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Guo Q, Yang W, Robinson G, Chaludiya K, Abdulkadir AN, Roy FG, Shivakumar D, Ahmad AN, Abdulkadir SA, Kirschner AN. Unlocking the Radiosensitizing Potential of MYC inhibition in Neuroendocrine Malignancies. Int J Radiat Oncol Biol Phys 2025:S0360-3016(25)00431-6. [PMID: 40354951 DOI: 10.1016/j.ijrobp.2025.04.034] [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: 11/03/2024] [Revised: 04/04/2025] [Accepted: 04/28/2025] [Indexed: 05/14/2025]
Abstract
The MYC family of transcription factors-comprising c-MYC, N-MYC, and L-MYC-plays a pivotal role in oncogenesis, driving cancer progression and resistance to therapy. While MYC proteins have long been considered challenging drug targets due to their intricate structures, recent advances have led to the development of promising inhibitors. This review explores the role of MYC overexpression in promoting radiotherapy resistance in aggressive neuroendocrine malignancies through multiple mechanisms, including increased tumor cell invasion, enhanced DNA damage repair and oxidative stress management, pro-survival autophagy, survival of circulating tumor cells, angiogenesis, awakening from dormancy, and modulation of chronic inflammation and host immunity. Paradoxically, MYC overexpression can also enhance radiosensitivity in certain cancer cells by driving pro-apoptotic pathways, such as reactive oxygen species (ROS)-induced DNA damage that overwhelms cellular repair mechanisms, ultimately leading to cell death. Additionally, we provide a comprehensive summary of direct MYC inhibitors, detailing their current stage of preclinical and clinical development as novel anti-cancer therapeutics. This review highlights MYC's role in cancer metastasis and radiotherapy resistance while examining the potential of MYC inhibitors as radiosensitizers in adult and pediatric neuroendocrine malignancies, including small cell lung cancer, large cell neuroendocrine lung cancer, Merkel cell carcinoma, neuroendocrine-differentiated prostate cancer, neuroblastoma, central nervous system embryonal tumors, and medulloblastoma.
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Affiliation(s)
- Qianyu Guo
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA 32224; Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA 32224; Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA; Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611.
| | - William Yang
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611.
| | - Guy Robinson
- Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA 32224; Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
| | - Keyur Chaludiya
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905
| | | | - Falguni Ghosh Roy
- MGM Institute of Health Sciences, Navi Mumbai, Maharashtra, India 410209
| | - Divya Shivakumar
- Kamineni Academy of Medical Science and Research Centre, Hyderabad, Telangana, India 500068
| | - Ayesha N Ahmad
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611; Boonshoft School of Medicine, Wright State University, Fairborn, OH, USA 45324
| | - Sarki A Abdulkadir
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611.
| | - Austin N Kirschner
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA 37232.
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Bartoszewska E, Misiąg P, Czapla M, Rakoczy K, Tomecka P, Filipski M, Wawrzyniak-Dzierżek E, Choromańska A. The Role of microRNAs in Lung Cancer: Mechanisms, Diagnostics and Therapeutic Potential. Int J Mol Sci 2025; 26:3736. [PMID: 40332376 PMCID: PMC12027727 DOI: 10.3390/ijms26083736] [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: 01/31/2025] [Revised: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules that do not have coding functions but play essential roles in various biological processes. In lung cancer, miRNAs affect the processes of tumor initiation, progression, metastasis, and resistance to treatment by regulating gene expression. Tumor-suppressive miRNAs inhibit oncogenic pathways, while oncogenic miRNAs, known as oncomiRs, promote malignant transformation and tumor growth. These dual roles position miRNAs as critical players in lung cancer biology. Studies in recent years have shown the significant potential of miRNAs as both prognostic and diagnostic biomarkers. Circulating miRNAs in plasma or sputum demonstrate specificity and sensitivity in detecting early-stage lung cancer. Liquid biopsy-based miRNA panels distinguish malignant from benign lesions, and specific miRNA expression patterns correlate with disease progression, response to treatment, and overall survival. Therapeutically, miRNAs hold promise for targeted interventions. Strategies such as miRNA replacement therapy using mimics for tumor-suppressive miRNAs and inhibition of oncomiRs with antagomiRs or miRNA sponges have shown preclinical success. Key miRNAs, including the let-7 family, miR-34a, and miR-21, are under investigation for their therapeutic potential. It should be emphasized that delivery difficulties, side effects, and limited stability of therapeutic miRNA molecules remain obstacles to their clinical use. This article examines the roles of miRNAs in lung cancer by indicating their mechanisms of action, diagnostic significance, and therapeutic potential. By addressing current limitations, miRNA-based approaches could revolutionize lung cancer management, offering precise, personalized, and minimally invasive solutions for diagnosis and treatment.
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Affiliation(s)
- Elżbieta Bartoszewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Piotr Misiąg
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Melania Czapla
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Paulina Tomecka
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Michał Filipski
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Elżbieta Wawrzyniak-Dzierżek
- Department and Clinic of Bone Marrow Transplantation, Oncology and Pediatric Hematology, Borowska 213, 50-556 Wroclaw, Poland;
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Gerini G, Mari E, Pontecorvi P, Camero S, Romano E, Ranieri D, Megiorni F, Fioramonti P, Angeloni A, Marchese C, Ceccarelli S. 3D culturing as a promising strategy to enhance the angiogenic potential of adipose stem cell-derived secretome: insights into the role of miR-145-5p/ANGPT2 axis. Stem Cell Res Ther 2025; 16:153. [PMID: 40155988 PMCID: PMC11951674 DOI: 10.1186/s13287-025-04277-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/12/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Adipose-derived mesenchymal stem cells (ASCs) represent a valid therapeutic option for clinical application in several diseases, mostly due to the paracrine activity of their secretome, exerting pro-angiogenic, antinflammatory and immunosuppressive effects. Recently, 3D culturing models has been shown to significantly influence the intrinsic characteristics of these cells, their gene expression and the secretome's composition, thus affecting ASC paracrine effects and clinical potential. This study aims to investigate the feasibility of exploiting 3D culturing as a tool to improve ASC secretome therapeutic efficacy. METHODS ASCs were cultured in monolayers via conventional two-dimensional (2D) methods or induced to form 3D spheroids by seeding them on 96-well ultra-low attachment (ULA) plates. The phenotypical characterization of 3D-ASCs was performed through immunofluorescence analyses. The composition and angiogenic potential of 3D-ASC-derived secretome was assessed by means of protein array and functional tube formation assay, respectively. We analyzed the expression profile of 92 angiogenesis-related genes in 2D versus 3D cultures through a qRT-PCR array, and GO term enrichment analysis followed by network analysis was applied to identify the top hub genes. The expression of specific angiomiRs in 3D-ASCs and their secretome was assessed by qRT-PCR. The role of miR-145-5p was investigated through transfection with specific mimics/anti-miR. RESULTS 3D-ASCs showed increased stemness, cell-cell and cell-ECM interactions with respect to 2D-cultured cells. 3D culturing increased the secretion of cytokines involved in the promotion of angiogenesis, resulting in improved angiogenic effects on HUVEC cells. Mechanistically, qRT-PCR array data indicated downregulation of angiopoietin-2 (ANGPT2) as a key factor in the 3D-ASC-secretome-induced angiogenesis. In addition, ANGPT2 was recognized as a predicted target of miR-145-5p, one of the angiomiRs found upregulated in 3D-ASCs. Depletion of miR-145-5p significantly altered ASC secretome angiogenic potential and ANGPT2 expression on HUVEC cells. CONCLUSIONS All these findings corroborate our hypothesis that 3D culturing is able to positively modulate ASC gene expression and secretome composition in terms of pro-angiogenic potential. Indeed, our study contributes to shed light on the role of the miR-145-5p/ANGPT2 axis in this process, opening the way to innovative potentiation strategies to implement secretome-based therapies, with broad clinical applications.
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Affiliation(s)
- G Gerini
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - E Mari
- Department of Life Science, Health and Health Professions, Link Campus University, Via del Casale di San Pio V 44, 00165, Rome, Italy
| | - P Pontecorvi
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - S Camero
- Department of Life Science, Health and Health Professions, Link Campus University, Via del Casale di San Pio V 44, 00165, Rome, Italy
| | - E Romano
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - D Ranieri
- Department of Life Science, Health and Health Professions, Link Campus University, Via del Casale di San Pio V 44, 00165, Rome, Italy
| | - F Megiorni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - P Fioramonti
- Unit of Plastic Surgery "P. Valdoni", Department of Surgery "P. Valdoni", Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - A Angeloni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - C Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - S Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
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Tuo Y, Ye Y. Sterile Alpha Motif Domain-Containing 5 Suppresses Malignant Phenotypes and Tumor Growth in Breast Cancer: Regulation of Polo-Like Kinase 1 and c-Myc Signaling in a Xenograft Model. Cureus 2024; 16:e73259. [PMID: 39524172 PMCID: PMC11550111 DOI: 10.7759/cureus.73259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
Background Breast cancer, particularly the triple-negative breast cancer (TNBC) subtype, remains a significant clinical challenge due to its resistance to standard chemotherapy and high recurrence rate. In this study, we explored the role of Sterile Alpha Motif Domain-Containing 5 (SAMD5) as a potential regulatory partner with the c-Myc oncogenic signaling pathway in breast cancer. Materials and methods Functional assays were conducted to investigate the effects of SAMD5 overexpression on cell viability, colony formation, and invasive behavior in TNBC cell lines. This study further assessed the expression levels of proliferation and invasion markers, including Ki67 (a marker for cell proliferation), Matrix Metalloproteinase-2 (MMP2), and Matrix Metalloproteinase-9 (MMP9). Mechanistic analyses identified a negative correlation between SAMD5 and Polo-like Kinase 1 (PLK1), a gene frequently overexpressed in breast cancer, particularly in TNBC. The effects of PLK1 knockdown on cell viability, colony formation, and invasion were observed, along with the impact of PLK1 overexpression on SAMD5's inhibitory activity. In vivo studies were performed using a xenograft tumor model in nude mice to evaluate the impact of SAMD5 overexpression on tumor weight and volume. Results SAMD5 overexpression significantly reduced cell viability, colony formation, and invasion in TNBC cells, and downregulated key proteins in the c-Myc signaling pathway, including c-Myc itself, β-catenin, Cyclin-Dependent Kinase 4 (CDK4), Cyclin-Dependent Kinase 6 (CDK6), and Cyclin D1. PLK1 overexpression was found to counteract SAMD5's inhibitory effects. In vivo experiments demonstrated that SAMD5 overexpression led to a marked reduction in tumor weight and volume, effects that were partially reversed by PLK1 overexpression. Conclusions SAMD5 acts as a tumor suppressor in breast cancer, particularly in TNBC, by inhibiting critical cellular processes and downregulating the c-Myc signaling pathway. This effect appears to be mediated, in part, through its negative association with PLK1. Targeting the SAMD5/PLK1 axis offers a promising therapeutic strategy for addressing aggressive breast cancers.
