|
1
|
Aloliqi AA, Alnuqaydan AM, Albutti A, Alharbi BF, Rahmani AH, Khan AA. Current updates regarding biogenesis, functions and dysregulation of microRNAs in cancer: Innovative approaches for detection using CRISPR/Cas13‑based platforms (Review). Int J Mol Med 2025; 55:90. [PMID: 40242952 PMCID: PMC12021393 DOI: 10.3892/ijmm.2025.5531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/04/2025] [Indexed: 04/18/2025] Open
Abstract
MicroRNAs (miRNAs) are short non‑coding RNAs, which perform a key role in cellular differentiation and development. Most human diseases, particularly cancer, are linked to miRNA functional dysregulation implicated in the expression of tumor‑suppressive or oncogenic targets. Cancer hallmarks such as continued proliferative signaling, dodging growth suppressors, invasion and metastasis, triggering angiogenesis, and avoiding cell death have all been demonstrated to be affected by dysregulated miRNAs. Thus, for the treatment of different cancer types, the detection and quantification of this type of RNA is significant. The classical and current methods of RNA detection, including northern blotting, reverse transcription‑quantitative PCR, rolling circle amplification and next‑generation sequencing, may be effective but differ in efficiency and accuracy. Furthermore, these approaches are expensive, and require special instrumentation and expertise. Thus, researchers are constantly looking for more innovative approaches for miRNA detection, which can be advantageous in all aspects. In this regard, an RNA manipulation tool known as the CRISPR and CRISPR‑associated sequence 13 (CRISPR/Cas13) system has been found to be more advantageous in miRNA detection. The Cas13‑based miRNA detection approach is cost effective and requires no special instrumentation or expertise. However, more research and validation are required to confirm the growing body of CRISPR/Cas13‑based research that has identified miRNAs as possible cancer biomarkers for diagnosis and prognosis, and as targets for treatment. In the present review, current updates regarding miRNA biogenesis, structural and functional aspects, and miRNA dysregulation during cancer are described. In addition, novel approaches using the CRISPR/Cas13 system as a next‑generation tool for miRNA detection are discussed. Furthermore, challenges and prospects of CRISPR/Cas13‑based miRNA detection approaches are described.
Collapse
Affiliation(s)
- Abdulaziz A. Aloliqi
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Abdullah M. Alnuqaydan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Aqel Albutti
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Basmah F. Alharbi
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| |
Collapse
|
|
2
|
Shah K, Anastasakou E, Sejour L, Wang Y, Wert-Lamas L, Rauchet C, Studer S, Goller S, Distel RJ, Marasco W, Perera L, Vlachos IS, Novina CD. LncRNA SLNCR phenocopies the E2F1 DNA binding site to promote melanoma progression. Cell Rep 2025; 44:115608. [PMID: 40279246 DOI: 10.1016/j.celrep.2025.115608] [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: 07/01/2024] [Revised: 02/20/2025] [Accepted: 04/02/2025] [Indexed: 04/27/2025] Open
Abstract
The long non-coding RNA SLNCR and the transcription factor E2F1 are known melanoma oncogenes. We show that SLNCR binds to E2F1 to promote the proliferation, invasion, and migration of melanoma cells from the bloodstream into the lungs. Blocking SLNCR-E2F1 complex formation without reducing the levels of either SLNCR or E2F1 prevents lung extravasation in mice. A 60-nt fragment of SLNCR contains two RNA analogs of the E2F1 DNA binding site (BS) in opposite orientations and can form a hairpin RNA that phenocopies the E2F1 DNA BS. Molecular dynamics (MD) simulations and biochemical experiments indicate that this fragment of SLNCR binds to the E2F1 DNA-binding domain more effectively than the E2F1 DNA BS. MD simulations predict higher affinity for DNA-E2F1 complex formation but faster kinetics and a greater number of RNA-amino acid contacts for the RNA-E2F1 complex, suggesting that RNA binding to E2F1 is more kinetically favorable.
Collapse
Affiliation(s)
- Kushani Shah
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Eleni Anastasakou
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Leinal Sejour
- Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Yufei Wang
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Leon Wert-Lamas
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Christopher Rauchet
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Sabine Studer
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Simon Goller
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Robert J Distel
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Wayne Marasco
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Lalith Perera
- Genome Integrity and Structural Biology Laboratory, NIEHS, NIH, Durham, NC 27709, USA
| | - Ioannis S Vlachos
- Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Spatial Technologies Unit, Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
| | - Carl D Novina
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
| |
Collapse
|
|
3
|
Vitulano C, Forcina G, Colosimo S, Frattolillo V, Villani AV, Marzuillo P, Miraglia Del Giudice E, Di Sessa A. A miRNA-Based Approach in Autosomal Dominant Polycystic Kidney Disease: Challenges and Insights from Adult to Pediatric Evidence. Mol Diagn Ther 2025; 29:183-193. [PMID: 39820940 DOI: 10.1007/s40291-024-00761-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/01/2024] [Indexed: 01/19/2025]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) represents the most common inherited kidney disorder leading to kidney failure in a significant percentage of patients over time. Although previously considered as an adult disease, robust evidence demonstrated that clinical manifestations might occur during childhood and adolescence. Therefore, early identification and treatment of the disease are of cardinal importance for pediatricians to ensure the best long-term outcomes. To date, licensed treatment options are limited but promising potential therapeutic targets are emerging. Among these, an intriguing pathophysiological role for microRNAs as small molecules with a critical role in regulating gene expression has been considered possible in ADPKD. Indeed, numerous circulating microRNAs have been found to be dysregulated in ADPKD, suggesting their potential role as biomarkers and therapeutic targets. Based on this background, further detailed insights into the mechanisms of miRNAs contributing to ADPKD development might pave the way for their effective application as a targeted treatment in young patients with ADPKD. We aimed to summarize the most recent evidence in this fascinating research area, providing a comprehensive overview of the current landscape of specific microRNAs in ADPKD as a potential innovative therapeutic strategy for these young patients.
Collapse
Affiliation(s)
- Caterina Vitulano
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Gianmario Forcina
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Simone Colosimo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Vittoria Frattolillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Annalisa Valentina Villani
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy
| | - Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via L. De Crecchio, 4, 80138, Naples, Italy.
| |
Collapse
|
|
4
|
Yang YC, Ho KH, Hua KT, Chien MH. Roles of K(H)SRP in modulating gene transcription throughout cancer progression: Insights from cellular studies to clinical perspectives. Biochim Biophys Acta Rev Cancer 2024; 1879:189202. [PMID: 39447687 DOI: 10.1016/j.bbcan.2024.189202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/15/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
The KH-type splicing regulatory protein (KHSRP), also known as KSRP, is an RNA-binding protein that regulates gene expressions through various mechanisms, including messenger (m)RNA degradation, micro (mi)RNA maturation, and transcriptional activity. KSRP has been implicated in a wide range of physiological and pathological processes, with emerging evidence highlighting its role in modulating diverse aspects of cancer behaviors. In this review, we provide a comprehensive overview of KSRP's clinical relevance and its multifaceted regulatory mechanisms in cancer. Our extensive pan-cancer analysis uncovers associations of KSRP with clinical outcomes and identifies cell cycle progression as a key signaling pathway correlated with KSRP expression. Furthermore, we identify miR-17-5p as critical miRNAs positively correlated with KSRP, and it is associated with poor survival in various cancers. Collectively, this review offers new insights into the potential of KSRP as a target for therapeutic strategies in cancer treatment.
Collapse
Affiliation(s)
- Yi-Chieh Yang
- Department of Medical Research, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Hao Ho
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Tai Hua
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
5
|
Baby J, Gull B, Ahmad W, Baki HA, Khader TA, Panicker NG, Akhlaq S, Rizvi TA, Mustafa F. The Host miR-17-92 Cluster Negatively Regulates Mouse Mammary Tumor Virus (MMTV) Replication Primarily Via Cluster Member miR-92a. J Mol Biol 2024; 436:168738. [PMID: 39117177 DOI: 10.1016/j.jmb.2024.168738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 08/01/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024]
Abstract
The mouse mammary tumor virus (MMTV) is a well-known causative agent of breast cancer in mice. Previously, we have shown that MMTV dysregulates expression of the host miR-17-92 cluster in MMTV-infected mammary glands and MMTV-induced tumors. This cluster, better known as oncomiR-1, is frequently dysregulated in cancers, particularly breast cancer. In this study, our aim was to uncover a functional interaction between MMTV and the cluster. Our results reveal that MMTV expression led to dysregulation of the cluster in both mammary epithelial HC11 and HEK293T cells with the expression of miR-92a cluster member being affected the most. Conversely, overexpression of the whole or partial cluster significantly repressed MMTV expression. Notably, overexpression of cluster member miR-92a alone repressed MMTV expression to the same extent as overexpression of the complete/partial cluster. Inhibition of miR-92a led to nearly a complete restoration of MMTV expression, while deletion/substitution of the miR-92a seed sequence rescued MMTV expression. Dual luciferase assays identified MMTV genomic RNA as the potential target of miR-92a. These results show that the miR-17-92 cluster acts as part of the cell's well-known miRNA-based anti-viral response to thwart incoming MMTV infection. Thus, this study provides the first evidence highlighting the biological significance of host miRNAs in regulating MMTV replication and potentially influencing tumorigenesis.
Collapse
Affiliation(s)
- Jasmin Baby
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE.
| | - Bushra Gull
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE.
| | - Waqar Ahmad
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE.
| | - Hala Abdul Baki
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE.
| | - Thanumol Abdul Khader
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE; ASPIRE Research Institute in Precision Medicine, Abu Dhabi, UAE.
| | - Neena G Panicker
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE.
| | - Shaima Akhlaq
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE.
| | - Tahir A Rizvi
- Department of Microbiology and Immunology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE; Zayed Center for Health Sciences (ZCHS), UAE University, Al Ain, UAE; ASPIRE Research Institute in Precision Medicine, Abu Dhabi, UAE.
| | - Farah Mustafa
- Department of Biochemistry and Molecular Biology, College of Medicine & Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain, UAE; Zayed Center for Health Sciences (ZCHS), UAE University, Al Ain, UAE; ASPIRE Research Institute in Precision Medicine, Abu Dhabi, UAE.
| |
Collapse
|
|
6
|
Rodrigues P, Rizaev JA, Hjazi A, Altalbawy FMA, H M, Sharma K, Sharma SK, Mustafa YF, Jawad MA, Zwamel AH. Dual role of microRNA-31 in human cancers; focusing on cancer pathogenesis and signaling pathways. Exp Cell Res 2024; 442:114236. [PMID: 39245198 DOI: 10.1016/j.yexcr.2024.114236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
Widespread changes in the expression of microRNAs in cancer result in abnormal gene expression for the miRNAs that control those genes, which in turn causes changes to entire molecular networks and pathways. The frequently altered miR-31, which is found in a wide range of cancers, is one cancer-related miRNA that is particularly intriguing. MiR-31 has a very complicated set of biological functions, and depending on the type of tumor, it may act both as a tumor suppressor and an oncogene. The endogenous expression levels of miR-31 appear to be a key determinant of the phenotype brought on by aberrant expression. Varied expression levels of miR-31 could affect cell growth, metastasis, drug resistance, and other process by several mechanisms like targeting BRCA1-associated protein-1 (BAP1), large tumor suppressor kinase 1 (LATS1) and protein phosphatase 2 (PP2A). This review highlights the current understanding of the genes that miR-31 targets while summarizing the complex expression patterns of miR-31 in human cancers and the diverse phenotypes brought on by altered miR-31 expression.
