRNAs in the biology of breast cancer; emerging evidence in the last decade. J Cell Physiol 2018; 234:8316-8326. [PMID: 30422324 DOI: 10.1002/jcp.27716] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/16/2018] [Indexed: 12/12/2022]
Abstract
microRNAs (miRNAs) are a family of small noncoding RNAs that play a pivotal role in the regulation of main biological and physiological processes, including cell cycle regulation, proliferation, differentiation, apoptosis, stem cell maintenance, and organ development. Dysregulation of these tiny molecules has been related to different human diseases, such as cancer. It has been estimated that more than 50% of these noncoding RNA sequences are placed on fragile sites or cancer-associated genomic regions. After the discovery of the first specific miRNA signatures in breast cancer, many studies focused on the involvement of these small RNAs in the pathophysiology of breast tumors and their possible clinical implications as reliable prognostic biomarkers or as a new therapeutic approach. Therefore, the present review will focus on the recent findings on the involvement of miRNAs in the biology of breast cancer associated with their clinical implications.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary, Medicine, University of Tabriz, Tabriz, East Azerbaijan, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary, Medicine, University of Tabriz, Tabriz, East Azerbaijan, Iran
| | - Hamed Ezzati
- Department of Pathology, Faculty of Veterinary, Medicine, University of Tabriz, Tabriz, East Azerbaijan, Iran
| | - Farinaz Jigari-Asl
- Department of Pathology, Faculty of Veterinary, Medicine, University of Tabriz, Tabriz, East Azerbaijan, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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45
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Mortazavi D, Sharifi M. Antiproliferative effect of upregulation of hsa-let-7c-5p in human acute erythroleukemia cells. Cytotechnology 2018; 70:1509-1518. [PMID: 30073438 DOI: 10.1007/s10616-018-0241-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 07/24/2018] [Indexed: 12/21/2022] Open
Abstract
New achievements in the field of cancer treatment are results of recent advances in molecular medicine and gene therapy. Usage of microRNAs (miRNAs) which are small noncoding RNAs is one of the molecular research lines for the diagnosis and treatment of cancers. miRNAs have an important role in post-transcriptional regulation of the gene expression and are involved in cellular activities such as growth, differentiation, cell death and cancer development. One of the miRNAs that showed downregulation in human acute erythroleukemia is hsa-let-7c-5p. Down-regulation of hsa-let-7c-5p has been reported in in vitro studies of different cancers. In the present study, upregulation of hsa-let-7c-5p is performed in human acute erythroleukemia cell line (KG-1) using miRNA mimic. qRT-PCR, MTT assay, Annexin-V, and propidium iodide staining at different time points after miRNA mimic transfection were accomplished to assess the expression level of hsa-let-7c-5p, cell viability, apoptosis and late apoptosis. In addition, the expression level of PBX2 oncogene, a validated target gene of hsa-let-7c-5p, is evaluated by RT-qPCR to show the effectivity of this approach on erythroleukemia cancer cells. Our results can be used in translational medicine for future investigation in acute erythroleukemia and to approach treatment based on miRNA mimic therapy.
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Affiliation(s)
- Deniz Mortazavi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, 81744-176, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, 81744-176, Iran.
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46
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The microRNA signatures: aberrantly expressed miRNAs in prostate cancer. Clin Transl Oncol 2018; 21:126-144. [DOI: 10.1007/s12094-018-1910-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 06/18/2018] [Indexed: 01/27/2023]
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47
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Ghosh A, Degyatoreva N, Kukielski C, Story S, Bhaduri S, Maiti K, Nahar S, Ray A, Arya DP, Maiti S. Targeting miRNA by tunable small molecule binders: peptidic aminosugar mediated interference in miR-21 biogenesis reverts epithelial to mesenchymal transition. MEDCHEMCOMM 2018; 9:1147-1154. [PMID: 30109002 DOI: 10.1039/c8md00092a] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 05/18/2018] [Indexed: 01/01/2023]
Abstract
Epithelial to mesenchymal transition (EMT) is a process in which epithelial cells lose cell polarity and cell-cell adhesion and gain migratory and invasive properties to become mesenchymal cells that are very vital for development, wound healing and stem cell behavior and contribute pathologically to fibrosis and cancer progression. miR21, a potent regulator of the tumor suppressor gene PTEN, can be silenced to reverse EMT, thereby providing an attractive target for abrogating the malignant behavior of breast cancer. Here, we report the design, synthesis and binding of a peptidic-aminoglycoside (PA) based chemical library against pre-miR21 that led to the identification of a group of small molecules that bind to pre-miR21 with high affinities and antagonize miR-21 maturation and function, thereby reversing EMT. The approach described here offers a promising miRNA targeting platform where such aminosugar conjugates can be similarly used to target other oncogenic miRNAs. Minor changes in the amino acid sequence allow us to tailor the binding effectiveness and downstream biological effects, thus making this approach a potentially tunable method of regulation of miRNA function.