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Affiliation(s)
- YouLin Tuo
- Department of Breast Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, CHN
| | - YiFeng Ye
- Department of Breast Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, CHN
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Huang H, Peng B, Chen Q, Wang Y, Li R. Long Non-Coding RNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) Facilitates Foam Cell Formation and Atherosclerosis Progression Through the miR-17-5p/Itchy E3 Ubiquitin Protein Ligase (ITCH)/Liver Kinase B1 (LKB1) Axis. Circ J 2024; 88:1697-1708. [PMID: 38631864 DOI: 10.1253/circj.cj-23-0769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2024]
Abstract
BACKGROUND Foam cell formation is an important step for atherosclerosis (AS) progression. We investigated the mechanism by which the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) regulates foam cell formation during AS progression. METHODS AND RESULTS An in vivo AS model was created by feeding ApoE-/-mice a high-fat diet. Oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages were used as a cellular AS model. Interactions between NEAT1, miR-17-5p, itchy E3 ubiquitin protein ligase (ITCH) and liver kinase B1 (LKB1) were analyzed. NEAT1 and ITCH were highly expressed in clinical samples collected from 10 AS patients and in ox-LDL-treated macrophages, whereas expression of both miR-17-5p and LKB1 was low. ITCH knockdown inhibited ox-LDL-induced lipid accumulation and LDL uptake in macrophages. Mechanistically speakingly, ITCH promoted LDL uptake and lipid accumulation in macrophages by mediating LKB1 ubiquitination degradation. NEAT1 knockdown reduced LDL uptake and lipid accumulation in macrophages and AS progression in vivo. NEAT1 promoted ITCH expression in macrophages by acting as a sponge for miR-17-5p. Inhibition of miR-17-5p facilitated ox-LDL-induced increase in LDL uptake and lipid accumulation in macrophages, which was reversed by NEAT1/ITCH knockdown. CONCLUSIONS NEAT1 accelerated foam cell formation during AS progression through the miR-17-5p/ITCH/LKB1 axis.
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Affiliation(s)
- Haifen Huang
- Health Management Center, The First People's Hospital of Chenzhou
| | - Bin Peng
- Department of Cardiovascular Medicine, The First People's Hospital of Chenzhou
| | - Qingyong Chen
- Department of Cardiovascular Medicine, The First People's Hospital of Chenzhou
| | - Yi Wang
- Department of Cardiovascular Medicine, The First People's Hospital of Chenzhou
| | - Ren Li
- Department of Cardiovascular Medicine, The First People's Hospital of Chenzhou
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Al-Hawary SIS, Abdalkareem Jasim S, Altalbawy FMA, Kumar A, Kaur H, Pramanik A, Jawad MA, Alsaad SB, Mohmmed KH, Zwamel AH. miRNAs in radiotherapy resistance of cancer; a comprehensive review. Cell Biochem Biophys 2024; 82:1665-1679. [PMID: 38805114 DOI: 10.1007/s12013-024-01329-2] [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] [Accepted: 05/18/2024] [Indexed: 05/29/2024]
Abstract
While intensity-modulated radiation therapy-based comprehensive therapy increases outcomes, cancer patients still have a low five-year survival rate and a high recurrence rate. The primary factor contributing to cancer patients' poor prognoses is radiation resistance. A class of endogenous non-coding RNAs, known as microRNAs (miRNAs), controls various biological processes in eukaryotes. These miRNAs influence tumor cell growth, death, migration, invasion, and metastasis, which controls how human carcinoma develops and spreads. The correlation between the unbalanced expression of miRNAs and the prognosis and sensitivity to radiation therapy is well-established. MiRNAs have a significant impact on the regulation of DNA repair, the epithelial-to-mesenchymal transition (EMT), and stemness in the tumor radiation response. But because radio resistance is a complicated phenomena, further research is required to fully comprehend these mechanisms. Radiation response rates vary depending on the modality used, which includes the method of delivery, radiation dosage, tumor stage and grade, confounding medical co-morbidities, and intrinsic tumor microenvironment. Here, we summarize the possible mechanisms through which miRNAs contribute to human tumors' resistance to radiation.
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Affiliation(s)
| | | | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Divison of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | | | - Salim Basim Alsaad
- Department of Pharmaceutics, Al-Hadi University College, Baghdad, 10011, 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
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Gan L, Zheng L, Zou J, Luo P, Chen T, Zou J, Li W, Chen Q, Cheng L, Zhang F, Qian B. MicroRNA-21 in urologic cancers: from molecular mechanisms to clinical implications. Front Cell Dev Biol 2024; 12:1437951. [PMID: 39114567 PMCID: PMC11304453 DOI: 10.3389/fcell.2024.1437951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/15/2024] [Indexed: 08/10/2024] Open
Abstract
The three most common kinds of urologic malignancies are prostate, bladder, and kidney cancer, which typically cause substantial morbidity and mortality. Early detection and effective treatment are essential due to their high fatality rates. As a result, there is an urgent need for innovative research to improve the clinical management of patients with urologic cancers. A type of small noncoding RNAs of 22 nucleotides, microRNAs (miRNAs) are well-known for their important roles in a variety of developmental processes. Among these, microRNA-21 (miR-21) stands out as a commonly studied miRNA with implications in tumorigenesis and cancer development, particularly in urological tumors. Recent research has shed light on the dysregulation of miR-21 in urological tumors, offering insights into its potential as a prognostic, diagnostic, and therapeutic tool. This review delves into the pathogenesis of miR-21 in prostate, bladder, and renal cancers, its utility as a cancer biomarker, and the therapeutic possibilities of targeting miR-21.
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Affiliation(s)
- Lifeng Gan
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Liying Zheng
- Department of Graduate, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junrong Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Peiyue Luo
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Tao Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Jun Zou
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Wei Li
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Qi Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Le Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Fangtao Zhang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Biao Qian
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
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Ghasemi N, Azizi H. Exploring Myc puzzle: Insights into cancer, stem cell biology, and PPI networks. Gene 2024; 916:148447. [PMID: 38583818 DOI: 10.1016/j.gene.2024.148447] [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: 10/05/2023] [Revised: 03/13/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024]
Abstract
"The grand orchestrator," "Universal Amplifier," "double-edged sword," and "Undruggable" are just some of the Myc oncogene so-called names. It has been around 40 years since the discovery of the Myc, and it remains in the mainstream of cancer treatment drugs. Myc is part of basic helix-loop-helix leucine zipper (bHLH-LZ) superfamily proteins, and its dysregulation can be seen in many malignant human tumors. It dysregulates critical pathways in cells that are connected to each other, such as proliferation, growth, cell cycle, and cell adhesion, impacts miRNAs action, intercellular metabolism, DNA replication, differentiation, microenvironment regulation, angiogenesis, and metastasis. Myc, surprisingly, is used in stem cell research too. Its family includes three members, MYC, MYCN, and MYCL, and each dysfunction was observed in different cancer types. This review aims to introduce Myc and its function in the body. Besides, Myc deregulatory mechanisms in cancer cells, their intricate aspects will be discussed. We will look at promising drugs and Myc-based therapies. Finally, Myc and its role in stemness, Myc pathways based on PPI network analysis, and future insights will be explained.
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Affiliation(s)
- Nima Ghasemi
- Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
| | - Hossein Azizi
- Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran.