Collapse
Affiliation(s)
- Paul Rodrigues
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Saudi Arabia.
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan.
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia.
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia.
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Kirti Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjheri, Mohali, 140307, Punjab, India.
| | - Satish Kumar Sharma
- Vice Chancellor of Department of Pharmacy (Pharmacology), The Glocal University, Saharanpur, India.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq.
| | | | - Ahmed Hussein Zwamel
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq; Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq.
| |
Collapse
|
|
7
|
Sun MR, Gonzalez S, Huang JB, Zhou Q, Cherukuri A, Adavadkar R, Yan HL, Sun SH, Zhou G, Raj JU, Chen T. Biphasic regulation of miR-17∼92 transcription during hypoxia: roles of HIF1 and p53 hyperphosphorylation at ser15. Am J Physiol Lung Cell Mol Physiol 2024; 327:L102-L113. [PMID: 38501173 PMCID: PMC11380943 DOI: 10.1152/ajplung.00127.2023] [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: 04/20/2023] [Revised: 03/07/2024] [Accepted: 03/07/2024] [Indexed: 03/20/2024] Open
Abstract
We have reported previously that during hypoxia exposure, the expression of mature miR-17∼92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo. Here, we investigated the mechanisms regulating this biphasic expression of miR-17∼92 in PASMC in hypoxia. We measured the level of primary miR-17∼92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3% O2, 6 h) induced the level of primary miR-17∼92, whereas long-term hypoxia exposure (3% O2, 24 h) decreased its level, suggesting a biphasic regulation of miR-17∼92 expression at the transcriptional level. We found that short-term hypoxia-induced upregulation of miR-17∼92 was hypoxia-inducible factor 1α (HIF1α) and E2F1 dependent. Two HIF1α binding sites on miR-17∼92 promoter were identified. We also found that long-term hypoxia-induced suppression of miR-17∼92 expression could be restored by silencing of p53. Mutation of the p53-binding sites in the miR-17∼92 promoter increased miR-17∼92 promoter activity in both normoxia and hypoxia. Our findings suggest that the biphasic transcriptional regulation of miR-17∼92 during hypoxia is controlled by HIF1/E2F1 and p53 in PASMC: during short-term hypoxia exposure, stabilization of HIF1 and induction of E2F1 induce the transcription of miR-17∼92, whereas during long-term hypoxia exposure, hyperphosphorylation of p53 suppresses the expression of miR-17∼92.NEW & NOTEWORTHY We showed that the biphasic transcriptional regulation of miR-17∼92 during hypoxia is controlled by two distinct mechanisms: during short-term hypoxia exposure, induction of HIF1 and E2F1 upregulates miR-17∼92. Longer hypoxia exposure induces hyperphosphorylation of p53 at ser15, which leads to its binding to miR-17∼92 promoter and inhibition of its expression. Our findings provide novel insights into the spatiotemporal regulation of miR-17∼92 that may play a role in the development of human lung diseases including pulmonary hypertension (PH).
Collapse
Affiliation(s)
- Miranda R Sun
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Susana Gonzalez
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Jason B Huang
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Qiyuan Zhou
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Arjun Cherukuri
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Rohan Adavadkar
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Hong-Li Yan
- Department of Medical Genetics, Second Military Medical University, Shanghai, People's Republic of China
| | - Shu-Han Sun
- Department of Medical Genetics, Second Military Medical University, Shanghai, People's Republic of China
| | - Guofei Zhou
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
- University of Illinois Cancer Center, Chicago, Illinois, United States
| | - J Usha Raj
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
- Children's Hospital University of Illinois, University of Illinois Hospital and Health Sciences System, Chicago, Illinois, United States
| | - Tianji Chen
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States
| |
Collapse
|
|
8
|
Umapathy VR, Natarajan PM, Swamikannu B. Molecular and Therapeutic Roles of Non-Coding RNAs in Oral Cancer-A Review. Molecules 2024; 29:2402. [PMID: 38792263 PMCID: PMC11123887 DOI: 10.3390/molecules29102402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/09/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
Oral cancer (OC) is among the most common malignancies in the world. Despite advances in therapy, the worst-case scenario for OC remains metastasis, with a 50% survival rate. Therefore, it is critical to comprehend the pathophysiology of the condition and to create diagnostic and treatment plans for OC. The development of high-throughput genome sequencing has revealed that over 90% of the human genome encodes non-coding transcripts, or transcripts that do not code for any proteins. This paper describes the function of these different kinds of non-coding RNAs (ncRNAs) in OC as well as their intriguing therapeutic potential. The onset and development of OC, as well as treatment resistance, are linked to dysregulated ncRNA expression. These ncRNAs' potentially significant roles in diagnosis and prognosis have been suggested by their differing expression in blood or saliva. We have outlined every promising feature of ncRNAs in the treatment of OC in this study.
Collapse
Affiliation(s)
- Vidhya Rekha Umapathy
- Department of Public Health Dentistry, Dr. M.G.R. Educational and Research Institute, Thai Moogambigai Dental College and Hospital, Chennai 600107, Tamil Nadu, India
| | - Prabhu Manickam Natarajan
- Department of Clinical Sciences, Centre of Medical and Bio-Allied Health Sciences and Research Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Bhuminathan Swamikannu
- Department of Prosthodontics, Sree Balaji Dental College and Hospital, Pallikaranai, BIHER, Chennai 600100, Tamil Nadu, India;
| |
Collapse
|
|
9
|
Bergez-Hernández F, Luque-Ortega F, García-Magallanes N, Alvarez-Arrazola M, Arámbula-Meraz E. Deletion in a regulatory region is associated with underexpression of miR-148b‑3p in patients with prostate cancer. Biomed Rep 2024; 20:52. [PMID: 38357236 PMCID: PMC10865175 DOI: 10.3892/br.2024.1740] [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: 09/18/2023] [Accepted: 01/02/2024] [Indexed: 02/16/2024] Open
Abstract
Prostate cancer (PCa) is the leading cause of cancer-related death in men. This pathology is complex and heterogeneous; therefore, elucidating the molecular mechanisms that lead to its origin and progression is imperative. MicroRNAs (miRNAs or miRs) are part of the epigenetic machinery that regulates the expression of human genes, therefore, mutations in the genes that encode them can lead to a dysregulation in their expression, which directly impacts their target genes, which could be oncogenes or tumor suppressor genes. In PCa several dysregulated expression levels of miRNAs are associated with perturbed cellular processes. A differential expression of miRNAs such as miR-145-5p and miR-148-3p has been observed in PCa, possibly due to mutations in regions near the miRNAs. However, the molecular mechanisms that lead to the dysregulation of these miRNAs still need to be clarified. Therefore, the present study aimed to analyze the expression of miRNAs and their relationship with mutations in patients with and without PCa. In total, 71 patients were analyzed: 41 of whom had PCa (CAP group) and 30 with benign pathology (BPD group). Underexpression was observed in miR-145-5p and miR-148b-3p in PCa patients (P=0.03 and P=0.001, respectively). In miR-145-5p, no mutations related to its expression were identified. For miR-148b-3p, a set of mutations were identified in the chr12:54337042/54337043 region, which were grouped into the mutation named DelsAAG. Although this mutation's abnormal allele is related to PCa (P=0.017), a statistically significant difference was observed in the expression of miR-148b-3p between carriers and non-carriers of the mutated allele, identifying a mechanism likely to be involved in the miR-148b-3p dysregulation.
Collapse
Affiliation(s)
- Fernando Bergez-Hernández
- Postgraduate in Biomedical Sciences, Faculty of Chemical-Biological Sciences, Autonomous University of Sinaloa, Culiacán, 80010 Sinaloa, México
| | - Fred Luque-Ortega
- Basic Sciences Laboratory, Faculty of Dentistry, Autonomous University of Sinaloa, Culiacán, 80100 Sinaloa, México
| | - Noemí García-Magallanes
- Laboratory of Biomedicine and Molecular Biology, Biotechnology Engineering, Polytechnic University of Sinaloa, Mazatlán, 82199 Sinaloa, México
| | | | - Eliakym Arámbula-Meraz
- Postgraduate in Biomedical Sciences, Faculty of Chemical-Biological Sciences, Autonomous University of Sinaloa, Culiacán, 80010 Sinaloa, México
- Laboratory of Genetics and Molecular Biology, Faculty of Chemical-Biological Sciences, Autonomous University of Sinaloa, Culiacán, 80010 Sinaloa, México
| |
Collapse
|
|
10
|
Temaj G, Chichiarelli S, Saha S, Telkoparan-Akillilar P, Nuhii N, Hadziselimovic R, Saso L. An intricate rewiring of cancer metabolism via alternative splicing. Biochem Pharmacol 2023; 217:115848. [PMID: 37813165 DOI: 10.1016/j.bcp.2023.115848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/11/2023]
Abstract
All human genes undergo alternative splicing leading to the diversity of the proteins. However, in some cases, abnormal regulation of alternative splicing can result in diseases that trigger defects in metabolism, reduced apoptosis, increased proliferation, and progression in almost all tumor types. Metabolic dysregulations and immune dysfunctions are crucial factors in cancer. In this respect, alternative splicing in tumors could be a potential target for therapeutic cancer strategies. Dysregulation of alternative splicing during mRNA maturation promotes carcinogenesis and drug resistance in many cancer types. Alternative splicing (changing the target mRNA 3'UTR binding site) can result in a protein with altered drug affinity, ultimately leading to drug resistance.. Here, we will highlight the function of various alternative splicing factors, how it regulates the reprogramming of cancer cell metabolism, and their contribution to tumor initiation and proliferation. Also, we will discuss emerging therapeutics for treating tumors via abnormal alternative splicing. Finally, we will discuss the challenges associated with these therapeutic strategies for clinical applications.
Collapse
Affiliation(s)
- Gazmend Temaj
- Faculty of Pharmacy, College UBT, 10000 Prishtina, Kosovo
| | - Silvia Chichiarelli
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
| | - Sarmistha Saha
- Department of Biotechnology, GLA University, Mathura 00185, Uttar Pradesh, India
| | | | - Nexhibe Nuhii
- Department of Pharmacy, Faculty of Medical Sciences, State University of Tetovo, 1200 Tetovo, Macedonia
| | - Rifat Hadziselimovic
- Faculty of Science, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", La Sapienza University, 00185 Rome, Italy.
| |
Collapse
|
|
11
|
Pan X, Cen X, Xiong X, Zhao Z, Huang X. miR-17-92 cluster in osteoarthritis: Regulatory roles and clinical utility. Front Genet 2022; 13:982008. [PMID: 36523768 PMCID: PMC9745093 DOI: 10.3389/fgene.2022.982008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2023] Open
Abstract
Osteoarthritis (OA) is the most prevalent articular disease, especially in aged population. Caused by multi-factors (e.g., trauma, inflammation, and overloading), OA leads to pain and disability in affected joints, which decreases patients' quality of life and increases social burden. In pathophysiology, OA is mainly characterized by cartilage hypertrophy or defect, subchondral bone sclerosis, and synovitis. The homeostasis of cell-cell communication is disturbed as well in such pro-inflammatory microenvironment, which provides clues for the diagnosis and treatment of OA. MicoRNAs (miRNAs) are endogenous non-coding RNAs that regulate various processes via post-transcriptional mechanisms. The miR-17-92 cluster is an miRNA polycistron encoded by the host gene called MIR17HG. Mature miRNAs generated from MIR17HG participate in biological activities such as oncogenesis, neurogenesis, and modulation of the immune system. Accumulating evidence also indicates that the expression level of miRNAs in the miR-17-92 cluster is tightly related to the pathological processes of OA, such as chondrocyte apoptosis, extracellular matrix degradation, bone remodeling, and synovitis. In this review, we aim to summarize the roles of the miR-17-92 cluster in the underlying molecular mechanism during the development and progression of OA and shed light on the new avenue of the diagnosis and treatment of OA.