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Affiliation(s)
- Arpita Ghosh
- CSIR, Institute of Genomics and Integrative Biology , New Delhi , India .
| | | | - Casey Kukielski
- Laboratory of Medicinal Chemistry , Clemson University , Clemson , SC 29634 , USA .
| | - Sandra Story
- NUBAD LLC , 900 B West Faris Road , Greenville , SC 29605 , USA
| | | | - Krishnagopal Maiti
- Laboratory of Medicinal Chemistry , Clemson University , Clemson , SC 29634 , USA .
| | - Smita Nahar
- CSIR, Institute of Genomics and Integrative Biology , New Delhi , India .
| | - Arjun Ray
- CSIR, Institute of Genomics and Integrative Biology , New Delhi , India .
| | - Dev P Arya
- NUBAD LLC , 900 B West Faris Road , Greenville , SC 29605 , USA.,Laboratory of Medicinal Chemistry , Clemson University , Clemson , SC 29634 , USA .
| | - Souvik Maiti
- CSIR, Institute of Genomics and Integrative Biology , New Delhi , India .
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48
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Zhu X, Shen H, Yin X, Long L, Chen X, Feng F, Liu Y, Zhao P, Xu Y, Li M, Xu W, Li Y. IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells. Oncotarget 2018; 8:39154-39166. [PMID: 28388577 PMCID: PMC5503602 DOI: 10.18632/oncotarget.16610] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 03/02/2017] [Indexed: 01/28/2023] Open
Abstract
Enhanced chemoresistance is, among other factors, believed to be responsible for treatment failure and tumor relapse in patients with epithelial ovarian cancer (EOC). Here, we exposed EOC cells to interleukin-6 (IL-6) to activate oncogenic STAT3, which directly repressed miR-204 via a conserved STAT3-binding site near the TRPM3 promoter region upstream of miR-204. Repression of miR-204 was required for IL-6-induced cisplatin (cDDP) resistance. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a direct miR-204 target. Importantly, the resulting IL-6R/STAT3/miR-204 feedback loop was identified in patients with EOC, and its activity correlated with chemosensitivity. Moreover, exogenous miR-204 blocked this circuit and enhanced cDDP sensitivity both in vitro and in vivo by inactivating IL-6R/STAT3 signaling and subsequently decreasing the expression of anti-apoptotic proteins. Our findings illustrate the function of this feedback loop in cDDP-based therapy and may offer a broadly useful approach to improve EOC therapy.
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Affiliation(s)
- Xiaolan Zhu
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.,Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China
| | - Huiling Shen
- Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China.,Department of Oncology, The Affiliated People Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Xinming Yin
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Lulu Long
- Department of Oncology, The Affiliated People Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Xiaofang Chen
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Fan Feng
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Yueqin Liu
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Peiqing Zhao
- Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China
| | - Yue Xu
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Mei Li
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Wenlin Xu
- Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Yuefeng Li
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
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49
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Differential expression profiles of miRNAs and correlation with clinical outcomes in acute myeloid leukemia. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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50
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Zhang Q, Zhang B, Sun L, Yan Q, Zhang Y, Zhang Z, Su Y, Wang C. MicroRNA-130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β-catenin pathway. Cell Biochem Funct 2018; 36:194-202. [PMID: 29653464 PMCID: PMC6001533 DOI: 10.1002/cbf.3331] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 03/04/2018] [Indexed: 01/06/2023]
Abstract
More and more studies indicate the relevance of miRNAs in inducing certain drug resistance. Our study aimed to investigate whether microRNA‐130b‐3p (miR‐130b) mediates the chemoresistance as well as proliferation of lung cancer (LC) cells. MTS assay and apoptosis analysis were conducted to determine cell proliferation and apoptosis, respectively. Binding sites were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT‐PCR and immunoblot, respectively. Mouse xenograft model was used to evaluate the role of miR‐130b in cisplatin resistance in vivo. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. We identified PTEN as miR‐130b's major target and inversely correlated with miR‐130b expression in LC. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. Suppression of miR‐130b enhanced drug cytotoxicity and reduced proliferation of A549/CR cells both internally and externally. Particularly, miR‐130b mediated Wnt/β‐catenin signalling pathway activities, chemoresistance and proliferation in LC cell, which was partially blocked following knockdown of PTEN. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway.
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Affiliation(s)
- Qiang Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Bin Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Leina Sun
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qingna Yan
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yu Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhenfa Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanjun Su
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Changli Wang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin Lung Cancer Center, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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