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Sultana P, Novotny J. Clusterin: a double-edged sword in cancer and neurological disorders. EXCLI JOURNAL 2024; 23:912-936. [PMID: 39253532 PMCID: PMC11382300 DOI: 10.17179/excli2024-7369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 06/26/2024] [Indexed: 09/11/2024]
Abstract
Clusterin is a ubiquitously expressed glycoprotein that is involved in a whole range of biological processes. This protein is known to promote tumor survival and resistance to therapy in cancer, which contrasts sharply with its neuroprotective functions in various neurological diseases. This duality has led to recent investigations into the potential therapeutic applications of clusterin inhibition, particularly in cancer treatment. Inhibition of clusterin has been shown to be able to induce cancer cell senescence, suppress their growth and increase their sensitivity to therapy. The involvement of clusterin in the aging process makes its biological effects even more complex and offers a broad perspective for research and therapeutic exploration of various pathological conditions. This review critically examines the multiple functions of clusterin in cancer and neurological disorders and addresses the controversies surrounding its role in these areas. The assessment includes an in-depth analysis of the existing literature and examining the relationship of clusterin to fundamental aspects of cancer progression, including cell proliferation, apoptosis, metastasis, and drug resistance. In addition, the review addresses the neurobiological implications of clusterin and examines its controversial role in neuroprotection, neurodegeneration, and synaptic plasticity. Attention is also paid to the epigenetic regulation of clusterin expression. By clarifying conflicting findings and discrepancies in the literature, this review aims to provide a nuanced understanding of the molecular mechanisms underlying clusterin functions and its potential clinical implications in both cancer and neurodisorders. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Pinky Sultana
- Department of Physiology, Faculty of Science, Charles University, Prague 128 00, Czechia
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague 142 20, Czechia
| | - Jiri Novotny
- Department of Physiology, Faculty of Science, Charles University, Prague 128 00, Czechia
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10
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Hushmandi K, Saadat SH, Raei M, Daneshi S, Aref AR, Nabavi N, Taheriazam A, Hashemi M. Implications of c-Myc in the pathogenesis and treatment efficacy of urological cancers. Pathol Res Pract 2024; 259:155381. [PMID: 38833803 DOI: 10.1016/j.prp.2024.155381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/08/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024]
Abstract
Urological cancers, including prostate, bladder, and renal cancers, are significant causes of death and negatively impact the quality of life for patients. The development and progression of these cancers are linked to the dysregulation of molecular pathways. c-Myc, recognized as an oncogene, exhibits abnormal levels in various types of tumors, and current evidence supports the therapeutic targeting of c-Myc in cancer treatment. This review aims to elucidate the role of c-Myc in driving the progression of urological cancers. c-Myc functions to enhance tumorigenesis and has been documented to increase growth and metastasis in prostate, bladder, and renal cancers. Furthermore, the dysregulation of c-Myc can result in a diminished response to therapy in these cancers. Non-coding RNAs, β-catenin, and XIAP are among the regulators of c-Myc in urological cancers. Targeting and suppressing c-Myc therapeutically for the treatment of these cancers has been explored. Additionally, the expression level of c-Myc may serve as a prognostic factor in clinical settings.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health,School of Health,Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Amir Reza Aref
- Department of Translational Sciences, Xsphera Biosciences Inc. Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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11
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Chai R, Zhou C, Hu Z, Hu J. Diagnostic predictability of serum miR-4793-3p and miR-1180-3p expression in community-acquired pneumonia. Biomark Med 2024; 18:231-241. [PMID: 38456294 PMCID: PMC11216277 DOI: 10.2217/bmm-2023-0463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 12/07/2023] [Indexed: 03/09/2024] Open
Abstract
Background: Early identification of community-acquired pneumonia (CAP) is crucial to prevent severe progression. Methods: The authors enrolled 150 hospitalized CAP patients and collected clinicopathologic features and blood indicators. Plasma miRNA profiling was conducted using microarray detection, and selected miRNAs were tested with reverse transcription quantitative PCR. Predictive models were built using least shrinkage and selection operator regression. Results: Least shrinkage and selection operator regression identified two miRNAs (miR-4793-3p and miR-1180-3p) that distinguished mild from severe CAP patients (area under the curve = 0.948). The miRNA model outperformed D-dimer, platelet and procalcitonin (max area under the curve = 0.729). Conclusion: Increased levels of miR-4793-3p and miR-1180-3p may indicate severe pneumonia development. Plasma miRNA profiling enables early prediction of severe CAP, aiding therapeutic decisions.
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Affiliation(s)
- Rong Chai
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, Navy Military Medical University, No. 168 Changhai RD, Yangpu District, Shanghai, P.R. China
| | - Cihang Zhou
- Department of General Practice Teaching & Research Office, Changhai Hospital, Navy Military Medical University, No. 168 Changhai RD, Yangpu District, Shanghai, P.R. China
| | - Zhenli Hu
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, Navy Military Medical University, No. 168 Changhai RD, Yangpu District, Shanghai, P.R. China
| | - Jingjing Hu
- Department of Clinical Laboratory, Changhai Hospital, Navy Military Medical University, No. 168 Changhai RD, Yangpu District, Shanghai, P.R. China
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12
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Ozler S, Kebapcilar A, Ozdemir EM, Mert M, Arıkan MN, Celik C. Are Vascular Endothelium and Angiogenesis Effective MicroRNA Biomarkers Associated with the Prediction of Early-Onset Preeclampsia (EOPE) and Adverse Perinatal Outcomes? Reprod Sci 2024; 31:803-810. [PMID: 37848644 DOI: 10.1007/s43032-023-01367-w] [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: 05/14/2023] [Accepted: 09/20/2023] [Indexed: 10/19/2023]
Abstract
MicroRNA is associated with angiogenesis, invasion, proliferation, and vascular endothelial remodeling of various diseases. We aimed to investigate serum MicroRNA (miRNA) levels in preeclampsia (PE) and to determine whether any changes in miRNA levels are useful in predicting early onset preeclampsia (EOPE) and adverse perinatal outcomes. A total of 89 pregnant patients were enrolled in this prospective case-control study (55 PE and 34 healthy controls). miR-17, miR-20a, miR-20b, miR126, miR155, miR-200, miR-222, and miR-210 levels were studied in maternal serum in preeclamptic pregnant women. Multiple logistic regression analyses analyzed the risk factors which are associated with EOPE and adverse maternal outcomes. The Real-time RT-PCR method was used to determine maternal serum miRNA levels. Serum miR-17, miR-20a, miR-20b, miR126, and miR-210 levels were significantly higher in PE than the control group (p < .001, p < .001, p < .001, p < .001 and p = .047 respectively). Increased miR-17, miR-20a, and miR-20b levels were independently associated with PE (OR: 0.642, 95%Cl: 0.486-0.846, p = .002; OR: 0.899, 95%Cl: 0.811-0.996, p = .042 and OR: 0.817, 95%Cl: 0.689-0.970, p = .021). Increased miR-17 and miR-126 levels were negatively correlated with serum EOPE in PE (r = -.313, p = .020), and increased miR-210 levels were significantly positively correlated with EOPE in PE (r = .285, p = .005). Increased expression of serum miR-17, miR-20a, miR-20b, miR126, and miR-210 were found to be associated with PE, also increased expression of miR-17, miR-20a, and miR-20b were to be predicted with PE, also increased maternal serum miR-17 and miR-126 expressions were negatively correlated and increased miR-210 expression was positively correlated with EOPE in PE women.
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Affiliation(s)
- Sibel Ozler
- Department of Perinatology, KTO Karatay University Faculty of Medicine, Konya, Turkey.
| | - Aysegul Kebapcilar
- Obstetrics and Gynecology, Selcuk University Faculty of Medicine, Konya, Turkey
| | | | - Muhammed Mert
- Obstetrics and Gynecology, Health Ministry Of Turkish Republic, Dr. Ali Kemal Belviranlı Obstetrıcs And Gynecology Hospıtal, Konya, Turkey
| | | | - Cetin Celik
- Obstetrics and Gynecology, Selcuk University Faculty of Medicine, Konya, Turkey
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13
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Al-Nakhle HH. Unraveling the Multifaceted Role of the miR-17-92 Cluster in Colorectal Cancer: From Mechanisms to Biomarker Potential. Curr Issues Mol Biol 2024; 46:1832-1850. [PMID: 38534736 DOI: 10.3390/cimb46030120] [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: 01/20/2024] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease driven by intricate mechanisms, making it challenging to understand and manage. The miR-17-92 cluster has gained significant attention in CRC research due to its diverse functions and crucial role in various aspects of the disease. This cluster, consisting of multiple individual miRNAs, influences critical processes like tumor initiation, angiogenesis, metastasis, and the epithelial-mesenchymal transition (EMT). Beyond its roles in tumorigenesis and progression, miR-17-92's dysregulation in CRC has substantial implications for diagnosis, prognosis, and treatment, including chemotherapy responsiveness. It also shows promise as a diagnostic and prognostic biomarker, offering insights into treatment responses and disease progression. This review provides a comprehensive overview of recent advancements and the context-dependent role of the miR-17-92 cluster in colorectal cancer, drawing from the latest high-quality published data. It summarizes the established mechanisms governing miR-17-92 expression and the molecular pathways under its influence. Furthermore, it examines instances where it functions as an oncogene or a tumor suppressor, elucidating how cellular contexts dictate its biological effects. Ultimately, miR-17-92 holds promise as a biomarker for prognosis and therapy response, as well as a potential target for cancer prevention and therapeutic interventions. In essence, this review underscores the multifaceted nature of miR-17-92 in CRC research, offering promising avenues for enhancing the management of CRC patients.
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Affiliation(s)
- Hakeemah H Al-Nakhle
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Monawarah 42353, Saudi Arabia
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14
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Rezaie M, Nasehi M, Shimia M, Ebrahimnezhad M, Yousefi B, Majidinia M. Polyphenols Modulate the miRNAs Expression that Involved in Glioblastoma. Mini Rev Med Chem 2024; 24:1953-1969. [PMID: 38639278 DOI: 10.2174/0113895575304605240408105201] [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: 01/15/2024] [Revised: 03/11/2024] [Accepted: 03/16/2024] [Indexed: 04/20/2024]
Abstract
Glioblastoma multiforme (GBM), a solid tumor that develops from astrocytes, is one of the most aggressive types of brain cancer. While there have been improvements in the efficacy of treating GBM, many problems remain, especially with traditional therapy methods. Therefore, recent studies have extensively focused on developing novel therapeutic agents for combating glioblastoma. Natural polyphenols have been studied for their potential as chemopreventive and chemotherapeutic agents due to their wide range of positive qualities, including antioxidant, antiinflammatory, cytotoxic, antineoplastic, and immunomodulatory activities. These natural compounds have been suggested to act via modulated various macromolecules within cells, including microRNAs (miRNAs), which play a crucial role in the molecular milieu. In this article, we focus on how polyphenols may inhibit tumor growth by influencing the expression of key miRNAs that regulate oncogenes and tumor suppressor genes.
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Affiliation(s)
- Maede Rezaie
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Nasehi
- Cognitive and Neuroscience Research Center, Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Shimia
- Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohamad Ebrahimnezhad
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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15
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Cao Y, Zheng M, Sewani MA, Wang J. The miR-17-92 cluster in cardiac health and disease. Birth Defects Res 2024; 116:e2273. [PMID: 37984445 PMCID: PMC11418803 DOI: 10.1002/bdr2.2273] [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: 07/01/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 11/22/2023]
Abstract
MicroRNAs (miRs) are small noncoding RNAs that play important roles in both physiological and pathological processes through post-transcriptional regulation. The miR-17-92 cluster includes six individual members: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1. The miR-17-92 cluster has been extensively studied and reported to broadly function in cancer biology, immunology, neurology, pulmonology, and cardiology. This review focuses on its roles in heart development and cardiac diseases. We briefly introduce the nature of the miR-17-92 cluster and its crucial roles in both normal development and the pathogenesis of various diseases. We summarize the recent progress in understanding the versatile roles of miR-17-92 during cardiac development, regeneration, and aging. Additionally, we highlight the indispensable roles of the miR-17-92 cluster in pathogenesis and therapeutic potential in cardiac birth defects and adult cardiac diseases.