Collapse
Affiliation(s)
- Xuefeng Pan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Cen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiner Xiong
- Hospital of Stomatology, Zunyi Medical University, Zunyi, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xinqi Huang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
12
|
Mokhtari F, Kaboosi H, Mohebbi SR, Asadzadeh Aghdaei H, Zali MRZ, Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran, Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Evaluation of Circulating MicroRNA-222 in Patients with Chronic Hepatitis B virus Infection as a Potential Noninvasive Diagnostic Biomarker. IRANIAN JOURNAL OF MEDICAL MICROBIOLOGY 2022. [DOI: 10.30699/ijmm.16.6.543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
13
|
Visceral Adipose Tissue E2F1-miRNA206/210 Pathway Associates with Type 2 Diabetes in Humans with Extreme Obesity. Cells 2022; 11:cells11193046. [PMID: 36231008 PMCID: PMC9562862 DOI: 10.3390/cells11193046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
Objective: Up-regulated expression of transcription-factor E2F1 in human visceral adipose tissue (VAT) characterizes a dysmetabolic obesity sub-phenotype. An E2F1-miRNA network has been described in multiple cancers. Here we investigated whether elevated VAT-E2F1 in obesity is associated with VAT-miRNA alterations similar to, or distinct from, those described in cancer. Furthermore, we assessed if E2F1-associated miRNA changes may contribute to the link between high- VAT-E2F1 and a dysmetabolic obesity phenotype. Methods: We assembled a cohort of patients with obesity and high-VAT-E2F1, matched by age, sex, ±BMI to patients with low-VAT-E2F1, with and without obesity (8 patients/groupX3 groups). We performed Nanostring©-based miRNA profiling of VAT samples from all 24 patients. Candidate E2F1-related miRNAs were validated by qPCR in an independent cohort of patients with extreme obesity, with or without type-2-diabetes (T2DM) (n = 20). Bioinformatic tools and manipulation of E2F1 expression in cells were used to establish the plausibility of the functional VAT-E2F1-miRNA network in obesity. Results: Among n = 798 identified miRNAs, 17 were differentially expressed in relation to E2F1 and not to obesity itself. No evidence for the cancer-related E2F1-miRNA network was identified in human VAT in obesity. In HEK293-cells, overexpression/downregulation of E2F1 correspondingly altered the expression of miRNA-206 and miRNA-210-5p, two miRNAs with reported metabolic functions consistent with those of E2F1. In VAT from both cohorts, the expression of both miRNA-206 and 210-5p intercorrelated, and correlated with the expression of E2F1. In cohort 1 we did not detect significant associations with biochemical parameters. In cohort 2 of patients with extreme obesity, all those with high VAT-E2F1 showed a diabetes-complicated obesity phenotype and higher expression of miRNA-206 and miRNA-210-5p, which also correlated with fasting glucose levels (both miRNAs) and fasting insulin (miRNA-210-5p). Conclusions: Whilst the previously described cancer-related E2F1-miRNA network does not appear to operate in VAT in obesity, miRNAs-206 and 210-5p may link high-E2F1 expression in VAT with diabetes-complicated extreme obesity phenotype.
Collapse
|
|
14
|
MiRNAs in Lung Cancer: Diagnostic, Prognostic, and Therapeutic Potential. Diagnostics (Basel) 2022; 12:diagnostics12071610. [PMID: 35885514 PMCID: PMC9322918 DOI: 10.3390/diagnostics12071610] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the dominant emerging factor in cancer-related mortality around the globe. Therapeutic interventions for lung cancer are not up to par, mainly due to reoccurrence/relapse, chemoresistance, and late diagnosis. People are currently interested in miRNAs, which are small double-stranded (20–24 ribonucleotides) structures that regulate molecular targets (tumor suppressors, oncogenes) involved in tumorigeneses such as cell proliferation, apoptosis, metastasis, and angiogenesis via post-transcriptional regulation of mRNA. Many studies suggest the emerging role of miRNAs in lung cancer diagnostics, prognostics, and therapeutics. Therefore, it is necessary to intensely explore the miRNOME expression of lung tumors and the development of anti-cancer strategies. The current review focuses on the therapeutic, diagnostic, and prognostic potential of numerous miRNAs in lung cancer.
Collapse
|
|
15
|
miR-106b as an emerging therapeutic target in cancer. Genes Dis 2022; 9:889-899. [PMID: 35685464 PMCID: PMC9170583 DOI: 10.1016/j.gendis.2021.02.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/24/2021] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) comprise short non-coding RNAs that function in regulating the expression of tumor suppressors or oncogenes and modulate oncogenic signaling pathways in cancer. miRNAs expression alters significantly in several tumor tissues and cancer cell lines. For example, miR-106b functions as an oncogene and increases in multiple cancers. The miR-106b directly targets genes involved in tumorigenesis, proliferation, invasion, migration, and metastases. This review has focused on the miR-106b function and its downstream target in different cancers and provide perspective into how miR-106 regulates cancer cell proliferation, migration, invasion, and metastases by regulating the tumor suppressor genes. Since miRNAs-based therapies are currently being developed to enhance cancer therapy outcomes, miR-106b could be an attractive and prospective candidate in different cancer types for detection, diagnosis, and prognosis assessment in the tumor.
Collapse
|
|
16
|
Stieg DC, Wang Y, Liu LZ, Jiang BH. ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance. Int J Mol Sci 2022; 23:ijms23126702. [PMID: 35743145 PMCID: PMC9223852 DOI: 10.3390/ijms23126702] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/05/2022] [Accepted: 06/14/2022] [Indexed: 12/11/2022] Open
Abstract
The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are involved in regulating OC angiogenesis through mediating multiple angiogenic factors such as hypoxia-induced factor (HIF-1) and vascular endothelial growth factor (VEGF). The NAPDH oxidase subunit NOX4 plays an important role in inducing endogenous ROS production in OC. This review will discuss several important miRNAs, NOX4, and ROS, which contribute to therapeutic resistance in OC, highlighting the effective therapeutic potential of OC through these mechanisms.
Collapse
Affiliation(s)
- David C. Stieg
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (D.C.S.); (L.-Z.L.)
| | - Yifang Wang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Ling-Zhi Liu
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (D.C.S.); (L.-Z.L.)
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
- Correspondence:
| |
Collapse
|
|
17
|
Arzhanov I, Sintakova K, Romanyuk N. The Role of miR-20 in Health and Disease of the Central Nervous System. Cells 2022; 11:cells11091525. [PMID: 35563833 PMCID: PMC9100679 DOI: 10.3390/cells11091525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 12/18/2022] Open
Abstract
Current understanding of the mechanisms underlying central nervous system (CNS) injury is limited, and traditional therapeutic methods lack a molecular approach either to prevent acute phase or secondary damage, or to support restorative mechanisms in the nervous tissue. microRNAs (miRNAs) are endogenous, non-coding RNA molecules that have recently been discovered as fundamental and post-transcriptional regulators of gene expression. The capacity of microRNAs to regulate the cell state and function through post-transcriptionally silencing hundreds of genes are being acknowledged as an important factor in the pathophysiology of both acute and chronic CNS injuries. In this study, we have summarized the knowledge concerning the pathophysiology of several neurological disorders, and the role of most canonical miRNAs in their development. We have focused on the miR-20, the miR-17~92 family to which miR-20 belongs, and their function in the normal development and disease of the CNS.
Collapse
Affiliation(s)
- Ivan Arzhanov
- Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague, Czech Republic; (I.A.); (K.S.)
- Department of Neuroscience, 2nd Medical Faculty, Charles University, 150 00 Prague, Czech Republic
| | - Kristyna Sintakova
- Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague, Czech Republic; (I.A.); (K.S.)
- Department of Neuroscience, 2nd Medical Faculty, Charles University, 150 00 Prague, Czech Republic
| | - Nataliya Romanyuk
- Department of Neuroregeneration, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague, Czech Republic; (I.A.); (K.S.)
- Correspondence:
| |
Collapse
|
|
18
|
Ravi S, Alencar AM, Arakelyan J, Xu W, Stauber R, Wang CCI, Papyan R, Ghazaryan N, Pereira RM. An Update to Hallmarks of Cancer. Cureus 2022; 14:e24803. [PMID: 35686268 PMCID: PMC9169686 DOI: 10.7759/cureus.24803] [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] [Accepted: 05/06/2022] [Indexed: 12/03/2022] Open
Abstract
In the last decade, there has been remarkable progress in research toward understanding and refining the hallmarks of cancer. In this review, we propose a new hallmark - "pro-survival autophagy." The importance of pro-survival autophagy is well established in tumorigenesis, as it is related to multiple steps in cancer progression and vital for some cancers. Autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate as a new hallmark of cancer. We describe two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer - "tumor-promoting microenvironment and macroenvironment" and "cancer epigenetics, genome instability and mutation." We also discuss the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011. Understanding these hallmarks and enabling characteristics is key not only to developing new ways to treat cancer efficiently but also to exploring options to overcome cancer resistance to treatment.
