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1
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Cortellesi E, Savini I, Veneziano M, Gambacurta A, Catani MV, Gasperi V. Decoding the Epigenome of Breast Cancer. Int J Mol Sci 2025; 26:2605. [PMID: 40141248 PMCID: PMC11942310 DOI: 10.3390/ijms26062605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/06/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Breast cancer (BC) is the most prevalent malignancy among women, characterized by extensive heterogeneity stemming from molecular and genetic alterations. This review explores the intricate epigenetic landscape of BC, highlighting the significant role of epigenetic modifications-particularly DNA methylation, histone modifications, and the influence of non-coding RNAs-in the initiation, progression, and prognosis of the disease. Epigenetic alterations drive crucial processes, including gene expression regulation, cell differentiation, and tumor microenvironment interactions, contributing to tumorigenesis and metastatic potential. Notably, aberrations in DNA methylation patterns, including global hypomethylation and hypermethylation of CpG islands, have been associated with distinct BC subtypes, with implications for early detection and risk assessment. Furthermore, histone modifications, such as acetylation and methylation, affect cancer cell plasticity and aggressiveness by profoundly influencing chromatin dynamics and gene transcription. Finally, non-coding RNAs contribute by modulating epigenetic machinery and gene expression. Despite advances in our knowledge, clinical application of epigenetic therapies in BC is still challenging, often yielding limited efficacy when used alone. However, combining epi-drugs with established treatments shows promise for enhancing therapeutic outcomes. This review underscores the importance of integrating epigenetic insights into personalized BC treatment strategies, emphasizing the potential of epigenetic biomarkers for improving diagnosis, prognosis, and therapeutic response in affected patients.
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Affiliation(s)
- Elisa Cortellesi
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Isabella Savini
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Matteo Veneziano
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Alessandra Gambacurta
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
- NAST Centre (Nanoscience & Nanotechnology & Innovative Instrumentation), Tor Vergata University of Rome, 00133 Rome, Italy
| | - Maria Valeria Catani
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Valeria Gasperi
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
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2
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Jame-Chenarboo F, Reyes JN, Twells NM, Ng HH, Macdonald D, Hernando E, Mahal LK. Screening the human miRNA interactome reveals coordinated up-regulation in melanoma, adding bidirectional regulation to miRNA networks. SCIENCE ADVANCES 2025; 11:eadr0277. [PMID: 39792681 PMCID: PMC11721578 DOI: 10.1126/sciadv.adr0277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 12/06/2024] [Indexed: 01/12/2025]
Abstract
Cellular protein expression is coordinated posttranscriptionally by an intricate regulatory network. The current presumption is that microRNAs (miRNAs) work by repression of functionally related targets within a system. In recent work, up-regulation of protein expression via direct interactions of messenger RNA with miRNA has been found in dividing cells, providing an additional mechanism of regulation. Herein, we demonstrate coordinated up-regulation of functionally coupled proteins by miRNA. We focused on CD98hc, the heavy chain of the amino acid transporter LAT-1, and α-2,3-sialyltransferases ST3GAL1 and ST3GAL2, which are critical for CD98hc stability in melanoma. Profiling miRNA regulation using our high-throughput miRFluR assay, we identified miRNA that up-regulated the expression of both CD98hc and either ST3GAL1 or ST3GAL2. These co-up-regulating miRNAs were enriched in melanoma datasets associated with transformation and progression. Our findings add co-up-regulation by miRNA into miRNA regulatory networks and add a bidirectional twist to the impact miRNAs have on protein regulation and glycosylation.
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Affiliation(s)
| | - Joseph N. Reyes
- Department of Chemistry, University of Alberta, Edmonton, Canada
| | | | - Hoi Hei Ng
- Department of Chemistry, University of Alberta, Edmonton, Canada
| | - Dawn Macdonald
- Department of Chemistry, University of Alberta, Edmonton, Canada
| | - Eva Hernando
- Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Lara K. Mahal
- Department of Chemistry, University of Alberta, Edmonton, Canada
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3
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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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4
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Rio PD, DiMarco S, Madan P. MicroRNAomic Analysis of Spent Media from Slow- and Fast-Growing Bovine Embryos Reveal Distinct Differences. Animals (Basel) 2024; 14:2331. [PMID: 39199865 PMCID: PMC11350645 DOI: 10.3390/ani14162331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/07/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
In bovine embryos, the microRNA (miRNA) expression has been profiled at each stage of early development in vitro. The miRNAomic analysis of spent media has the potential to reveal characteristics of embryo health; however, applications are limited without categorizing miRNA profiles by embryo quality. Time-lapse imaging has shown the timing of embryo development in vitro may be indicative of their developmental potential. The study aimed to characterize miRNAs in the spent media of bovine embryos with different growth rates during the pre-implantation phase. Bovine cumulus-oocyte complexes were aspirated from ovaries, fertilized, and cultured to blastocyst stage of development. At the 2-cell, 8-cell, and blastocyst stage, each microdrop of 30 presumptive zygotes were classified as slow- or fast-growing based on the percentage of embryos that had reached the desired morphological stage. A comparative analysis was performed on the spent media of slow- and fast-growing embryos using the results of a GeneChip miRNA 4.0 array hybridization. In total, 34 differentially expressed miRNAs were identified between the comparison groups: 14 miRNAs were found in the 2-cell samples, 7 in the 8-cell samples, and 12 in the blastocyst samples. The results demonstrate distinct miRNAs populations can be identified between slow- and fast-growing embryos, highlighting the novel biomarkers of developmental potential at each stage of pre-implantation development.