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Affiliation(s)
- Yuhan Cao
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Mingjie Zheng
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Maham A Sewani
- Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston, TX 77030, USA
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA
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16
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Thapa K, Khan H, Kaur G, Kumar P, Singh TG. Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development. Biochem Biophys Res Commun 2023; 687:149130. [PMID: 37944468 DOI: 10.1016/j.bbrc.2023.149130] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/12/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
The formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies.
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Affiliation(s)
- Komal Thapa
- Chitkara School of Pharmacy, Chitkara University, 174103, Himachal Pradesh, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
| | - Gagandeep Kaur
- Chitkara School of Pharmacy, Chitkara University, 174103, Himachal Pradesh, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, 151401, Bathinda, India
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17
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Khan MM, Sharma V, Serajuddin M. Emerging role of miRNA in prostate cancer: A future era of diagnostic and therapeutics. Gene 2023; 888:147761. [PMID: 37666374 DOI: 10.1016/j.gene.2023.147761] [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: 04/12/2023] [Revised: 08/17/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
Prostate cancer (PCa) is the most common cancer in men (20%) and is responsible for 6.8% (1/5) of all cancer-related deaths in men around the world. The development and spread of prostate cancer are driven by a wide variety of genomic changes and extensive epigenetic events. Because of this, the MicroRNA (miRNA) and associated molecular mechanisms involved in PCa genesis and aggressive were only partially identified until today. The miRNAs are a newly discovered category of regulatorsthat have recently been recognized to have a significant role in regulating numerous elements of cancer mechanisms, such as proliferation, differentiation, metabolism, and apoptosis. The miRNAs are a type of small (22-24 nucleotides), non-coding, endogenous, single-stranded RNA and work as potent gene regulators. Various types of cancer, including PCa, have found evidence that miRNA genes, which are often located in cancer-related genetic regions or fragile locations, have a role in the primary steps of tumorigenesis, either as oncogenes or tumorsuppressors. To explain the link between miRNAs and their function in the initiation and advancement of PCa, we conducted a preliminary assessment. The purpose of this research was to enhance our understanding of the connection between miRNA expression profiles and PCa by elucidating the fundamental processes of miRNA expression and the target genes.
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Affiliation(s)
- Mohd Mabood Khan
- Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India.
| | - Vineeta Sharma
- Department of Medicine, Vanderbilt University Medical Center, Nashville 37232, TN, USA
| | - Mohammad Serajuddin
- Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
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18
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Albaradei S, Alganmi N, Albaradie A, Alharbi E, Motwalli O, Thafar MA, Gojobori T, Essack M, Gao X. A deep learning model predicts the presence of diverse cancer types using circulating tumor cells. Sci Rep 2023; 13:21114. [PMID: 38036622 PMCID: PMC10689793 DOI: 10.1038/s41598-023-47805-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/18/2023] [Indexed: 12/02/2023] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and intravasate into the bloodstream. Thus, non-invasive liquid biopsies are being used to analyze CTC-expressed genes to identify potential cancer biomarkers. In this regard, several studies have used gene expression changes in blood to predict the presence of CTC and, consequently, cancer. However, the CTC mRNA data has not been used to develop a generic approach that indicates the presence of multiple cancer types. In this study, we developed such a generic approach. Briefly, we designed two computational workflows, one using the raw mRNA data and deep learning (DL) and the other exploiting five hub gene ranking algorithms (Degree, Maximum Neighborhood Component, Betweenness Centrality, Closeness Centrality, and Stress Centrality) with machine learning (ML). Both workflows aim to determine the top genes that best distinguish cancer types based on the CTC mRNA data. We demonstrate that our automated, robust DL framework (DNNraw) more accurately indicates the presence of multiple cancer types using the CTC gene expression data than multiple ML approaches. The DL approach achieved average precision of 0.9652, recall of 0.9640, f1-score of 0.9638 and overall accuracy of 0.9640. Furthermore, since we designed multiple approaches, we also provide a bioinformatics analysis of the gene commonly identified as top-ranked by the different methods. To our knowledge, this is the first study wherein a generic approach has been developed to predict the presence of multiple cancer types using raw CTC mRNA data, as opposed to other models that require a feature selection step.
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Affiliation(s)
- Somayah Albaradei
- Computer Science Department, Faculty of Computing and Information Technology, King Abdulaziz University, 80200, Jeddah, Saudi Arabia
| | - Nofe Alganmi
- Computer Science Department, Faculty of Computing and Information Technology, King Abdulaziz University, 80200, Jeddah, Saudi Arabia
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | | | - Eaman Alharbi
- Computer Science Department, Faculty of Computing and Information Technology, King Abdulaziz University, 80200, Jeddah, Saudi Arabia
| | - Olaa Motwalli
- College of Computing and Informatics, Saudi Electronic University (SEU), Madinah, Saudi Arabia
| | - Maha A Thafar
- College of Computers and Information Technology, Taif University, Taif, Saudi Arabia
| | - Takashi Gojobori
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Magbubah Essack
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
| | - Xin Gao
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
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19
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Nour SM, Abbasi N, Sadi S, Ravan N, Alipourian A, Yarizadeh M, Soofi A, Ataei A, Tehrany PM. miRNAs as key modulators between normal cells and tumor microenvironment interactions. Chem Biol Drug Des 2023; 102:939-950. [PMID: 37402595 DOI: 10.1111/cbdd.14285] [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: 02/09/2023] [Revised: 06/08/2023] [Accepted: 06/12/2023] [Indexed: 07/06/2023]
Abstract
The tumor microenvironment (TME) is well-defined target for understanding tumor progression and various cell types. Major elements of the tumor microenvironment are the followings: endothelial cells, fibroblasts, signaling molecules, extracellular matrix, and infiltrating immune cells. MicroRNAs (miRNAs) are a group of small noncoding RNAs with major functions in the gene expression regulation at post-transcriptional level that have also appeared to exerts key functions in the cancer initiation/progression in diverse biological processes and the tumor microenvironment. This study summarized various roles of miRNAs in the complex interactions between the tumor and normal cells in their microenvironment.
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Affiliation(s)
| | - Nadia Abbasi
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sima Sadi
- Medical Doctor, Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Navid Ravan
- Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Alipourian
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahsa Yarizadeh
- Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Asma Soofi
- Department of Physical Chemistry, School of Chemistry, College of Sciences, University of Tehran, Tehran, Iran
| | - Ali Ataei
- School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Pooya M Tehrany
- Faculty of Medicine, National University of Malaysia, Bani, Malaysia
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20
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Farzaei MH, Ramezani-Aliakbari F, Ramezani-Aliakbari M, Zarei M, Komaki A, Shahidi S, Sarihi A, Salehi I. Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1633-1646. [PMID: 36971866 DOI: 10.1007/s00210-023-02469-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/19/2023] [Indexed: 03/29/2023]
Abstract
Ischemia/reperfusion (I/R) injury is a tissue damage during reperfusion after an ischemic condition. I/R injury is induced by pathological cases including stroke, myocardial infarction, circulatory arrest, sickle cell disease, acute kidney injury, trauma, and sleep apnea. It can lead to increased morbidity and mortality in the context of these processes. Mitochondrial dysfunction is one of the hallmarks of I/R insult, which is induced via reactive oxygen species (ROS) production, apoptosis, and autophagy. MicroRNAs (miRNAs, miRs) are non-coding RNAs that play a main regulatory role in gene expression. Recently, there are evidence, which miRNAs are the major modulators of cardiovascular diseases, especially myocardial I/R injury. Cardiovascular miRNAs, specifically miR-21, and probably miR-24 and miR-126 have protective effects on myocardial I/R injury. Trimetazidine (TMZ) is a new class of metabolic agents with an anti-ischemic activity. It has beneficial effects on chronic stable angina by suppressing mitochondrial permeability transition pore (mPTP) opening. The present review study addressed the different mechanistic effects of TMZ on cardiac I/R injury. Online databases including Scopus, PubMed, Web of Science, and Cochrane library were assessed for published studies between 1986 and 2021. TMZ, an antioxidant and metabolic agent, prevents the cardiac reperfusion injury by regulating AMP-activated protein kinase (AMPK), cystathionine-γ-lyase enzyme (CSE)/hydrogen sulfide (H2S), and miR-21. Therefore, TMZ protects the heart against I/R injury by inducing key regulators such as AMPK, CSE/H2S, and miR-21.
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Affiliation(s)
- Mohammad Hosein Farzaei
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Maryam Ramezani-Aliakbari
- Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Zarei
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Siamak Shahidi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Abdolrahman Sarihi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Salehi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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21
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Carena MC, Badi I, Polkinghorne M, Akoumianakis I, Psarros C, Wahome E, Kotanidis CP, Akawi N, Antonopoulos AS, Chauhan J, Sayeed R, Krasopoulos G, Srivastava V, Farid S, Walcot N, Douglas G, Channon KM, Casadei B, Antoniades C. Role of Human Epicardial Adipose Tissue-Derived miR-92a-3p in Myocardial Redox State. J Am Coll Cardiol 2023; 82:317-332. [PMID: 37468187 PMCID: PMC10368522 DOI: 10.1016/j.jacc.2023.05.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 05/08/2023] [Accepted: 05/09/2023] [Indexed: 07/21/2023]
Abstract
BACKGROUND Visceral obesity is directly linked to increased cardiovascular risk, including heart failure. OBJECTIVES This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes. METHODS This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years. RESULTS EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase-derived superoxide (O2.-) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events. CONCLUSIONS EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.