Collapse
Affiliation(s)
- Swapna Ravi
- Department of Medicine, St. Luke's Hospital, Duluth, USA
| | - Antonio M Alencar
- Department of Medical Oncology, Hospital Universitário da Universidade Federal do Maranhão, Hospital São Domingos, São Luís, BRA
| | - Jemma Arakelyan
- Department of Oncology/Solid Tumors, Yerevan State Medical University, Hematology Center After Prof. R. Yeolyan, Yerevan, ARM
| | - Weihao Xu
- Department of Business Development, Harbour BioMed, Boston, USA
| | - Roberta Stauber
- Department of Oncology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BRA
| | - Cheng-Chi I Wang
- Department of Research and Development, Beltie Bio, Inc, San Diego, USA
| | - Ruzanna Papyan
- Department of Pediatric Oncology and Hematology, Yerevan State Medical University, Pediatric Center and Blood Disorders Center of Armenia, Yerevan, ARM
| | - Narine Ghazaryan
- Department of Molecular Biology, L.A. Orbeli Institute of Physiology National Academy of Sciences, Republic of Armenia (NAS RA) Hematology Center After Prof. R. Yeolyan, Yerevan, ARM
| | - Rosalina M Pereira
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, USA
| |
Collapse
|
|
19
|
Supadmanaba IGP, Mantini G, Randazzo O, Capula M, Muller IB, Cascioferro S, Diana P, Peters GJ, Giovannetti E. Interrelationship between miRNA and splicing factors in pancreatic ductal adenocarcinoma. Epigenetics 2022; 17:381-404. [PMID: 34057028 PMCID: PMC8993068 DOI: 10.1080/15592294.2021.1916697] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of diagnosis at late stage and inherent/acquired chemoresistance. Recent advances in genomic profiling and biology of this disease have not yet been translated to a relevant improvement in terms of disease management and patient's survival. However, new possibilities for treatment may emerge from studies on key epigenetic factors. Deregulation of microRNA (miRNA) dependent gene expression and mRNA splicing are epigenetic processes that modulate the protein repertoire at the transcriptional level. These processes affect all aspects of PDAC pathogenesis and have great potential to unravel new therapeutic targets and/or biomarkers. Remarkably, several studies showed that they actually interact with each other in influencing PDAC progression. Some splicing factors directly interact with specific miRNAs and either facilitate or inhibit their expression, such as Rbfox2, which cleaves the well-known oncogenic miRNA miR-21. Conversely, miR-15a-5p and miR-25-3p significantly downregulate the splicing factor hnRNPA1 which acts also as a tumour suppressor gene and is involved in processing of miR-18a, which in turn, is a negative regulator of KRAS expression. Therefore, this review describes the interaction between splicing and miRNA, as well as bioinformatic tools to explore the effect of splicing modulation towards miRNA profiles, in order to exploit this interplay for the development of innovative treatments. Targeting aberrant splicing and deregulated miRNA, alone or in combination, may hopefully provide novel therapeutic approaches to fight the complex biology and the common treatment recalcitrance of PDAC.
Collapse
Affiliation(s)
- I Gede Putu Supadmanaba
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUMC), Amsterdam, The Netherlands
- Biochemistry Department, Faculty of Medicine, Universitas Udayana, Denpasar, Bali, Indonesia
| | - Giulia Mantini
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUMC), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start up Unit, Fondazione Pisana per La Scienza, Pisa, Italy
| | - Ornella Randazzo
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUMC), Amsterdam, The Netherlands
- Dipartimento Di Scienze E Tecnologie Biologiche Chimiche E Farmaceutiche (STEBICEF), Università Degli Studi Di Palermo, Palermo, Italy
| | - Mjriam Capula
- Cancer Pharmacology Lab, AIRC Start up Unit, Fondazione Pisana per La Scienza, Pisa, Italy
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Ittai B. Muller
- Department of Clinical Chemistry, Amsterdam UMC, VU University Medical Center (VUMC), Amsterdam, The Netherlands
| | - Stella Cascioferro
- Dipartimento Di Scienze E Tecnologie Biologiche Chimiche E Farmaceutiche (STEBICEF), Università Degli Studi Di Palermo, Palermo, Italy
| | - Patrizia Diana
- Dipartimento Di Scienze E Tecnologie Biologiche Chimiche E Farmaceutiche (STEBICEF), Università Degli Studi Di Palermo, Palermo, Italy
| | - Godefridus J. Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUMC), Amsterdam, The Netherlands
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUMC), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start up Unit, Fondazione Pisana per La Scienza, Pisa, Italy
| |
Collapse
|
|
20
|
Sweat Y, Ries RJ, Sweat M, Su D, Shao F, Eliason S, Amendt BA. miR-17 acts as a tumor suppressor by negatively regulating the miR-17-92 cluster. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1148-1158. [PMID: 34853714 PMCID: PMC8601969 DOI: 10.1016/j.omtn.2021.10.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 08/09/2021] [Accepted: 10/19/2021] [Indexed: 01/14/2023]
Abstract
Anaplastic thyroid cancer (ATC) is an aggressive, highly metastatic cancer that expresses high levels of the microRNA (miR)-17-92 cluster. We employ an miR inhibitor system to study the function of the different miRs within the miR-17-92 cluster based on seed sequence homology in the ATC SW579 cell line. While three of the four miR-17-92 families were oncogenic, we uncovered a novel role for miR-17 as a tumor suppressor in vitro and in vivo. Surprisingly, miR-17 inhibition increased expression of the miR-17-92 cluster and significantly increased the levels of the miR-18a and miR-19a mature miRs. miR-17 inhibition increased expression of the cell cycle activator CCND2, associated with increased cell proliferation and tumor growth in transplanted SW579 cells in xenograft mice. miR-17 regulates MYCN and c-MYC expression in SW579 cells, and the inhibition of miR-17 increased MYCN and c-MYC expression, which increased pri-miR-17-92 transcripts. Thus, inhibition of miR-17 activated the expression of the oncogenic miRs, miR-18a and miR-19a. While many cancers express high levels of miR-17, linking it with tumorigenesis, we demonstrate that miR-17 inhibition does not inhibit thyroid tumor growth in SW579 and MDA-T32 ATC cells but increases expression of the other miR-17-92 family members and genes to induce cancer progression.
Collapse
Affiliation(s)
- Yan Sweat
- Harvard University, Boston, MA 02115, USA
| | - Ryan J. Ries
- Weill-Cornell Medical College, Cornell University, New York, NY 10075, USA
| | | | - Dan Su
- The University of Iowa, Department of Anatomy and Cell Biology, Iowa City, IA 52242, USA
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
| | - Fan Shao
- The University of Iowa, Department of Anatomy and Cell Biology, Iowa City, IA 52242, USA
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
| | - Steven Eliason
- The University of Iowa, Department of Anatomy and Cell Biology, Iowa City, IA 52242, USA
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
| | - Brad A. Amendt
- The University of Iowa, Department of Anatomy and Cell Biology, Iowa City, IA 52242, USA
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA 52242, USA
- Corresponding author: Brad A. Amendt, PhD, Carver College of Medicine, Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
| |
Collapse
|
|
21
|
Marima R, Francies FZ, Hull R, Molefi T, Oyomno M, Khanyile R, Mbatha S, Mabongo M, Owen Bates D, Dlamini Z. MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets. Biomedicines 2021; 9:1818. [PMID: 34944633 PMCID: PMC8698559 DOI: 10.3390/biomedicines9121818] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3'UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3'UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA-mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.
Collapse
Affiliation(s)
- Rahaba Marima
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
| | - Flavia Zita Francies
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
| | - Thulo Molefi
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - Meryl Oyomno
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - Richard Khanyile
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - Sikhumbuzo Mbatha
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - Mzubanzi Mabongo
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
- Department of Maxillofacial and Oral Surgery, School of Dentistry, University of Pretoria, Hatfield, Pretoria 0028, South Africa
| | - David Owen Bates
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
- Centre for Cancer Sciences, Division of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfiel, Pretoria 0028, South Africa; (R.M.); (F.Z.F.); (R.H.); (T.M.); (M.O.); (R.K.); (S.M.); (M.M.); (D.O.B.)
| |
Collapse
|
|
22
|
Epstein-Barr Virus miR-BART1-3p Regulates the miR-17-92 Cluster by Targeting E2F3. Int J Mol Sci 2021; 22:ijms222010936. [PMID: 34681596 PMCID: PMC8539899 DOI: 10.3390/ijms222010936] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 12/21/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with several tumors and generates BamHI A rightward transcript (BART) microRNAs (miRNAs) from BART transcript introns. These BART miRNAs are expressed at higher levels in EBV-associated epithelial malignancies than in EBV-infected B lymphomas. To test the effects of EBV miRNA on the cell cycle and cell growth, we transfected miR-BART1-3p, a highly expressed EBV-associated miRNA, into gastric carcinoma cells. We found that miR-BART1-3p induced G0/G1 arrest and suppressed cell growth in gastric carcinoma cells. As our microarray analyses showed that E2F3, a cell cycle regulator, was inhibited by EBV infection, we hypothesized that miR-BART1-3p regulates E2F3. Luciferase assays revealed that miR-BART1-3p directly targeted the 3′-UTR of E2F3 mRNA. Both E2F3 mRNA and encoded protein levels were reduced following miR-BART1-3p transfection. In contrast, E2F3 expression in AGS-EBV cells transfected with a miR-BART1-3p inhibitor was enhanced. As E2F3 has been shown to regulate the expression of highly conserved miR-17-92 clusters in vertebrates, we examined whether this expression is affected by miR-BART1-3p, which can downregulate E2F3. The expression of E2F3, miR-17-92a-1 cluster host gene (MIR17HG), and miR-17-92 cluster miRNAs was significantly reduced in EBV-associated gastric carcinoma (EBVaGC) patients compared with EBV-negative gastric carcinoma (EBVnGC) patients. Further, miR-BART1-3p as well as the siRNA specific to E2F3 inhibited the expression of the miR-17-92 cluster, while inhibition of miR-BART1-3p enhanced the expression of the miR-17-92 cluster in cultured GC cells. Our results suggest a possible role of miR-BART1-3p in cell cycle regulation and in regulation of the miR-17-92 cluster through E2F3 suppression.
Collapse
|
|
23
|
Aslani M, Mortazavi-Jahromi SS, Mirshafiey A. Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology. Immunol Lett 2021; 238:1-20. [PMID: 34293378 DOI: 10.1016/j.imlet.2021.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/03/2021] [Accepted: 07/15/2021] [Indexed: 12/16/2022]
Abstract
Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.
Collapse
Affiliation(s)
- Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
24
|
Pajares MJ, Alemany-Cosme E, Goñi S, Bandres E, Palanca-Ballester C, Sandoval J. Epigenetic Regulation of microRNAs in Cancer: Shortening the Distance from Bench to Bedside. Int J Mol Sci 2021; 22:ijms22147350. [PMID: 34298969 PMCID: PMC8306710 DOI: 10.3390/ijms22147350] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy.
Collapse
Affiliation(s)
- María J. Pajares
- Biochemistry Area, Department of Health Sciences, Public University of Navarre, 31008 Pamplona, Spain; (M.J.P.); (S.G.)
- IDISNA Navarra’s Health Research Institute, 31008 Pamplona, Spain;
| | - Ester Alemany-Cosme
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 460026 Valencia, Spain; (E.A.-C.); (C.P.-B.)
| | - Saioa Goñi
- Biochemistry Area, Department of Health Sciences, Public University of Navarre, 31008 Pamplona, Spain; (M.J.P.); (S.G.)
| | - Eva Bandres
- IDISNA Navarra’s Health Research Institute, 31008 Pamplona, Spain;
- Immunology Unit, Department of Hematology, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
| | - Cora Palanca-Ballester
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 460026 Valencia, Spain; (E.A.-C.); (C.P.-B.)
| | - Juan Sandoval
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, 460026 Valencia, Spain; (E.A.-C.); (C.P.-B.)
- Epigenomics Core Facility, Health Research Institute la Fe, 46026 Valencia, Spain
- Correspondence: ; Tel.: +34-961246709
| |
Collapse
|
|
25
|
Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells. Nat Commun 2021; 12:3392. [PMID: 34099666 PMCID: PMC8184997 DOI: 10.1038/s41467-021-23593-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/27/2021] [Indexed: 12/14/2022] Open
Abstract
Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection. Cells infected with pathogens can release signals that instruct neighbouring cells to mount an immune response or that reduce these cells’ susceptibility to infection. Here, Aguilar et al. show the opposite effect: cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells by activating their ER-stress response.