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Affiliation(s)
| | | | - Pavneesh Madan
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada
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Leng X, Zhang M, Xu Y, Wang J, Ding N, Yu Y, Sun S, Dai W, Xue X, Li N, Yang Y, Shi Z. Non-coding RNAs as therapeutic targets in cancer and its clinical application. J Pharm Anal 2024; 14:100947. [PMID: 39149142 PMCID: PMC11325817 DOI: 10.1016/j.jpha.2024.02.001] [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: 10/27/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 08/17/2024] Open
Abstract
Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression. Oncogenes promote cell growth and proliferation, whereas tumor suppressor genes inhibit cell growth and division. The dysregulation of these genes can lead to the development of cancer. Recent studies have focused on non-coding RNAs (ncRNAs), including circular RNA (circRNA), long non-coding RNA (lncRNA), and microRNA (miRNA), as therapeutic targets for cancer. In this article, we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets. Here, we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment. Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.
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Affiliation(s)
- Xuejiao Leng
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Mengyuan Zhang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yujing Xu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jingjing Wang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ning Ding
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yancheng Yu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shanliang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Weichen Dai
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xin Xue
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Nianguang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ye Yang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhihao Shi
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China
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Xiong S, Song K, Xiang H, Luo G. Dual-target inhibitors based on ERα: Novel therapeutic approaches for endocrine resistant breast cancer. Eur J Med Chem 2024; 270:116393. [PMID: 38588626 DOI: 10.1016/j.ejmech.2024.116393] [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: 05/25/2023] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024]
Abstract
Estrogen receptor alpha (ERα), a nuclear transcription factor, is a well-validated therapeutic target for more than 70% of all breast cancers (BCs). Antagonizing ERα either by selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) forms the foundation of endocrine therapy and has achieved great success in the treatment of ERα positive (ERα+) BCs. Unfortunately, despite initial effectiveness, endocrine resistance eventually emerges in up to 30% of ERα+ BC patients and remains a significant medical challenge. Several mechanisms implicated in endocrine resistance have been extensively studied, including aberrantly activated growth factor receptors and downstream signaling pathways. Hence, the crosstalk between ERα and another oncogenic signaling has led to surge of interest to develop combination therapies and dual-target single agents. This review briefly introduces the synergisms between ERα and another anticancer target and summarizes the recent advances of ERα-based dual-targeting inhibitors from a medicinal chemistry perspective. Accordingly, their rational design strategies, structure-activity relationships (SARs) and biological activities are also dissected to provide some perspectives on future directions for ERα-based dual target drug discovery in BC therapy.
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Affiliation(s)
- Shuangshuang Xiong
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ke Song
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua Xiang
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Guoshun Luo
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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Turkoglu F, Calisir A, Ozturk B. Clinical importance of serum miRNA levels in breast cancer patients. Discov Oncol 2024; 15:19. [PMID: 38280134 PMCID: PMC10821853 DOI: 10.1007/s12672-024-00871-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 01/21/2024] [Indexed: 01/29/2024] Open
Abstract
There is limited data on the relationship of miRNAs with parameters that may affect surgical management or reflect tumour prognosis. It was aimed to evaluate serum miRNA levels in breast carcinoma cases and reveal the relationship between these levels and prognosis-related factors such as the histological type of the tumour, estrogen receptor, progesterone receptor, Ki-67 index, HER-2neu, E-cadherin, tumour size, CK5/6, CA15.3 levels, number of tumour foci, number of metastatic lymph nodes, and status of receiving neoadjuvant therapy. Thirty-five patients with a histopathologically confirmed breast carcinoma diagnosis in the case group and 35 healthy individuals in the control group were examined. miR-206, miR-17-5p, miR-125a, miR-125b, miR-200a, Let-7a, miR-34a, miR-31, miR-21, miR-155, miR-10b, miR-373, miR-520c, miR-210, miR-145, miR-139-5p, miR-195, miR-99a, miR-497 and miR-205 expression levels in the serum of participants were determined using the Polymerase Chain Reaction method. While serum miR-125b and Let-7a expression levels were significantly higher in breast cancer patients, miR-17-5p, miR-125a, miR-200a, miR-34a, miR-21, miR-99a and miR-497 levels were significantly lower in them. The Let-7a expression level had a statistically significant relationship with breast cancer histological type and HER-2neu parameters, miR-17-5p, miR-125b, Let-7a, miR-34a, miR-21 and miR-99a levels with E-cadherin, miR-34a, miR-99a and miR-497 with CA15.3, miR-125b, miR-200a and miR-34a with the number of metastatic lymph nodes, miR-125a with the number of tumour foci and miR-200a with the status of having the neoadjuvant therapy. Serum miR-17-5p, miR-125a, miR-125b, miR-200a, Let-7a, miR-34a, miR-21, miR-99a and miR-497 expression levels were determined to have predictive and prognostic importance in breast cancer.