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Affiliation(s)
- Maria Cristina Carena
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Ileana Badi
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Murray Polkinghorne
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Ioannis Akoumianakis
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Costas Psarros
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Elizabeth Wahome
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Christos P Kotanidis
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Nadia Akawi
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Alexios S Antonopoulos
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Jagat Chauhan
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rana Sayeed
- Cardiothoracic Surgery Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - George Krasopoulos
- Cardiothoracic Surgery Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Vivek Srivastava
- Cardiothoracic Surgery Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Shakil Farid
- Cardiothoracic Surgery Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Nicholas Walcot
- Cardiothoracic Surgery Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Gillian Douglas
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Keith M Channon
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Acute Multidisciplinary Imaging and Interventional Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Barbara Casadei
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Charalambos Antoniades
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Acute Multidisciplinary Imaging and Interventional Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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22
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Shen Y, Xu M, Ren L, Li X, Han X, Cao X, Yao J, Yan B. A novel retinoic acid drug, EYE-502, inhibits choroidal neovascularization by targeting endothelial cells and pericytes. Sci Rep 2023; 13:10439. [PMID: 37369771 DOI: 10.1038/s41598-023-37619-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/24/2023] [Indexed: 06/29/2023] Open
Abstract
Choroidal neovascularization (CNV) occurs in neovascular age-related macular degeneration (AMD) and often leads to permanent visual impairment. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is the gold standard for the treatment of CNV. However, anti-VEGF treatment did not always cause vision improvement and sometimes had detrimental effects on normal retinal tissues. Herein, we identified a novel retinoic acid drug, EYE-502, which had great therapeutic effects on CNV. Administration of EYE-502 could inhibit VEGF-induced dysfunction of endothelial cells (ECs) and reduce platelet-derived growth factor (PDGF)-induced recruitment of pericytes to ECs in vitro. Administration of EYE-502 could reduce the area of choroidal sprouting and laser-induced CNV, exhibiting similar anti-angiogenic effects as aflibercept. Moreover, administration of EYE-502 could reduce pericyte coverage in the sprouting vessels and choroidal neovascularization. Mechanistically, EYE-502 primarily bound to retinoic acid receptors (RARs) and exerted the anti-angiogenic effects by targeting ECs and pericytes via affecting the activation of Wnt/β-catenin and PDGF/PDGFR/PI3K/Akt signaling. Taken together, this study reports a novel retinoic acid drug, EYE-502, which can exert the anti-angiogenic effects by simultaneous targeting of ECs and pericytes.
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Affiliation(s)
- Yaming Shen
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Miao Xu
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Ling Ren
- Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiumiao Li
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaoyan Han
- Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xin Cao
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jin Yao
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
| | - Biao Yan
- Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
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23
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Stainthorp AK, Lin CC, Wang D, Medhi R, Ahmed Z, Suen KM, Miska EA, Whitehouse A, Ladbury JE. Regulation of microRNA expression by the adaptor protein GRB2. Sci Rep 2023; 13:9784. [PMID: 37328606 PMCID: PMC10276003 DOI: 10.1038/s41598-023-36996-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/14/2023] [Indexed: 06/18/2023] Open
Abstract
Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.
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Affiliation(s)
- Amy K Stainthorp
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Chi-Chuan Lin
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Dapeng Wang
- LeedsOmics, University of Leeds, Leeds, LS2 9JT, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
- National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK
| | - Ragini Medhi
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Zamal Ahmed
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kin Man Suen
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Eric A Miska
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - John E Ladbury
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
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24
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Orozco-García E, van Meurs DJ, Calderón JC, Narvaez-Sanchez R, Harmsen MC. Endothelial plasticity across PTEN and Hippo pathways: A complex hormetic rheostat modulated by extracellular vesicles. Transl Oncol 2023; 31:101633. [PMID: 36905871 PMCID: PMC10020115 DOI: 10.1016/j.tranon.2023.101633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/20/2022] [Accepted: 01/25/2023] [Indexed: 03/11/2023] Open
Abstract
Vascularization is a multifactorial and spatiotemporally regulated process, essential for cell and tissue survival. Vascular alterations have repercussions on the development and progression of diseases such as cancer, cardiovascular diseases, and diabetes, which are the leading causes of death worldwide. Additionally, vascularization continues to be a challenge for tissue engineering and regenerative medicine. Hence, vascularization is the center of interest for physiology, pathophysiology, and therapeutic processes. Within vascularization, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Hippo signaling have pivotal roles in the development and homeostasis of the vascular system. Their suppression is related to several pathologies, including developmental defects and cancer. Non-coding RNAs (ncRNAs) are among the regulators of PTEN and/or Hippo pathways during development and disease. The purpose of this paper is to review and discuss the mechanisms by which exosome-derived ncRNAs modulate endothelial cell plasticity during physiological and pathological angiogenesis, through the regulation of PTEN and Hippo pathways, aiming to establish new perspectives on cellular communication during tumoral and regenerative vascularization.
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Affiliation(s)
- Elizabeth Orozco-García
- Physiology and biochemistry research group - PHYSIS, Faculty of Medicine, University of Antioquia, Colombia; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands
| | - D J van Meurs
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands
| | - J C Calderón
- Physiology and biochemistry research group - PHYSIS, Faculty of Medicine, University of Antioquia, Colombia
| | - Raul Narvaez-Sanchez
- Physiology and biochemistry research group - PHYSIS, Faculty of Medicine, University of Antioquia, Colombia
| | - M C Harmsen
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands.
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25
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Yang L, Yu Q, Zhu Y, Ali Mallah M, Wang W, Feng F, Zhang Q. Core genes in lung adenocarcinoma identified by integrated bioinformatic analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2023; 33:243-257. [PMID: 34961365 DOI: 10.1080/09603123.2021.2016660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/05/2021] [Indexed: 06/14/2023]
Abstract
This study aims to identify potential core genes of lung adenocarcinoma (LUAD). Three datasets (GSE32863, GSE43458, and GSE116959) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between LUAD and normal tissues were filtrated by GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed via Metascape database. The protein-protein interaction (PPI) network was constructed and core genes were identified using STRING and Cytoscape. Core genes expressions and their relevant clinical characteristics were performed via Oncomine and UALCAN databases respectively. The correlation between core genes and immune infiltrates was investigated by TIMER database. Kaplan-Meier plotter was performed for survival analysis. The signal pathway network of core genes was mapped by KEGG Mapper analysis tool. In this study, ten core genes were significantly related to overall survival (OS) of LUAD patients, which can provide clues for prognosis of LUAD.
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Affiliation(s)
- Liu Yang
- Department of Toxicology, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
| | - Qi Yu
- Department of Toxicology, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
| | - Yonghang Zhu
- Department of Toxicology, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
| | - Manthar Ali Mallah
- Department of Toxicology, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
| | - Wei Wang
- Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
| | - Feifei Feng
- Department of Toxicology, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
| | - Qiao Zhang
- Department of Toxicology, College of Public Health, Zhengzhou University, Zhongyuan District, Zhengzhou, Henan Province, China
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26
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Yang M, Zhang Y, Li M, Liu X, Darvishi M. The various role of microRNAs in breast cancer angiogenesis, with a special focus on novel miRNA-based delivery strategies. Cancer Cell Int 2023; 23:24. [PMID: 36765409 PMCID: PMC9912632 DOI: 10.1186/s12935-022-02837-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/20/2022] [Indexed: 02/12/2023] Open
Abstract
After skin malignancy, breast cancer is the most widely recognized cancer detected in women in the United States. Breast cancer (BCa) can happen in all kinds of people, but it's much more common in women. One in four cases of cancer and one in six deaths due to cancer are related to breast cancer. Angiogenesis is an essential factor in the growth of tumors and metastases in various malignancies. An expanded level of angiogenesis is related to diminished endurance in BCa patients. This function assumes a fundamental part inside the human body, from the beginning phases of life to dangerous malignancy. Various factors, referred to as angiogenic factors, work to make a new capillary. Expanding proof demonstrates that angiogenesis is managed by microRNAs (miRNAs), which are small non-coding RNA with 19-25 nucleotides. MiRNA is a post-transcriptional regulator of gene expression that controls many critical biological processes. Endothelial miRNAs, referred to as angiomiRs, are probably concerned with tumor improvement and angiogenesis via regulation of pro-and anti-angiogenic factors. In this article, we reviewed therapeutic functions of miRNAs in BCa angiogenesis, several novel delivery carriers for miRNA-based therapeutics, as well as CRISPR/Cas9 as a targeted therapy in breast cancer.
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Affiliation(s)
- Min Yang
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Ying Zhang
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Min Li
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Xinglong Liu
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medical Sciences, Tehran, Iran
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27
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Gao FY, Li XT, Xu K, Wang RT, Guan XX. c-MYC mediates the crosstalk between breast cancer cells and tumor microenvironment. Cell Commun Signal 2023; 21:28. [PMID: 36721232 PMCID: PMC9887805 DOI: 10.1186/s12964-023-01043-1] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 01/08/2023] [Indexed: 02/01/2023] Open
Abstract
The MYC oncogenic family is dysregulated in diverse tumors which is generally linked to the poor prognosis of tumors. The members in MYC family are transcription factors which are responsible for the regulation of various genes expression. Among them, c-MYC is closely related to the progression of tumors. Furthermore, c-MYC aberrations is tightly associated with the prevalence of breast cancer. Tumor microenvironment (TME) is composed of many different types of cellular and non-cellular factors, mainly including cancer-associated fibroblasts, tumor-associated macrophages, vascular endothelial cells, myeloid-derived suppressor cells and immune cells, all of which can affect the diagnosis, prognosis, and therapeutic efficacy of breast cancer. Importantly, the biological processes occurred in TME, such as angiogenesis, immune evasion, invasion, migration, and the recruition of stromal and tumor-infiltrating cells are under the modulation of c-MYC. These findings indicated that c-MYC serves as a critical regulator of TME. Here, we aimed to summarize and review the relevant research, thus to clarify c-MYC is a key mediator between breast cancer cells and TME. Video Abstract.
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Affiliation(s)
- Fang-yan Gao
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
| | - Xin-tong Li
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
| | - Kun Xu
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
| | - Run-tian Wang
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
| | - Xiao-xiang Guan
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
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28
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Meng Q, Deng Y, Lu Y, Wu C, Tang S. Tumor-derived miRNAs as tumor microenvironment regulators for synergistic therapeutic options. J Cancer Res Clin Oncol 2023; 149:423-439. [PMID: 36378341 DOI: 10.1007/s00432-022-04432-0] [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: 09/21/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022]
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs that perform post-transcriptional gene regulation. This review focuses on the role of tumor cell-derived miRNAs in the regulation of the tumor microenvironment (TME) via receptor cell recoding, including angiogenesis, expression of immunosuppressive molecules, formation of radiation resistance, and chemoresistance. Furthermore, we discuss the potential of these molecules as adjuvant therapies in combination with chemotherapy, radiotherapy, or immunotherapy, as well as their advantages as efficacy predictors for personalized therapy. MiRNA-based therapeutic agents for tumors are currently in clinical trials, and while challenges remain, additional research on tumor-derived miRNAs is warranted, which may provide significant clinical benefits to cancer patients.