Collapse
|
|
26
|
Budakoti M, Panwar AS, Molpa D, Singh RK, Büsselberg D, Mishra AP, Coutinho HDM, Nigam M. Micro-RNA: The darkhorse of cancer. Cell Signal 2021; 83:109995. [PMID: 33785398 DOI: 10.1016/j.cellsig.2021.109995] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 12/21/2022]
Abstract
The discovery of micro RNAs (miRNA) in cancer has opened up new vistas for researchers in recent years. Micro RNAs area set of small, endogenous, highly conserved, non-coding RNAs that control the expression of about 30% genes at post-transcriptional levels. Typically, microRNAs impede the translation and stability of messenger RNAs (mRNA), control genes associated with cellular processes namely inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Compelling findings revealed that miRNA mutations or disruption correspond to diverse human cancers and suggest that miRNAs can function as tumor suppressors or oncogenes. Here we summarize the literature on these master regulators in clinical settings from last three decades as both abrupt cancer therapeutics and as an approach to sensitize tumors to chemotherapy. This review highlights (I) the prevailing perception of miRNA genomics, biogenesis, as well as function; (II) the significant advancements in regulatory mechanisms in the expression of carcinogenic genes; and (III) explains, how miRNA is utilized as a diagnostic and prognostic biomarker for the disease stage indicating survival as well as therapeutic targets in cancer.
Collapse
Affiliation(s)
- Mridul Budakoti
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Abhay Shikhar Panwar
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Diksha Molpa
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Rahul Kunwar Singh
- Department of Microbiology, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Abhay Prakash Mishra
- Department of Pharmaceutical Chemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
| | | | - Manisha Nigam
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
| |
Collapse
|
|
27
|
Lv Q, Wang G, Zhang Y, Shen A, Tang J, Sun Y, Ma C, Wang P. CircAGAP1 promotes tumor progression by sponging miR-15-5p in clear cell renal cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:76. [PMID: 33618745 PMCID: PMC7901094 DOI: 10.1186/s13046-021-01864-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/01/2021] [Indexed: 12/24/2022]
Abstract
Background Accumulating evidence has revealed that circular RNAs (circRNAs), as novel noncoding RNAs, play critical roles in carcinogenesis and tumor progression. However, the functions and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) are largely unknown. Methods The expression and functions of circAGAP1 were identified in clinical samples, ccRCC cells and in vivo animal models. The molecular mechanism of circAGAP1 was investigated by fluorescence in situ hybridization, RNA immunoprecipitation and luciferase assays. Results circAGAP1 (circ0058792) expression was significantly upregulated in ccRCC tissues compared to adjacent nontumor tissues. Moreover, the expression of circAGAP1 was closely related to the tumor size, nuclear grade and clinical stage of ccRCC in patients. Mechanistic studies demonstrated that cytoplasmic circAGAP1 targeted miR-15-5p in an RNA-induced silencing complex. Additionally, miR-15-5p expression was downregulated in ccRCC. Luciferase reporter assays showed that E2F transcription factor 3 (E2F3) was a target of miR-15-5p, and upregulated E2F3 expression was positively correlated with circAGAP1 in ccRCC. Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo. Conclusion Our results clarify that circAGAP1 exerts its oncogenic functions as a competitive endogenous RNA (ceRNA) by sponging miR-15-5p, which promotes E2F3 expression. Targeting circAGAP1 might be a new attractive therapeutic strategy in ccRCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01864-3.
Collapse
Affiliation(s)
- Qi Lv
- Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China
| | - Gangmin Wang
- Department of Urology, Huashan Hospital, Fudan University, Urumuqi Road No. 12, Shanghai, 200040, China
| | - Yinan Zhang
- Department of Urology, Shandong Provincial Hospital affiliated with Shandong University, Jingwuweiqi Road No. 324, Jinan, 250021, Shandong, China
| | - Aijun Shen
- Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China
| | - Junjun Tang
- Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China
| | - Yi Sun
- Department of Urology, No.971 Hospital of the PLA Navy, Qingdao, 266071, Shandong, China
| | - Chunhui Ma
- Department of Orthopedics, Shanghai General Hospital of Shanghai Jiaotong University, Wujin Road No. 85, Shanghai, 200080, China.
| | - Peijun Wang
- Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China.
| |
Collapse
|
|
28
|
Singh S, Raza W, Parveen S, Meena A, Luqman S. Flavonoid display ability to target microRNAs in cancer pathogenesis. Biochem Pharmacol 2021; 189:114409. [PMID: 33428895 DOI: 10.1016/j.bcp.2021.114409] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-coding, conserved, single-stranded nucleotide sequences involved in physiological and developmental processes. Recent evidence suggests an association between miRNAs' deregulation with initiation, promotion, progression, and drug resistance in cancer cells. Besides, miRNAs are known to regulate the epithelial-mesenchymal transition, angiogenesis, autophagy, and senescence in different cancer types. Previous reports proposed that apart from the antioxidant potential, flavonoids play an essential role in miRNAs modulation associated with changes in cancer-related proteins, tumor suppressor genes, and oncogenes. Thus, flavonoids can suppress proliferation, help in the development of drug sensitivity, suppress metastasis and angiogenesis by modulating miRNAs expression. In the present review, we summarize the role of miRNAs in cancer, drug resistance, and the chemopreventive potential of flavonoids mediated by miRNAs. The potential of flavonoids to modulate miRNAs expression in different cancer types demonstrate their selectivity and importance as regulators of carcinogenesis. Flavonoids as chemopreventive agents targeting miRNAs are extensively studied in vitro, in vivo, and pre-clinical studies, but their efficiency in targeting miRNAs in clinical studies is less investigated. The evidence presented in this review highlights the potential of flavonoids in cancer prevention/treatment by regulating miRNAs, although further investigations are required to validate and establish their clinical usefulness.
Collapse
Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Waseem Raza
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Jawahar Lal Nehru University, New Delhi 110067, India
| | - Shahnaz Parveen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
| |
Collapse
|
|
29
|
mRNA and miRNA Expression Analyses of the MYC/ E2F/miR-17-92 Network in the Most Common Pediatric Brain Tumors. Int J Mol Sci 2021; 22:ijms22020543. [PMID: 33430425 PMCID: PMC7827072 DOI: 10.3390/ijms22020543] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/25/2022] Open
Abstract
Numerous molecular factors disrupt the correctness of the cell cycle process leading to the development of cancer due to increased cell proliferation. Among known causative factors of such process is abnormal gene expression. Nowadays in the light of current knowledge such alterations are frequently considered in the context of mRNA–miRNA correlation. One of the molecular factors with potential value in tumorigenesis is the feedback loop between MYC and E2F genes in which miR-17-5p and miR-20a from the miR-17-92 cluster are involved. The current literature shows that overexpression of the members of the OncomiR-1 are involved in the development of many solid tumors. In the present work, we investigated the expression of components of the MYC/E2F/miR-17-92 network and their closely related elements including members of MYC and E2F families and miRNAs from two paralogs of miR-17-92: miR-106b-25 and miR-106a-363, in the most common brain tumors of childhood, pilocytic astrocytoma (PA), WHO grade 1; ependymoma (EP), WHO grade 2; and medulloblastoma (MB), WHO grade 4. We showed that the highest gene expression was observed in the MYC family for MYCN and in the E2F family for E2F2. Positive correlation was observed between the gene expression and tumor grade and type, with the highest expression being noted for medulloblastomas, followed by ependymomas, and the lowest for pilocytic astrocytomas. Most members of miR-17-92, miR-106a-363 and miR-106b-25 clusters were upregulated and the highest expression was noted for miR-18a and miR-18b. The rest of the miRNAs, including miR-19a, miR-92a, miR-106a, miR-93, or miR-25 also showed high values. miR-17-5p, miR-20a obtained a high level of expression in medulloblastomas and ependymomas, while close to the control in the pilocytic astrocytoma samples. miRNA expression also depended on tumor grade and histology.
Collapse
|
|
30
|
Read DE, Gupta A, Cawley K, Fontana L, Agostinis P, Samali A, Gupta S. Downregulation of miR-17-92 Cluster by PERK Fine-Tunes Unfolded Protein Response Mediated Apoptosis. Life (Basel) 2021; 11:life11010030. [PMID: 33418948 PMCID: PMC7825066 DOI: 10.3390/life11010030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/31/2020] [Accepted: 01/02/2021] [Indexed: 01/07/2023] Open
Abstract
An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to the miR-17-92 cluster are decreased during UPR. We found that miR-17-92 promoter reporter activity was reduced during UPR in a PERK-dependent manner. Furthermore, we show that activity of the miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. Promoter deletion analysis mapped the region responding to UPR-mediated repression to a site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to the miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for ATF4 and NRF2, where repression of the miR-17-92 cluster plays an important role in ER stress-mediated apoptosis. Mechanistic details are provided for the potentiation of cell death via sustained PERK signalling mediated repression of the miR-17-92 cluster.
Collapse
Affiliation(s)
- Danielle E. Read
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, National University of Ireland-Galway, H91 TK33 Galway, Ireland;
| | - Ananya Gupta
- Discipline of Physiology, School of Medicine, National University of Ireland-Galway, H91 TK33 Galway, Ireland;
| | - Karen Cawley
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland Galway, H91 TK33 Galway, Ireland; (K.C.); (A.S.)
| | - Laura Fontana
- Ragon Institute of MGH, MIT and Harvard, Cambridge, 02138 MA, USA;
| | - Patrizia Agostinis
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium;
- VIB Center for Cancer Biology Research, 3000 Leuven, Belgium
| | - Afshin Samali
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland Galway, H91 TK33 Galway, Ireland; (K.C.); (A.S.)
| | - Sanjeev Gupta
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, National University of Ireland-Galway, H91 TK33 Galway, Ireland;
- Correspondence:
| |
Collapse
|
|
31
|
Zhong Y, Li L, Chen Z, Diao S, He Y, Zhang Z, Zhang H, Yuan X, Li J. MIR143 Inhibits Steroidogenesis and Induces Apoptosis Repressed by H3K27me3 in Granulosa Cells. Front Cell Dev Biol 2020; 8:565261. [PMID: 33195195 PMCID: PMC7604341 DOI: 10.3389/fcell.2020.565261] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022] Open
Abstract
The granulosa cell growth factor and apoptotic factor are two factors to determine follicular apoptosis. Whether ssc-miR-143-3p (MIR143) plays as an apoptosis factor in porcine granulosa cells (pGCs) remain unclear. This study tries to investigate what function of MIR143 is and how MIR143 gets these functions in pGCs from 3 to 5 mm medium-sized follicles. Firstly, 5' RACE was used to identify the structure of MIR143, and in situ hybridization, qPCR, and DNA pull-down were employed to exhibit the spatio-temporal expression and transcriptional regulation of MIR143. Furthermore, ELISA, Western blotting, and flow cytometry were adopted to explore the functions of MIR143 in pGCs. It was found that MIR143 was an exonic miRNA located in host gene LOC100514340 with an increasing expression during follicular growth. Moreover, MIR143 suppressed steroidogenesis related genes of HSD17β4, ER1, and PTGS2, negatively regulating estrogen, androgen, progesterone, and prostaglandin. MIR143 induced the apoptosis via activation of BAX-dependent Caspase 3 signaling. Furthermore, H3K27me3 influenced the recruitment of transcription factors and binding proteins to repress MIR143 transcription. At last, H3K27me3 agonist with MIR143 inhibition activated steroidogenesis but repressed apoptosis. These findings suggest that H3K27me3-mediated MIR143 inhibition play a critical role in follicular atresia by regulating cell apoptosis and steroidogenesis, which will provide useful information for further investigations of H3K27me3-miediated MIR143 epigenetic regulation in follicular growth in mammals.