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Affiliation(s)
- Fatih Turkoglu
- Department of General Surgery, Faculty of Medicine, Selcuk University, Akademi Mahallesi Yeni İstanbul Caddesi No:313, Selçuk Üniversitesi Alaeddin Keykubat Yerleşkesi, Selçuklu, Konya, 42130, Turkey.
| | - Akin Calisir
- Department of General Surgery, Faculty of Medicine, Selcuk University, Akademi Mahallesi Yeni İstanbul Caddesi No:313, Selçuk Üniversitesi Alaeddin Keykubat Yerleşkesi, Selçuklu, Konya, 42130, Turkey
| | - Bahadir Ozturk
- Department of Biochemistry, Faculty of Medicine, Selcuk University, Konya, Turkey
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8
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Batan S, Kuppuswamy S, Wood M, Reddy M, Annex B, Ganta V. Inhibiting anti-angiogenic VEGF165b activates a miR-17-20a-Calcipressin-3 pathway that revascularizes ischemic muscle in peripheral artery disease. COMMUNICATIONS MEDICINE 2024; 4:3. [PMID: 38182796 PMCID: PMC10770062 DOI: 10.1038/s43856-023-00431-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 12/19/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND VEGF165a increases the expression of the microRNA-17-92 cluster, promoting developmental, retinal, and tumor angiogenesis. We have previously shown that VEGF165b, an alternatively spliced anti-angiogenic VEGF-A isoform, inhibits the VEGFR-STAT3 pathway in ischemic endothelial cells (ECs) to decrease their angiogenic capacity. In ischemic macrophages (Møs), VEGF165b inhibits VEGFR1 to induce S100A8/A9 expression, which drives M1-like polarization. Our current study aims to determine whether VEGF165b inhibition promotes perfusion recovery by regulating the microRNA(miR)-17-92 cluster in preclinical PAD. METHODS Femoral artery ligation and resection was used as a preclinical PAD model. Hypoxia serum starvation (HSS) was used as an in vitro PAD model. VEGF165b was inhibited/neutralized by an isoform-specific VEGF165b antibody. RESULTS Here, we show that VEGF165b-inhibition induces the expression of miR-17-20a (within miR-17-92 (miR-17-18a-19a-19b-20a-92) cluster) in HSS-ECs and HSS-Møs vs. respective normal and/or isotype-matched IgG controls to enhance perfusion recovery. Consistent with the bioinformatics analysis that revealed RCAN3 as a common target of miR-17 and miR-20a, Argonaute-2 pull-down assays showed decreased miR-17-20a expression and higher RCAN3 expression in the RNA-induced silencing complex of HSS-ECs and HSS-Møs vs. respective controls. Inhibiting miR-17-20a induced RCAN3 levels to decrease ischemic angiogenesis and promoted M1-like polarization to impair perfusion recovery. Finally, using STAT3 inhibitors, S100A8/A9 silencers, and VEGFR1-deficient ECs and Møs, we show that VEGF165b-inhibition activates the miR-17-20a-RCAN3 pathway independent of VEGFR1-STAT3 or VEGFR1-S100A8/A9 in ischemic-ECs and ischemic-Møs respectively. CONCLUSIONS Our data revealed a hereunto unrecognized therapeutic 'miR-17-20a-RCAN3' pathway in the ischemic vasculature that is VEGFR1-STAT3/S100A8/A9 independent and is activated only upon VEGF165b-inhibition in PAD.
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Affiliation(s)
- Sonia Batan
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta, GA, 30912, USA
| | - Sivaraman Kuppuswamy
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta, GA, 30912, USA
| | - Madison Wood
- Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Meghana Reddy
- Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Brian Annex
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta, GA, 30912, USA
| | - Vijay Ganta
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta, GA, 30912, USA.