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Affiliation(s)
- Qiuxing Meng
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Yaoming Deng
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Yu Lu
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Chunfeng Wu
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Shifu Tang
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China. .,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China.
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29
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Abstract
C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells' metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not "undruggable" and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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30
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Vazifehmand R, Ali DS, Othman Z, Chau DM, Stanslas J, Shafa M, Sekawi Z. The evaluation expression of non-coding RNAs in response to HSV-G47∆ oncolytic virus infection in glioblastoma multiforme cancer stem cells. J Neurovirol 2022; 28:566-582. [PMID: 35951174 DOI: 10.1007/s13365-022-01089-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 07/11/2022] [Accepted: 07/25/2022] [Indexed: 01/13/2023]
Abstract
Glioblastoma multiforme is the most aggressive astrocytes brain tumor. Glioblastoma cancer stem cells and hypoxia conditions are well-known major obstacles in treatment. Studies have revealed that non-coding RNAs serve a critical role in glioblastoma progression, invasion, and resistance to chemo-radiotherapy. The present study examined the expression levels of microRNAs (in normoxic condition) and long non-coding RNAs (in normoxic and hypoxic conditions) in glioblastoma stem cells treated with the HSV-G47∆. The expression levels of 43 miRNAs and 8 lncRNAs isolated from U251-GBM-CSCs were analyzed using a miRCURY LNA custom PCR array and a quantitative PCR assay, respectively. The data revealed that out of 43 miRNAs that only were checked in normoxic condition, the only 8 miRNAs, including miR-7-1, miR-let-7b, miR-130a, miR-137, miR-200b, miR-221, miR-222, and miR-874, were markedly upregulated. The expression levels of lncRNAs, including LEF1 antisense RNA 1 (LEF1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein coding RNA 470 (LINC00470), tumor suppressor candidate 7 (TUSC7), HOX transcript antisense RNA (HOTAIR), nuclear paraspeckle assembly transcript 1 (NEAT1), and X inactive specific transcript (XIST), were markedly downregulated in the hypoxic microenvironment, and H19-imprinted maternally expressed transcript (H19) was not observed to be dysregulated in this environment. Under normoxic conditions, LEF1-AS1, MALAT1, LINC00470, H19, HOTAIR, NEAT1, and XIST were downregulated and TUSC7 was not targeted by HSV-G47∆. Overall, the present data shows HSVG47Δ treatment deregulates non-coding RNA expression in GBM-CSC tumor microenvironments.
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Affiliation(s)
- Reza Vazifehmand
- Department of Medical Microbiology & Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia
| | - Dhuha Saeed Ali
- Halal Products Research Institute, Universiti Putra Malaysia UPM, Serdang, Selangor, 43400, Malaysia
| | - Zulkefley Othman
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia
| | - De-Ming Chau
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia UPM, Serdang, Selangor, 43400, Malaysia
| | - Mehdi Shafa
- Cell Therapy process development, Lonza Houston Inc, Houston, TX, USA
| | - Zamberi Sekawi
- Department of Medical Microbiology & Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia.
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31
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Cui Y, Liu R, Hong Y, Wang Y, Zhu Y, Wen T, Lu J, Mao S, Wang X, Pan J, Luo Y. MicroRNA-92a-3p Regulates Retinal Angiogenesis by Targeting SGK3 in Vascular Endothelial Cells. Invest Ophthalmol Vis Sci 2022; 63:19. [PMID: 36269185 PMCID: PMC9617502 DOI: 10.1167/iovs.63.11.19] [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] [Indexed: 02/05/2023] Open
Abstract
Purpose The purpose of this study was to investigate the effects and mechanism of microRNA (miR)-92a-3p in retinal angiogenesis in vitro and in vivo. Methods The expression of miR-92a-3p was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Agomir-92a-3p was intravitreally injected into the right eye on postnatal day 3 (P3), P5, and P8 in the mice, with the agomir-NC injected left eye as the control. At P7, P9, and P12, immunofluorescence was performed to examine the retinal superficial vascular plexus, deep vascular plexus, proliferation, and apoptosis in retinal vascular endothelial cells (ECs). Human retinal microvascular endothelial cells (HRMECs) were treated with mimic-NC and mimic-92a-3p, then the tube formation, cell migration, and wound healing assays were used to detect the effect of miR-92a-3p on retinal angiogenesis in vitro. Agomir-92a-3p was also intravitreally injected into the right eye of oxygen-induced retinopathy (OIR) mice at P12, with the agomir-NC injected left eye as the control, the neovascularization was observed by retinal flatmount staining with isolectin B4 at P17. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of miR-92a-3p. RT-qPCR and Western blot were carried out to detect the expression of SGK3, p-GSK3β, GSK3β, Bcl-xL, and cleaved caspase-3 in the HRMECs and mouse retinas. Results The overexpression of miR-92a-3p inhibited the development of retinal superficial vascular plexus and deep vascular plexus, decreased the expression of Ki67, and increased the expression of cleaved caspase-3 in isolectin B4-labeled retinal vascular ECs. In vitro, the overexpression of miR-92a-3p markedly suppressed the tube formation, cell migration, and wound healing of cultured ECs. Overexpression of miR-92a-3p inhibited both in vivo and in vitro physiological angiogenesis by downregulating the expression of SGK3, p-GSK3β/GSK3β, and Bcl-xL. In addition, agomir-92a-3p inhibited the pathological retinal neovascularization of OIR mice, by targeting SGK3, p-GSK3β/GSK3β, and Bcl-xL. Conclusions The miR-92a-3p could affect retinal angiogenesis by targeting SGK3 pathway, suggesting that miR-92a-3p may be a potential anti-angiogenic factor for retinal vascular disease.
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Affiliation(s)
- Yamei Cui
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ruyuan Liu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yiwen Hong
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yishen Wang
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yanjie Zhu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tao Wen
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jing Lu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shudi Mao
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiao Wang
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianying Pan
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan Luo
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
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Liu Y, Munsayac A, Hall I, Keane SC. Solution Structure of NPSL2, A Regulatory Element in the oncomiR-1 RNA. J Mol Biol 2022; 434:167688. [PMID: 35717998 PMCID: PMC9474619 DOI: 10.1016/j.jmb.2022.167688] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 12/22/2022]
Abstract
The miR-17 ∼ 92a polycistron, also known as oncomiR-1, is commonly overexpressed in multiple cancers and has several oncogenic properties. OncomiR-1 encodes six constituent microRNAs (miRs), each enzymatically processed with different efficiencies. However, the structural mechanism that regulates this differential processing remains unclear. Chemical probing of oncomiR-1 revealed that the Drosha cleavage sites of pri-miR-92a are sequestered in a four-way junction. NPSL2, an independent stem loop element, is positioned just upstream of pri-miR-92a and sequesters a crucial part of the sequence that constitutes the basal helix of pri-miR-92a. Disruption of the NPSL2 hairpin structure could promote the formation of a pri-miR-92a structure that is primed for processing by Drosha. Thus, NPSL2 is predicted to function as a structural switch, regulating pri-miR-92a processing. Here, we determined the solution structure of NPSL2 using solution NMR spectroscopy. This is the first high-resolution structure of an oncomiR-1 element. NPSL2 adopts a hairpin structure with a large, but highly structured, apical and internal loops. The 10-bp apical loop contains a pH-sensitive A+·C mismatch. Additionally, several adenosines within the apical and internal loops have elevated pKa values. The protonation of these adenosines can stabilize the NPSL2 structure through electrostatic interactions. Our study provides fundamental insights into the secondary and tertiary structure of an important RNA hairpin proposed to regulate miR biogenesis.
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Affiliation(s)
- Yaping Liu
- Biophysics Program, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109, USA. https://twitter.com/YapingLiu5
| | - Aldrex Munsayac
- Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109, USA
| | - Ian Hall
- Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109, USA. https://twitter.com/ihallu14
| | - Sarah C Keane
- Biophysics Program, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109, USA; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109, USA.
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Sufianov A, Begliarzade S, Kudriashov V, Nafikova R, Ilyasova T, Liang Y. Role of miRNAs in vascular development. Noncoding RNA Res 2022; 8:1-7. [PMID: 36262425 PMCID: PMC9552023 DOI: 10.1016/j.ncrna.2022.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/27/2022] Open
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Phowira J, Ahmed FW, Bakhashab S, Weaver JU. Upregulated miR-18a-5p in Colony Forming Unit-Hill’s in Subclinical Cardiovascular Disease and Metformin Therapy; MERIT Study. Biomedicines 2022; 10:biomedicines10092136. [PMID: 36140236 PMCID: PMC9496122 DOI: 10.3390/biomedicines10092136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Colony forming unit-Hill’s (CFU-Hill’s) colonies are hematopoietic-derived cells that participate in neovasculogenesis and serve as a biomarker for vascular health. In animals, overexpression of miR-18a-5p was shown to be pro-atherogenic. We had shown that well-controlled type 1 diabetes mellitus (T1DM) is characterized by an inflammatory state, endothelial dysfunction, and reduced number of CFU-Hill’s, a model of subclinical cardiovascular disease (CVD). MERIT study explored the role of miR-18a-5p expression in CFU-Hill’s colonies in T1DM, and the cardioprotective effect of metformin in subclinical CVD. In T1DM, miR-18a-5p was significantly upregulated whereas metformin reduced it to HC levels. MiR-18a-5p was inversely correlated with CFU-Hill’s colonies, CD34+, CD34+CD133+ cells, and positively with IL-10, C-reactive protein, vascular endothelial growth factor-D (VEGF-D), and thrombomodulin. The receiver operating characteristic curve demonstrated, miR-18a-5p as a biomarker of T1DM, and upregulated miR-18a-5p defining subclinical CVD at HbA1c of 44.5 mmol/mol (pre-diabetes). Ingenuity pathway analysis documented miR-18a-5p inhibiting mRNA expression of insulin-like growth factor-1, estrogen receptor-1, hypoxia-inducible factor-1α cellular communication network factor-2, and protein inhibitor of activated STAT 3, whilst metformin upregulated these mRNAs via transforming growth factor beta-1 and VEGF. We confirmed the pro-atherogenic effect of miR-18a-5p in subclinical CVD and identified several target genes for future CVD therapies.