Collapse
Affiliation(s)
- Yuyi Zhong
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Liying Li
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zitao Chen
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Shuqi Diao
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yingting He
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zhe Zhang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Hao Zhang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xiaolong Yuan
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China
| | - Jiaqi Li
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| |
Collapse
|
|
32
|
Mortazavi-Jahromi SS, Aslani M, Mirshafiey A. A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases. Immunol Lett 2020; 227:8-27. [PMID: 32810557 DOI: 10.1016/j.imlet.2020.07.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/10/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are single-strand endogenous and non-coding RNA molecules with a length of about 22 nucleotides, which regulate genes expression, through modulating the translation and stability of their target mRNAs. miR-146a is one of the most studied miRNAs, due to its central role in immune system homeostasis and control of the innate and acquired immune responses. Accordingly, abnormal expression or function of miR-146a results in the incidence and progression of immune and non-immune inflammatory diseases. Its deregulated expression pattern and inefficient function have been reported in a wide spectrum of these illnesses. Based on the existing evidence, this miRNA qualifies as an ideal biomarker for diagnosis, prognosis, and activity evaluation of immune and non-immune inflammatory disorders. Moreover, much attention has recently been paid to therapeutic potential of miR-146a and several researchers have assessed the effects of different drugs on expression and function of this miRNA at diverse experimental, animal, besides human levels, reporting motivating results in the treatment of the diseases. Here, in this comprehensive review, we provide an overview of miR-146a role in the pathogenesis and progression of several immune and non-immune inflammatory diseases such as Rheumatoid arthritis, Systemic lupus erythematosus, Inflammatory bowel disease, Multiple sclerosis, Psoriasis, Graves' disease, Atherosclerosis, Hepatitis, Chronic obstructive pulmonary disease, etc., discuss about its eligibility for being a desirable biomarker for these disorders, and also highlight its therapeutic potential. Understanding these mechanisms underlies the selecting and designing the proper therapeutic targets and medications, which eventually facilitate the treatment process.
Collapse
Affiliation(s)
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
33
|
Shah V, Shah J. Recent trends in targeting miRNAs for cancer therapy. J Pharm Pharmacol 2020; 72:1732-1749. [PMID: 32783235 DOI: 10.1111/jphp.13351] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/12/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVES MicroRNAs (miRNAs) are a type of small noncoding RNA employed by the cells for gene regulation. A single miRNA, typically 22 nucleotides in length, can regulate the expression of numerous genes. Over the past decade, the study of miRNA biology in the context of cancer has led to the development of new diagnostic and therapeutic opportunities. KEY FINDINGS MicroRNA dysregulation is commonly associated with cancer, in part because miRNAs are actively involved in the mechanisms like genomic instabilities, aberrant transcriptional control, altered epigenetic regulation and biogenesis machinery defects. MicroRNAs can regulate oncogenes or tumour suppressor genes and thus when altered can lead to tumorigenesis. Expression profiling of miRNAs has boosted the possibilities of application of miRNAs as potential cancer biomarkers and therapeutic targets, although the feasibility of these approaches will require further validation. SUMMARY In this review, we will focus on how miRNAs regulate tumour development and the potential applications of targeting miRNAs for cancer therapy.
Collapse
Affiliation(s)
- Vandit Shah
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| | - Jigna Shah
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| |
Collapse
|
|
34
|
Kolenda T, Guglas K, Kopczyńska M, Sobocińska J, Teresiak A, Bliźniak R, Lamperska K. Good or not good: Role of miR-18a in cancer biology. Rep Pract Oncol Radiother 2020; 25:808-819. [PMID: 32884453 DOI: 10.1016/j.rpor.2020.07.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/24/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
miR-18a is a member of primary transcript called miR-17-92a (C13orf25 or MIR17HG) which also contains five other miRNAs: miR-17, miR-19a, miR-20a, miR-19b and miR-92a. This cluster as a whole shows specific characteristics, where miR-18a seems to be unique. In contrast to the other members, the expression of miR-18a is additionally controlled and probably functions as its own internal controller of the cluster. miR-18a regulates many genes involved in proliferation, cell cycle, apoptosis, response to different kinds of stress, autophagy and differentiation. The disturbances of miR-18a expression are observed in cancer as well as in different diseases or pathological states. The miR-17-92a cluster is commonly described as oncogenic and it is known as 'oncomiR-1', but this statement is a simplification because miR-18a can act both as an oncogene and a suppressor. In this review we summarize the current knowledge about miR-18a focusing on its regulation, role in cancer biology and utility as a potential biomarker.
Collapse
Key Words
- 5-FU, 5-fluorouracyl
- ACVR2A, activin A receptor type 2A
- AKT, AKT serine/threonine kinase
- AR, androgen receptor
- ATG7, autophagy related 7
- ATM, ATM serine/threonine kinase
- BAX, BCL2 associated Xapoptosis regulator
- BCL2, BCL2 apoptosis regulator
- BCL2L10, BCL2 like 10
- BDNF, brain derived neurotrophic factor
- BLCA, bladder urothelial carcinoma
- BRCA, breast cancer
- Biomarker
- Bp, base pair
- C-myc (MYCBP), MYC binding protein
- CASC2, cancer susceptibility 2
- CD133 (PROM1), prominin 1
- CDC42, cell division cycle 42
- CDKN1, Bcyclin dependent kinase inhibitor 1B
- COAD, colon adenocarcinoma
- Cancer
- Circulating miRNA
- DDR, DNA damage repair
- E2F family (E2F1, E2F2, E2F3), E2F transcription factors
- EBV, Epstein-Barr virus
- EMT, epithelial-to-mesenchymal transition
- ER, estrogen receptor
- ERBB (EGFR), epidermal growth factor receptor
- ESCA, esophageal carcinoma
- FENDRR, FOXF1 adjacent non-coding developmental regulatory RNA
- FER1L4, fer-1 like family member 4 (pseudogene)
- GAS5, growth arrest–specific 5
- HIF-1α (HIF1A), hypoxia inducible factor 1 subunit alpha
- HNRNPA1, heterogeneous nuclear ribonucleoprotein A1
- HNSC, head and neck squamous cell carcinoma
- HRR, homologous recombination-based DNA repair
- IFN-γ (IFNG), interferon gamma
- IGF1, insulin like growth factor 1
- IL6, interleukin 6
- IPMK, inositol phosphate multikinase
- KIRC, clear cell kidney carcinoma
- KIRP, kidney renal papillary cell carcinoma
- KRAS, KRAS proto-oncogene, GTPase
- LIHC, liver hepatocellular carcinoma
- LMP1, latent membrane protein 1
- LUAD, lung adenocarcinoma
- LUSC, lung squamous cell carcinoma
- Liquid biopsy
- MAPK, mitogen-activated protein kinase
- MCM7, minichromosome maintenance complex component 7
- MET, mesenchymal-to-epithelial transition
- MTOR, mechanistic target of rapamycin kinase
- N-myc (MYCN), MYCN proto-oncogene, bHLH transcription factor
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NOTCH2, notch receptor 2
- Oncogene
- PAAD, pancreatic adenocarcinoma
- PERK (EIF2AK3), eukaryotic translation initiation factor 2 alpha kinase 3
- PI3K (PIK3CA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
- PIAS3, protein inhibitor of activated STAT 3
- PRAD, prostate adenocarcinoma
- RISC, RNA-induced silencing complex
- SMAD2, SMAD family member 2
- SMG1, SMG1 nonsense mediated mRNA decay associated PI3K related kinase
- SNHG1, small nucleolar RNA host gene 1
- SOCS5, suppressor of cytokine signaling 5
- STAD, stomach adenocarcinoma
- STAT3, signal transducer and activator of transcription 3
- STK4, serine/threonine kinase 4
- Suppressor
- TCGA
- TCGA, The Cancer Genome Atlas
- TGF-β (TGFB1), transforming growth factor beta 1
- TGFBR2, transforming growth factor beta receptor 2
- THCA, papillary thyroid carcinoma
- TNM, Classification of Malignant Tumors: T - tumor / N - lymph nodes / M – metastasis
- TP53, tumor protein p53
- TP53TG1, TP53 target 1
- TRIAP1, p53-regulating inhibitor of apoptosis gene
- TSC1, TSC complex subunit 1
- UCA1, urothelial cancer associated 1
- UCEC, uterine corpus endometrial carcinoma
- UTR, untranslated region
- WDFY3-AS2, WDFY3 antisense RNA 2
- WEE1, WEE1 G2 checkpoint kinase
- WNT family, Wingless-type MMTV integration site family/Wnt family ligands
- ZEB1/ZEB2, zinc finger E-box binding homeobox 1 and 2
- ceRNA, competitive endogenous RNA
- cncRNA, protein coding and non-coding RNA
- lncRNA, long-non coding RNA
- miR-17-92a
- miR-18a
- miRNA
Collapse
Affiliation(s)
- Tomasz Kolenda
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland.,Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warszawa, Poland
| | - Kacper Guglas
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warszawa, Poland
| | - Magda Kopczyńska
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland.,Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Joanna Sobocińska
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Anna Teresiak
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland
| | - Renata Bliźniak
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland
| | | |
Collapse
|
|
35
|
Cui J, Qu Z, Harata-Lee Y, Shen H, Aung TN, Wang W, Kortschak RD, Adelson DL. The effect of compound kushen injection on cancer cells: Integrated identification of candidate molecular mechanisms. PLoS One 2020; 15:e0236395. [PMID: 32730293 PMCID: PMC7392229 DOI: 10.1371/journal.pone.0236395] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 07/05/2020] [Indexed: 12/22/2022] Open
Abstract
Traditional Chinese Medicine (TCM) preparations are often extracts of single or multiple herbs containing hundreds of compounds, and hence it has been difficult to study their mechanisms of action. Compound Kushen Injection (CKI) is a complex mixture of compounds extracted from two medicinal plants and has been used in Chinese hospitals to treat cancer for over twenty years. To demonstrate that a systematic analysis of molecular changes resulting from complex mixtures of bioactives from TCM can identify a core set of differentially expressed (DE) genes and a reproducible set of candidate pathways. We used in vitro cancer models to measure the effect of CKI on cell cycle phases and apoptosis, and correlated those phenotypes with CKI induced changes in gene expression. We treated two cancer cell lines with or without CKI and assessed the resulting phenotypes by employing cell viability and proliferation assays. Based on these results, we carried out high-throughput transcriptome data analysis to identify genes and candidate pathways perturbed by CKI. We integrated these differential gene expression results with previously reported results and carried out validation of selected differentially expressed genes. CKI induced cell-cycle arrest and apoptosis in the cancer cell lines tested. In these cells CKI also altered the expression of 363 core candidate genes associated with cell cycle, apoptosis, DNA replication/repair, and various cancer pathways. Of these, 7 are clinically relevant to cancer diagnosis or therapy, 14 are cell cycle regulators, and most of these 21 candidates are downregulated by CKI. Comparison of our core candidate genes to a database of plant medicinal compounds and their effects on gene expression identified one-to-one, one-to-many and many-to-many regulatory relationships between compounds in CKI and DE genes. By identifying genes and promising candidate pathways associated with CKI treatment based on our transcriptome-based analysis, we have shown that this approach is useful for the systematic analysis of molecular changes resulting from complex mixtures of bioactives.
Collapse
Affiliation(s)
- Jian Cui
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Zhipeng Qu
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Yuka Harata-Lee
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Hanyuan Shen
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Thazin Nwe Aung
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Wei Wang
- Zhendong Research Institute, Shanxi-Zhendong Pharmaceutical Co Ltd, Beijing, China
| | - R. Daniel Kortschak
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - David L. Adelson
- Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
- * E-mail:
| |
Collapse
|
|
36
|
Wan S, Zhang J, Chen X, Lang J, Li L, Chen F, Tian L, Meng Y, Yu X. MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment. Front Endocrinol (Lausanne) 2020; 11:9. [PMID: 32038500 PMCID: PMC6989481 DOI: 10.3389/fendo.2020.00009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/07/2020] [Indexed: 02/05/2023] Open
Abstract
Objective: To clarify the role and mechanism of miR-17-92 cluster in islet beta-cell repair after streptozotocin intervention. Methods: Genetically engineered mice (miR-17-92βKO) and control RIP-Cre mice were intraperitoneally injected with multiple low dose streptozotocin. Body weight, random blood glucose (RBG), fasting blood glucose, and intraperitoneal glucose tolerance test (IPGTT) were monitored regularly. Mice were sacrificed for histological analysis 8 weeks later. Morphological changes of pancreas islets, quantity, quality, apoptosis, and proliferation of beta-cells were measured. Islets from four groups were isolated. MiRNA and mRNA were extracted and quantified. Results:MiR-17-92βKO mice showed dramatically elevated fasting blood glucose and impaired glucose tolerance after streptozotocin treatment in contrast to control mice, the reason of which is reduced beta-cell number and total mass resulting from reduced proliferation, enhanced apoptosis of beta-cells. Genes related to cell proliferation and insulin transcription repression were significantly elevated in miR-17-92βKO mice treated with streptozotocin. Furthermore, genes involved in DNA biosynthesis and damage repair were dramatically increased in miR-17-92βKO mice with streptozotocin treatment. Conclusion: Collectively, our results demonstrate that homozygous deletion of miR-17-92 cluster in mouse pancreatic beta-cells promotes the development of experimental diabetes, indicating that miR-17-92 cluster may be positively related to beta-cells restoration and adaptation after streptozotocin-induced damage.
Collapse
Affiliation(s)
- Shan Wan
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Zhang
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jiangli Lang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Fei Chen
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Li Tian
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Meng
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
37
|
From squamous intraepithelial lesions to cervical cancer: Circulating microRNAs as potential biomarkers in cervical carcinogenesis. Biochim Biophys Acta Rev Cancer 2019; 1872:188306. [DOI: 10.1016/j.bbcan.2019.08.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023]
|
|
38
|
Mai S, Xiao R, Shi L, Zhou X, Yang T, Zhang M, Weng N, Zhao X, Wang R, Liu J, Sun R, Qin H, Wang H. MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma. Cell Death Dis 2019; 10:819. [PMID: 31659158 PMCID: PMC6817863 DOI: 10.1038/s41419-019-2060-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/17/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.
Collapse
Affiliation(s)
- ShiJuan Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - RuoWen Xiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Lu Shi
- Department of thoracic oncology, the cancer center of the fifth affiliated hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - XiaoMin Zhou
- ZhouKou Hospital of Traditional Chinese Medicine, Zhoukou, 466000, China
| | - Te Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - MeiYin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - NuoQing Weng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - XinGe Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - RuiQi Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ji Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Rui Sun
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - HaiDe Qin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - HuiYun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| |
Collapse
|
|
39
|
Xiong P, Schneider RF, Hulsey CD, Meyer A, Franchini P. Conservation and novelty in the microRNA genomic landscape of hyperdiverse cichlid fishes. Sci Rep 2019; 9:13848. [PMID: 31554838 PMCID: PMC6761260 DOI: 10.1038/s41598-019-50124-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/05/2019] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) play crucial roles in the post-transcriptional control of messenger RNA (mRNA). These miRNA-mRNA regulatory networks are present in nearly all organisms and contribute to development, phenotypic divergence, and speciation. To examine the miRNA landscape of cichlid fishes, one of the most species-rich families of vertebrates, we profiled the expression of both miRNA and mRNA in a diverse set of cichlid lineages. Among these, we found that conserved miRNAs differ from recently arisen miRNAs (i.e. lineage specific) in average expression levels, number of target sites, sequence variability, and physical clustering patterns in the genome. Furthermore, conserved miRNA target sites tend to be enriched at the 5' end of protein-coding gene 3' UTRs. Consistent with the presumed regulatory role of miRNAs, we detected more negative correlations between the expression of miRNA-mRNA functional pairs than in random pairings. Finally, we provide evidence that novel miRNA targets sites are enriched in genes involved in protein synthesis pathways. Our results show how conserved and evolutionarily novel miRNAs differ in their contribution to the genomic landscape and highlight their particular evolutionary roles in the adaptive diversification of cichlids.
Collapse
Affiliation(s)
- Peiwen Xiong
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Ralf F Schneider
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
- Marine Ecology, Helmholtz-Zentrum für Ozeanforschung Kiel (GEOMAR), 24105 Kiel, Germany
| | - C Darrin Hulsey
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Axel Meyer
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Paolo Franchini
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
| |
Collapse
|
|
40
|
Behbahanipour M, Peymani M, Salari M, Hashemi MS, Nasr-Esfahani MH, Ghaedi K. Expression Profiling of Blood microRNAs 885, 361, and 17 in the Patients with the Parkinson's disease: Integrating Interaction Data to Uncover the Possible Triggering Age-Related Mechanisms. Sci Rep 2019; 9:13759. [PMID: 31551498 PMCID: PMC6760236 DOI: 10.1038/s41598-019-50256-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 09/09/2019] [Indexed: 01/23/2023] Open
Abstract
MicroRNAs (miRNAs) have been reported to contribute to the pathophysiology of the Parkinson’s disease (PD), an age related-neurodegenerative disorder. The aim of present study was to compare the expression profiles of a new set of candidate miRNAs related to aging and cellular senescence in peripheral blood mononuclear cells (PBMCs) obtained from the PD patients with healthy controls and then in the early and advanced stages of the PD patients with their controls to clarify whether their expression was correlated with the disease severity. We have also proposed a consensus-based strategy to interpret the miRNAs expression data to gain a better insight into the molecular regulatory alterations during the incidence of PD. We evaluated the miRNA expression levels in the PBMCs obtained from 36 patients with PD and 16 healthy controls by the reverse transcription-quantitative real-time PCR and their performance to discriminate the PD patients from the healthy subjects assessed using the receiver operating characteristic curve analysis. Also, we applied our consensus and integration approach to construct a deregulated miRNA-based network in PD with the respective targets and transcription factors, and the enriched gene ontology and pathways using the enrichment analysis approach were obtained. There was a significant overexpression of miR-885 and miR-17 and the downregulation of miR-361 in the PD patients compared to the controls. The blood expression of miR-885 and miR-17 tended to increase along with the disease severity. On the other hand, the lower levels of miR-361 in the early stages of the PD patients, as compared to controls, and its higher levels in the advanced stages of PD patients, as compared to the early stages of the PD patients, were observed. Combination of all three miRNAs showed an appropriate value of AUC (0.985) to discriminate the PD patients from the healthy subjects. Also, the deregulated miRNAs were linked to the known PD pathways and the candidate related target genes were presented. We revealed 3 candidate biomarkers related to aging and cellular senescence for the first time in the patients with PD. Our in-silico analysis identified candidate target genes and TFs, including those related to neurodegeneration and PD. Overall, our findings provided novel insights into the probable age-regulatory mechanisms underlying PD and a rationale to further clarify the role of the identified miRNAs in the PD pathogenesis.
Collapse
Affiliation(s)
- Molood Behbahanipour
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran. .,Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Mehri Salari
- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Motahare-Sadat Hashemi
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran. .,Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| |
Collapse
|
|
41
|
Xie L, Huang R, Liu S, Wu W, Su A, Li R, Liu X, Lei Y, Sun H, Liu X, Xu S. A positive feedback loop of SIRT1 and miR17HG promotes the repair of DNA double-stranded breaks. Cell Cycle 2019; 18:2110-2123. [PMID: 31290724 DOI: 10.1080/15384101.2019.1641388] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have emerged as critical regulators for gene expression in multiple levels and thus are involved in various physiological and pathological processes. Sirtuin 1 (SIRT1) has been established to exert key roles in the diverse biological process through deacetylation of substrates, including DNA damage repair. Nevertheless, the regulatory relationship between SIRT1 and lncRNAs, and the effect of lncRNA on SIRT1-mediated functions were still far to be elucidated. We herein uncovered that lncRNA miR17HG was notably down-regulated in SIRT1-deficient cells, and significantly up-regulated after ectopic expression of SIRT1. Subsequently, the results of dual luciferase reporter (DLR) showed that SIRT1 dramatically enhanced the promoter activity of the miR-17-92 cluster. Furthermore, we specifically knocked down the previous demonstrated transcription factor for the miR-17-92 cluster, C-Myc, which was the validated substrate of SIRT1. As expected, miR17HG and miR-17-92 miRNAs were evidently down-regulated after silencing of C-Myc; and silencing of C-Myc significantly reversed the effect of SIRT1 on miR17HG expression, suggesting that SIRT1 endowed cells with elevated miR17HG expression through stabilization of C-Myc. What is more, silencing of miR17HG significantly inhibited the repair of DNA DSBs, while enforced expression of miR17HG promoted DSBs repair. Fascinatingly, overexpression of miR17HG evidently enhanced the deacetylation activity of SIRT1, while silencing of miR17HG conferred diminished deacetylation activity. In addition, the results of RIP unraveled the physical interaction between miR17HG and SIRT1. Taken together, we presented evidences that miR17HG and SIRT1 probably formed a positive feedback loop, which exerted a crucial effect on DSBs repair.