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Affiliation(s)
- Jason Phowira
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Fahad W. Ahmed
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Diabetes, Queen Elizabeth Hospital, Gateshead, Newcastle upon Tyne NE9 6SH, UK
- Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Madinah 42522, Saudi Arabia
| | - Sherin Bakhashab
- Biochemistry Department, King Abdulaziz University, P.O. Box 80218, Jeddah 21589, Saudi Arabia
| | - Jolanta U. Weaver
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Diabetes, Queen Elizabeth Hospital, Gateshead, Newcastle upon Tyne NE9 6SH, UK
- Vascular Biology and Medicine Theme, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- Correspondence: ; Tel.: +44-191-445-2181
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Overexpression of the miR-17-92 cluster in colorectal adenoma organoids causes a carcinoma-like gene expression signature. Neoplasia 2022; 32:100820. [PMID: 35872559 PMCID: PMC9307940 DOI: 10.1016/j.neo.2022.100820] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022]
Abstract
Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma. The miR-17-92 cluster was overexpressed in human colorectal adenoma organoids without 13q gain and downstream effects on mRNA expression were investigated, along with functional consequences in vitro and in vivo. Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, tumor-associated characteristics, such as increased proliferation rate, were not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth. In conclusion, this study showed that miR-17-92 expression contributes to 13q gain-associated adenoma-to-carcinoma progression, however, this is insufficient to cause malignancy.
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Gerloff D, Kewitz-Hempel S, Hause G, Ehrenreich J, Golle L, Kingreen T, Sunderkötter C. Comprehensive Analyses of miRNAs Revealed miR-92b-3p, miR-182-5p and miR-183-5p as Potential Novel Biomarkers in Melanoma-Derived Extracellular Vesicles. Front Oncol 2022; 12:935816. [PMID: 35898875 PMCID: PMC9309285 DOI: 10.3389/fonc.2022.935816] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/16/2022] [Indexed: 11/20/2022] Open
Abstract
Extracellular vesicles (EVs) are important mediators in the intercellular communication, influencing the function and phenotype of different cell types within the tumor micro-milieu and thus promote tumor progression. Since EVs safely transport packages of proteins, lipids and also nucleic acids such as miRNAs, EVs and their cargo can serve as diagnostic and prognostic markers. Therefore, the aim of this study was to investigate EV embedded miRNAs specific for melanoma, which could serve as potential biomarkers. In contrast to previous studies, we not only analysed miRNAs from EVs, but also included the miRNA profiles from the EV-secreting cells to identify candidates as suitable biomarkers. While the characterization of EVs derived from normal melanocytes and melanoma cells showed largely comparable properties with regard to size distribution and expression of protein markers, the NGS analyses yielded marked differences for several miRNAs. While miRNA load of EVs derived from normal human epidermal melanocytes (NHEMs) and melanoma cells were very similar, they were highly different from their secreting cells. By comprehensive analyses, six miRNAs were identified to be enriched in both melanoma cells and melanoma cell-derived EVs. Of those, the accumulation of miR-92b-3p, miR-182-5p and miR-183-5p in EVs could be validated in vitro. By functional network generation and pathway enrichment analysis we revealed an association with different tumor entities and signaling pathways contributing melanoma progression. Furthermore, we found that miR-92b-3p, miR-182-5p and miR-183-5p were also enriched in EVs derived from serum of melanoma patients. Our results support the hypothesis that miRNAs derived from EVs can serve as prognostic or diagnostic liquid biopsy markers in melanoma. We identified EV-derived miRNAs and showed that those miRNAs, which were enriched in melanoma cells and EVs, are also found elevated in serum-derived EVs of patients with metastatic melanoma, but not in healthy subjects.
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Affiliation(s)
- Dennis Gerloff
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
- *Correspondence: Dennis Gerloff,
| | - Stefanie Kewitz-Hempel
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Gerd Hause
- Biocenter, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Jovine Ehrenreich
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Linda Golle
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Tim Kingreen
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Cord Sunderkötter
- Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
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Mousavi SM, Amin Mahdian SM, Ebrahimi MS, Taghizadieh M, Vosough M, Sadri Nahand J, Hosseindoost S, Vousooghi N, Javar HA, Larijani B, Hadjighassem MR, Rahimian N, Hamblin MR, Mirzaei H. Microfluidics for detection of exosomes and microRNAs in cancer: State of the art. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 28:758-791. [PMID: 35664698 PMCID: PMC9130092 DOI: 10.1016/j.omtn.2022.04.011] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Exosomes are small extracellular vesicles with sizes ranging from 30-150 nanometers that contain proteins, lipids, mRNAs, microRNAs, and double-stranded DNA derived from the cells of origin. Exosomes can be taken up by target cells, acting as a means of cell-to-cell communication. The discovery of these vesicles in body fluids and their participation in cell communication has led to major breakthroughs in diagnosis, prognosis, and treatment of several conditions (e.g., cancer). However, conventional isolation and evaluation of exosomes and their microRNA content suffers from high cost, lengthy processes, difficult standardization, low purity, and poor yield. The emergence of microfluidics devices with increased efficiency in sieving, trapping, and immunological separation of small volumes could provide improved detection and monitoring of exosomes involved in cancer. Microfluidics techniques hold promise for advances in development of diagnostic and prognostic devices. This review covers ongoing research on microfluidics devices for detection of microRNAs and exosomes as biomarkers and their translation to point-of-care and clinical applications.
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Affiliation(s)
- Seyed Mojtaba Mousavi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saereh Hosseindoost
- Pain Research Center, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran
| | - Nasim Vousooghi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Akbari Javar
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Hadjighassem
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Brain and Spinal Cord Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Zhang MX, Song Y, Xu WL, Zhang LX, Li C, Li YL. Natural Herbal Medicine as a Treatment Strategy for Myocardial Infarction through the Regulation of Angiogenesis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:8831750. [PMID: 35600953 PMCID: PMC9119779 DOI: 10.1155/2022/8831750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/25/2022] [Indexed: 11/18/2022]
Abstract
Methods We conducted a literature search on the bioactive components of medicinal plants and their effects on angiogenesis after MI. We searched for articles in Web of Science, MEDLINE, PubMed, Scopus, Google Scholar, and China National Knowledge Infrastructure databases before April 2021. Results In this article, we summarized the mechanisms by which copper ions, microRNA, Akt1, inflammation, oxidative stress, mitochondria, and pericytes are involved in angiogenesis after myocardial infarction. In addition, we reviewed the angiogenic effects of natural herbal medicines such as Salvia miltiorrhiza Bunge Bunge, Carthamus tinctorius L., Pueraria lobata, Astragalus, Panax ginseng C.A. Mey., Panax notoginseng (Burkill) F.H. Chen, Cinnamomum cassia (L.) J. Presl, Rehmannia glutinosa (Gaertn.) DC., Leonurus japonicus Houtt, Scutellaria baicalensis Georgi., and Geum macrophyllum Willd. Conclusions Some herbs have the effect of promoting angiogenesis. In the future, natural proangiogenic drugs may become candidates for the treatment of cardiovascular diseases.
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Affiliation(s)
- Mu-xin Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yu Song
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Wan-li Xu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Ling-xiao Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Chao Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yun-lun Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Department of Cardiology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
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Breast Cancer Subtype-Specific miRNAs: Networks, Impacts, and the Potential for Intervention. Biomedicines 2022; 10:biomedicines10030651. [PMID: 35327452 PMCID: PMC8945552 DOI: 10.3390/biomedicines10030651] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 02/01/2023] Open
Abstract
The regulatory and functional roles of non-coding RNAs are increasingly demonstrated as critical in cancer. Among non-coding RNAs, microRNAs (miRNAs) are the most well-studied with direct regulation of biological signals through post-transcriptional repression of mRNAs. Like the transcriptome, which varies between tissue type and disease condition, the miRNA landscape is also similarly altered and shows disease-specific changes. The importance of individual tumor-promoting or suppressing miRNAs is well documented in breast cancer; however, the implications of miRNA networks is less defined. Some evidence suggests that breast cancer subtype-specific cellular effects are influenced by distinct miRNAs and a comprehensive network of subtype-specific miRNAs and mRNAs would allow us to better understand breast cancer signaling. In this review, we discuss the altered miRNA landscape in the context of breast cancer and propose that breast cancer subtypes have distinct miRNA dysregulation. Further, given that miRNAs can be used as diagnostic and/or prognostic biomarkers, their impact as novel targets for subtype-specific therapy is also possible and suggest important implications for subtype-specific miRNAs.
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Pavlíková L, Šereš M, Breier A, Sulová Z. The Roles of microRNAs in Cancer Multidrug Resistance. Cancers (Basel) 2022; 14:cancers14041090. [PMID: 35205839 PMCID: PMC8870231 DOI: 10.3390/cancers14041090] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The resistance of neoplastic cells to multiple drugs is a serious problem in cancer chemotherapy. The molecular causes of multidrug resistance in cancer are largely known, but less is known about the mechanisms by which cells deliver phenotypic changes that resist the attack of anticancer drugs. The findings of RNA interference based on microRNAs represented a breakthrough in biology and pointed to the possibility of sensitive and targeted regulation of gene expression at the post-transcriptional level. Such regulation is also involved in the development of multidrug resistance in cancer. The aim of the current paper is to summarize the available knowledge on the role of microRNAs in resistance to multiple cancer drugs. Abstract Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed.
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Affiliation(s)
- Lucia Pavlíková
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
| | - Mário Šereš
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Albert Breier
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Zdena Sulová
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
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Kolawole OR, Kashfi K. NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 2022; 23:1432. [PMID: 35163356 PMCID: PMC8836048 DOI: 10.3390/ijms23031432] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
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Affiliation(s)
- Oluwafunke R. Kolawole
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10091, USA
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42
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Spectrum of microRNAs and their target genes in cancer: intervention in diagnosis and therapy. Mol Biol Rep 2022; 49:6827-6846. [PMID: 35031927 DOI: 10.1007/s11033-021-07040-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022]
Abstract
Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.