Collapse
Affiliation(s)
- Luoyijun Xie
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Ruxiao Huang
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Shuang Liu
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Weijia Wu
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Ailing Su
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Runkai Li
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Xu Liu
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Yiting Lei
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Huidi Sun
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Xinguang Liu
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| | - Shun Xu
- a Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, the Scientific Research Center of Dongguan, Guangdong Medical University , Dongguan , P.R.China
| |
Collapse
|
|
42
|
Yang XQ, Zhang CX, Wang JK, Wang L, Du X, Song YF, Liu D. Transcriptional regulation of the porcine miR-17-92 cluster. Mol Genet Genomics 2019; 294:1023-1036. [DOI: 10.1007/s00438-019-01560-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/06/2019] [Indexed: 01/28/2023]
|
|
43
|
Babion I, De Strooper LMA, Luttmer R, Bleeker MCG, Meijer CJLM, Heideman DAM, Wilting SM, Steenbergen RDM. Complementarity between miRNA expression analysis and DNA methylation analysis in hrHPV-positive cervical scrapes for the detection of cervical disease. Epigenetics 2019; 14:558-567. [PMID: 30955437 PMCID: PMC6557605 DOI: 10.1080/15592294.2019.1600390] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cervical screening by high-risk HPV (hrHPV) testing requires additional risk stratification (triage), as most infections are transient and only a subset of hrHPV-positive women harbours clinically relevant disease. Molecular triage markers such as microRNAs (miRNAs) and DNA methylation markers are particularly promising, as they can be objectively tested directly on hrHPV-positive scrapes and cervicovaginal self-samples. Here, we evaluated the marker potential of 10 candidate miRNAs in 209 hrHPV-positive scrapes of women with underlying precancer (cervical intraepithelial neoplasia, grade 2–3 (CIN2-3)), cancer, or without disease (CIN0/1). A predictive miRNA classifier for CIN3 detection was built using logistic regression, which was compared to and combined with DNA methylation marker FAM19A4. Markers were correlated to histology parameters and hrHPV genotype. A miRNA classifier consisting of miR-149, miR-20a, and miR-93 achieved an area under the curve (AUC) of 0.834 for CIN3 detection, which was not significantly different to that of FAM19A4 methylation (AUC: 0.862, p = 0.591). Combining miRNA and methylation analysis demonstrated complementarity between both marker types (AUC: 0.939). While the miRNA classifier seemed more predictive for CIN2, FAM19A4 methylation was particularly high in HPV16-positive and histologically advanced CIN3, i.e. CIN3 with high lesion volume. The miRNA classifier, FAM19A4 methylation, and the miRNA/methylation combination were highest in cancer-associated scrapes. In conclusion, a panel of three miRNAs is discriminatory for CIN3 in hrHPV-positive scrapes and can complement DNA methylation analysis for the efficient detection of cervical disease. Combined analysis of the two marker types warrants further evaluation as triage strategy in hrHPV-based screening.
Collapse
Affiliation(s)
- Iris Babion
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| | - Lise M A De Strooper
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| | - Roosmarijn Luttmer
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| | - Maaike C G Bleeker
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| | - Chris J L M Meijer
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| | - Daniëlle A M Heideman
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| | - Saskia M Wilting
- b Department of Medical Oncology, Erasmus MC Cancer Institute , Erasmus University Medical Center , Rotterdam , The Netherlands
| | - Renske D M Steenbergen
- a Pathology, Cancer Center Amsterdam , Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
| |
Collapse
|
|
44
|
Labi V, Schoeler K, Melamed D. miR-17∼92 in lymphocyte development and lymphomagenesis. Cancer Lett 2019; 446:73-80. [PMID: 30660648 DOI: 10.1016/j.canlet.2018.12.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/06/2018] [Accepted: 12/31/2018] [Indexed: 01/07/2023]
Abstract
microRNAs (miRNAs) down-modulate the levels of proteins by sequence-specific binding to their respective target mRNAs, causing translational repression or mRNA degradation. The miR-17∼92 cluster encodes for six miRNAs whose target recognition specificities are determined by their distinct sequence. In mice, the four miRNA families generated from the miR-17∼92 cluster coordinate to allow for proper lymphocyte development and effective adaptive immune responses following infection or immunization. Lymphocyte development and homeostasis rely on tight regulation of PI3K signaling to avoid autoimmunity or immunodeficiency, and the miR-17∼92 miRNAs appear as key mediators to appropriately tune PI3K activity. On the other hand, in lymphoid tumors overexpression of the miR-17∼92 miRNAs is a common oncogenic event. In this review, we touch on what we have learned so far about the miR-17∼92 miRNAs, particularly with respect to their role in lymphocyte development, homeostasis and pathology.
Collapse
Affiliation(s)
- Verena Labi
- Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, 6020, Austria.
| | - Katia Schoeler
- Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, 6020, Austria
| | - Doron Melamed
- Department of Immunology, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
| |
Collapse
|
|
45
|
Moyal L, Gorovitz‐Haris B, Yehezkel S, Jacob‐Hirsch J, Bershtein V, Barzilai A, Rotem C, Sherman S, Amitay‐Laish I, Feinmesser M, Hodak E. Unilesional mycosis fungoides is associated with increased expression of micro
RNA
‐17~92 and T helper 1 skewing. Br J Dermatol 2019; 180:1123-1134. [DOI: 10.1111/bjd.17425] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2018] [Indexed: 12/15/2022]
Affiliation(s)
- L. Moyal
- Laboratory for Molecular Dermatology Felsenstein Medical Research Center Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - B. Gorovitz‐Haris
- Laboratory for Molecular Dermatology Felsenstein Medical Research Center Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - S. Yehezkel
- Laboratory for Molecular Dermatology Felsenstein Medical Research Center Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - J. Jacob‐Hirsch
- Cancer Research Center Sheba Medical Center Tel HashomerIsrael
| | - V. Bershtein
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - A. Barzilai
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology Sheba Medical Center Tel Hashomer Israel
| | - C. Rotem
- Laboratory for Molecular Dermatology Felsenstein Medical Research Center Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - S. Sherman
- Laboratory for Molecular Dermatology Felsenstein Medical Research Center Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - I. Amitay‐Laish
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| | - M. Feinmesser
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Institute of Pathology Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - E. Hodak
- Laboratory for Molecular Dermatology Felsenstein Medical Research Center Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Department of Dermatology and Rabin Medical Center – Beilinson Hospital Petach TikvaIsrael
| |
Collapse
|
|
46
|
Zhao L, Zhang X, Wu Z, Huang K, Sun X, Chen H, Jin M. The Downregulation of MicroRNA hsa-miR-340-5p in IAV-Infected A549 Cells Suppresses Viral Replication by Targeting RIG-I and OAS2. MOLECULAR THERAPY-NUCLEIC ACIDS 2019; 14:509-519. [PMID: 30753994 PMCID: PMC6370596 DOI: 10.1016/j.omtn.2018.12.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/28/2018] [Accepted: 12/28/2018] [Indexed: 02/08/2023]
Abstract
The influenza A virus poses serious public health challenges worldwide. Strikingly, small noncoding microRNAs (miRNAs) that modulate gene expression are closely involved in antiviral responses, although the underlying mechanisms are essentially unknown. We now report that microRNA-340 (miR340) is downregulated following influenza A and other RNA virus infections, implying that host cells deplete miR340 as an antiviral defense mechanism. Accordingly, the inhibition or knockdown of endogenous miR340 clearly prevents the infection of cultured cells, whereas the forced expression of miR340 significantly enhances virus replication. Using next-generation sequencing, we found that miR340 attenuates cellular antiviral immunity. Moreover, mechanistic studies defined miR340 as a repressor of RIG-I and OAS2, critical factors for the establishment of an antiviral response. Collectively, these data indicate that host cells may lower their viral loads by regulating miRNA pathways, which may, in turn, provide new opportunities for treatment.
Collapse
Affiliation(s)
- Lianzhong Zhao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Xiaohan Zhang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Zhu Wu
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Kun Huang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Xiaomei Sun
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan 430070, Hubei Province, China
| | - Huanchun Chen
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan 430070, Hubei Province, China
| | - Meilin Jin
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan 430070, Hubei Province, China.
| |
Collapse
|
|
47
|
Swier LJYM, Dzikiewicz‐Krawczyk A, Winkle M, van den Berg A, Kluiver J. Intricate crosstalk between MYC and non-coding RNAs regulates hallmarks of cancer. Mol Oncol 2019; 13:26-45. [PMID: 30451365 PMCID: PMC6322196 DOI: 10.1002/1878-0261.12409] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/10/2018] [Accepted: 10/23/2018] [Indexed: 01/17/2023] Open
Abstract
Myelocytomatosis viral oncogene homolog (MYC) plays an important role in the regulation of many cellular processes, and its expression is tightly regulated at the level of transcription, translation, protein stability, and activity. Despite this tight regulation, MYC is overexpressed in many cancers and contributes to multiple hallmarks of cancer. In recent years, it has become clear that noncoding RNAs add a crucial additional layer to the regulation of MYC and its downstream effects. So far, twenty-five microRNAs and eighteen long noncoding RNAs that regulate MYC have been identified. Thirty-three miRNAs and nineteen lncRNAs are downstream effectors of MYC that contribute to the broad oncogenic role of MYC, including its effects on diverse hallmarks of cancer. In this review, we give an overview of this extensive, multilayered noncoding RNA network that exists around MYC. Current data clearly show explicit roles of crosstalk between MYC and ncRNAs to allow tumorigenesis.
Collapse
Affiliation(s)
- Lotteke J. Y. M. Swier
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| | | | - Melanie Winkle
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| | - Joost Kluiver
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| |
Collapse
|
|
48
|
Kral J, Korenkova V, Novosadova V, Langerova L, Schneiderova M, Liska V, Levy M, Veskrnova V, Spicak J, Opattova A, Jiraskova K, Vymetalkova V, Vodicka P, Slyskova J. Expression profile of miR-17/92 cluster is predictive of treatment response in rectal cancer. Carcinogenesis 2018; 39:1359-1367. [DOI: 10.1093/carcin/bgy100] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 08/05/2018] [Indexed: 12/11/2022] Open
Affiliation(s)
- Jan Kral
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vlasta Korenkova
- Laboratory of Gene Expression, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Vendula Novosadova
- Laboratory of Transgenic Models of Diseases, Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Division BIOCEV, Vestec, Czech Republic
| | - Lucie Langerova
- Laboratory of Gene Expression, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
| | | | - Vaclav Liska
- Department of Surgery, Teaching Hospital and Medical School of Charles University, Pilsen, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
| | - Miroslav Levy
- Department of Surgery, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
| | - Veronika Veskrnova
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
| | - Julius Spicak
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alena Opattova
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Katerina Jiraskova
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Veronika Vymetalkova
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Pavel Vodicka
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Jana Slyskova
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| |
Collapse
|
|
49
|
Splicing factors as regulators of miRNA biogenesis – links to human disease. Semin Cell Dev Biol 2018; 79:113-122. [DOI: 10.1016/j.semcdb.2017.10.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 10/09/2017] [Accepted: 10/09/2017] [Indexed: 12/16/2022]
|
|
50
|
Diamantopoulos MA, Tsiakanikas P, Scorilas A. Non-coding RNAs: the riddle of the transcriptome and their perspectives in cancer. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:241. [PMID: 30069443 DOI: 10.21037/atm.2018.06.10] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-coding RNAs (ncRNAs) constitute a heterogeneous group of RNA molecules in terms of biogenesis, biological function as well as length and structure. These biological molecules have gained attention recently as a potentially crucial layer of tumor cell progression or regulation. ncRNAs are expressed in a broad spectrum of tumors, and they play an important role not only in maintaining but also in promoting cancer development and progression. Recent discoveries have revealed that ncRNAs may act as key signal transduction mediators in tumor signaling pathways by interacting with RNA or proteins. These results reinforce the hypothesis, that ncRNAs constitute therapeutic targets, and point out their clinical potential as stratification markers. The major purpose of this review is to mention the emergence of the importance of ncRNAs, as molecules which are correlated with cancer, and to discuss their clinical implicit as prognostic diagnostic indicators, biomarkers, and therapeutic targets.
Collapse
Affiliation(s)
- Marios A Diamantopoulos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Tsiakanikas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|