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Torrence D, Antonescu CR. The genetics of vascular tumours: an update. Histopathology 2022; 80:19-32. [PMID: 34958509 PMCID: PMC8950088 DOI: 10.1111/his.14458] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 01/03/2023]
Abstract
Recent molecular advances have shed significant light on the classification of vascular tumours. Except for haemangiomas, vascular lesions remain difficult to diagnose, owing to their rarity and overlapping clinical, radiographic and histological features across malignancies. In particular, challenges still remain in the differential diagnosis of epithelioid vascular tumours, including epithelioid haemangioma and epithelioid haemangioendothelioma at the benign/low-grade end of the spectrum, and epithelioid angiosarcoma at the high-grade end. Historically, the classification of vascular tumours has been heavily dependent on the clinical setting and histological features, as traditional immunohistochemical markers across the group have often been non-discriminatory. The increased application of next-generation sequencing in clinical practice, in particular targeted RNA sequencing (such as Archer, Illumina), has led to numerous novel discoveries, mainly recurrent gene fusions (e.g. those involving FOS, FOSB, YAP1, and WWTR1), which have resulted in refined tumour classification and improved diagnostic reproducibility for vascular tumours. However, other molecular alterations besides fusions have been discovered in vascular tumours, including somatic mutations (e.g. involving GNA family and IDH genes) in a variety of haemangiomas, as well as copy number alterations in high-grade angiosarcomas (e.g. MYC amplifications). Moreover, the translation of these novel molecular abnormalities into diagnostic ancillary markers, either fluorescence in-situ hybridisation probes or surrogate immunohistochemical markers (FOSB, CAMTA1, YAP1, and MYC), has been remarkable. This review will focus on the latest molecular discoveries covering both benign and malignant vascular tumours, and will provide practical diagnostic algorithms, highlighting frequently encountered pitfalls and challenges in the diagnosis of vascular lesions.
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Affiliation(s)
- Dianne Torrence
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY,Corresponding author: Cristina R Antonescu, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065,
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Shui B, La Rocca G, Ventura A, Haigis KM. Interplay between K-RAS and miRNAs. Trends Cancer 2022; 8:384-396. [PMID: 35093302 PMCID: PMC9035052 DOI: 10.1016/j.trecan.2022.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/25/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023]
Abstract
K-RAS is frequently mutated in cancers, and its overactivation can lead to oncogene-induced senescence (OIS), a barrier to cellular transformation. Feedback onto K-RAS limits its signaling to avoid senescence while achieving the appropriate level of activation that promotes proliferation and survival. Such regulation could be mediated by miRNAs, as aberrant RAS signaling and miRNA activity coexist in several cancers, with miRNAs acting both up- and downstream of K-RAS. Several miRNAs both regulate and are regulated by K-RAS, suggesting a noncoding RNA-based feedback mechanism. Functional interactions between K-RAS and the miRNA machinery have also begun to unfold. This review comprehensively surveys the state of knowledge connecting K-RAS to miRNA function and proposes a model for the regulation of K-RAS signaling by noncoding RNAs.
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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.
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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.
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46
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Ramesh P, Lannagan TRM, Jackstadt R, Atencia Taboada L, Lansu N, Wirapati P, van Hooff SR, Dekker D, Pritchard J, Kirov AB, van Neerven SM, Tejpar S, Kops GJPL, Sansom OJ, Medema JP. BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer. Cell Death Differ 2021; 28:3282-3296. [PMID: 34117376 PMCID: PMC8630104 DOI: 10.1038/s41418-021-00816-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
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Affiliation(s)
- Prashanthi Ramesh
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | | | - Rene Jackstadt
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, G61 1BD, UK
| | - Lidia Atencia Taboada
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Nico Lansu
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Danielle Dekker
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Jessica Pritchard
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Aleksandar B Kirov
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Sanne M van Neerven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Sabine Tejpar
- Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Geert J P L Kops
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, G61 1QH, UK
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AmsterdamUMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Sehgal P, Lanauze C, Wang X, Hayer KE, Torres-Diz M, Leu NA, Sela Y, Stanger BZ, Lengner CJ, Thomas-Tikhonenko A. MYC Hyperactivates Wnt Signaling in APC/ CTNNB1-Mutated Colorectal Cancer Cells through miR-92a-Dependent Repression of DKK3. Mol Cancer Res 2021; 19:2003-2014. [PMID: 34593610 PMCID: PMC8642317 DOI: 10.1158/1541-7786.mcr-21-0666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022]
Abstract
Activation of Wnt signaling is among the earliest events in colon cancer development. It is achieved either via activating mutations in the CTNNB1 gene encoding β-catenin, the key transcription factor in the Wnt pathway, or most commonly by inactivating mutations affecting APC, a major β-catenin binding partner and negative regulator. However, our analysis of recent Pan Cancer Atlas data revealed that CTNNB1 mutations significantly co-occur with those affecting Wnt receptor complex components (e.g., Frizzled and LRP6), underscoring the importance of additional regulatory events even in the presence of common APC/CTNNB1 mutations. In our effort to identify non-mutational hyperactivating events, we determined that KRAS-transformed murine colonocytes overexpressing direct β-catenin target MYC show significant upregulation of the Wnt signaling pathway and reduced expression of Dickkopf 3 (DKK3), a reported ligand for Wnt co-receptors. We demonstrate that MYC suppresses DKK3 transcription through one of miR-17-92 cluster miRNAs, miR-92a. We further examined the role of DKK3 by overexpression and knockdown and discovered that DKK3 suppresses Wnt signaling in Apc-null murine colonic organoids and human colon cancer cells despite the presence of downstream activating mutations in the Wnt pathway. Conversely, MYC overexpression in the same cell lines resulted in hyperactive Wnt signaling, acquisition of epithelial-to-mesenchymal transition markers, and enhanced migration/invasion in vitro and metastasis in a syngeneic orthotopic mouse colon cancer model. IMPLICATIONS: Our results suggest that the MYC→miR-92a-|DKK3 axis hyperactivates Wnt signaling, forming a feed-forward oncogenic loop.
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Affiliation(s)
- Priyanka Sehgal
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Claudia Lanauze
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xin Wang
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Katharina E Hayer
- The Bioinformatics Group, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Manuel Torres-Diz
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - N Adrian Leu
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yogev Sela
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ben Z Stanger
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christopher J Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrei Thomas-Tikhonenko
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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The Diagnostic, Prognostic and Therapeutic Role of miRNAs in Adrenocortical Carcinoma: A Systematic Review. Biomedicines 2021; 9:biomedicines9111501. [PMID: 34829730 PMCID: PMC8614733 DOI: 10.3390/biomedicines9111501] [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: 09/02/2021] [Revised: 10/08/2021] [Accepted: 10/15/2021] [Indexed: 11/18/2022] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis and a high rate of recurrence and mortality. Therapeutic options are limited. In some cases, the distinction of ACCs from benign adrenal neoplasms with the existing widely available pathological and histopathological tools is difficult. Thus, new biomarkers have been tested. We conducted a review of the recent literature on the advances of the diagnostic, prognostic and therapeutic role of miRNAs on ACC patients. More than 10 miRNAs validated by multiple studies were found to present a diagnostic and prognostic role for ACC patients, from which miR-483-5p and miR-195 were the most frequently met biomarkers. In particular, upregulation of miR-483-5p and downregulation of miR-195 were the most commonly validated molecular alterations. Unfortunately, data on the therapeutic role of miRNA are still scarce and limited mainly at the experimental level. Thus, the role of miRNA regulation in ACC remains an area of active research.
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An Overview of miRNAs Involved in PASMC Phenotypic Switching in Pulmonary Hypertension. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5765029. [PMID: 34660794 PMCID: PMC8516547 DOI: 10.1155/2021/5765029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/03/2021] [Indexed: 12/31/2022]
Abstract
Pulmonary hypertension (PH) is occult, with no distinctive clinical manifestations and a poor prognosis. Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cells (PASMCs) phenotypic switching plays a crucial role. MicroRNAs (miRNAs) are a class of evolutionarily highly conserved single-stranded small noncoding RNAs. An increasing number of studies have shown that miRNAs play an important role in the occurrence and development of PH by regulating PASMCs phenotypic switching, which is expected to be a potential target for the prevention and treatment of PH. miRNAs such as miR-221, miR-15b, miR-96, miR-24, miR-23a, miR-9, miR-214, and miR-20a can promote PASMCs phenotypic switching, while such as miR-21, miR-132, miR-449, miR-206, miR-124, miR-30c, miR-140, and the miR-17~92 cluster can inhibit it. The article reviews the research progress on growth factor-related miRNAs and hypoxia-related miRNAs that mediate PASMCs phenotypic switching in PH.
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Wang Y, Chen J, Cowan DB, Wang DZ. Non-coding RNAs in cardiac regeneration: Mechanism of action and therapeutic potential. Semin Cell Dev Biol 2021; 118:150-162. [PMID: 34284952 PMCID: PMC8434979 DOI: 10.1016/j.semcdb.2021.07.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 12/19/2022]
Abstract
In the past two decades, thousands of non-coding RNAs (ncRNAs) have been discovered, annotated, and characterized in nearly every tissue under both physiological and pathological conditions. Here, we will focus on the role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ischemic heart disease (IHD), which remains the leading cause of morbidity and mortality in humans-resulting in 8.9 million deaths annually. Cardiomyocyte (CM) proliferation, differentiation, and survival in addition to neovascularization of injured tissues and the prevention of fibrosis are commonly regarded as critically important for the recovery of the heart following myocardial infarction (MI). An abundance of evidence has been accumulated to show ncRNAs participate in cardiac recovery after MI. Because miRNAs are important regulators of cardiac regeneration, the therapeutic potential of at least five of these molecules has been assessed in large animal models of human IHD. In particular, miRNA-based interventions based on miR-132 and miR-92a inhibition in related diseases have displayed favorable outcomes that have provided the impetus for miRNA-based clinical trials for IHD. At the same time, the functional roles of lncRNAs and circRNAs in cardiac regeneration are also being explored. In the present review, we will summarize the latest ncRNA studies aimed at reversing damage to the ischemic heart and discuss the therapeutic potential of targeting miRNAs, lncRNAs, and circRNAs to stimulate cardiac regeneration.
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Affiliation(s)
- Yi Wang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Jinghai Chen
- Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University, 268 Kaixuan Road, Hangzhou, China
| | - Douglas B Cowan
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
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