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Gaur P, Rajak N, Tiwari A, Kumar P, Garg N. Role of microRNAs in oncogenic viral infection diagnosis and therapeutics. MICRORNA IN HUMAN INFECTIOUS DISEASES 2024:179-200. [DOI: 10.1016/b978-0-323-99661-7.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Pagoni M, Cava C, Sideris DC, Avgeris M, Zoumpourlis V, Michalopoulos I, Drakoulis N. miRNA-Based Technologies in Cancer Therapy. J Pers Med 2023; 13:1586. [PMID: 38003902 PMCID: PMC10672431 DOI: 10.3390/jpm13111586] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/02/2023] [Accepted: 11/04/2023] [Indexed: 11/26/2023] Open
Abstract
The discovery of therapeutic miRNAs is one of the most exciting challenges for pharmaceutical companies. Since the first miRNA was discovered in 1993, our knowledge of miRNA biology has grown considerably. Many studies have demonstrated that miRNA expression is dysregulated in many diseases, making them appealing tools for novel therapeutic approaches. This review aims to discuss miRNA biogenesis and function, as well as highlight strategies for delivering miRNA agents, presenting viral, non-viral, and exosomic delivery as therapeutic approaches for different cancer types. We also consider the therapeutic role of microRNA-mediated drug repurposing in cancer therapy.
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Affiliation(s)
- Maria Pagoni
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15701 Athens, Greece
| | - Claudia Cava
- Department of Science, Technology and Society, University School for Advanced Studies IUSS Pavia, 27100 Pavia, Italy;
| | - Diamantis C. Sideris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece;
| | - Margaritis Avgeris
- Laboratory of Clinical Biochemistry—Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, “P. & A. Kyriakou” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vassilios Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece;
| | - Ioannis Michalopoulos
- Centre of Systems Biology, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece;
| | - Nikolaos Drakoulis
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15701 Athens, Greece
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11
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Muñoz JP, Pérez-Moreno P, Pérez Y, Calaf GM. The Role of MicroRNAs in Breast Cancer and the Challenges of Their Clinical Application. Diagnostics (Basel) 2023; 13:3072. [PMID: 37835815 PMCID: PMC10572677 DOI: 10.3390/diagnostics13193072] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/14/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a subclass of non-coding RNAs that exert substantial influence on gene-expression regulation. Their tightly controlled expression plays a pivotal role in various cellular processes, while their dysregulation has been implicated in numerous pathological conditions, including cancer. Among cancers affecting women, breast cancer (BC) is the most prevalent malignant tumor. Extensive investigations have demonstrated distinct expression patterns of miRNAs in normal and malignant breast cells. Consequently, these findings have prompted research efforts towards leveraging miRNAs as diagnostic tools and the development of therapeutic strategies. The aim of this review is to describe the role of miRNAs in BC. We discuss the identification of oncogenic, tumor suppressor and metastatic miRNAs among BC cells, and their impact on tumor progression. We describe the potential of miRNAs as diagnostic and prognostic biomarkers for BC, as well as their role as promising therapeutic targets. Finally, we evaluate the current use of artificial intelligence tools for miRNA analysis and the challenges faced by these new biomedical approaches in its clinical application. The insights presented in this review underscore the promising prospects of utilizing miRNAs as innovative diagnostic, prognostic, and therapeutic tools for the management of BC.
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Affiliation(s)
- Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
| | - Pablo Pérez-Moreno
- Programa de Comunicación Celular en Cáncer, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7780272, Chile
| | - Yasmín Pérez
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
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12
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Batan S, Kuppuswamy S, Wood M, Reddy M, Annex BH, Ganta VC. Inhibiting Anti-angiogenic VEGF165b Activates a Novel miR-17-20a-Calcipressin-3 Pathway that Revascularizes Ischemic Muscle in Peripheral Artery Disease. RESEARCH SQUARE 2023:rs.3.rs-3213504. [PMID: 37645966 PMCID: PMC10462251 DOI: 10.21203/rs.3.rs-3213504/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Background VEGF165a increases the expression of microRNA-17-92 cluster, promoting developmental, retinal, and tumor angiogenesis. We have previously shown that VEGF165b, an alternatively spliced VEGF-A isoform, inhibits the VEGFR-STAT3 pathway in ischemic endothelial cells (ECs) to decrease their angiogenic capacity. In ischemic macrophages (Møs), VEGF165b inhibits VEGFR1 to induce S100A8/A9 expression, which drives M1-like polarization. Our current study aims to determine whether VEGF165b inhibition promotes perfusion recovery by regulating the miR-17-92 cluster in preclinical PAD. Methods Hind limb ischemia (HLI) induced by femoral artery ligation and resection was used as a preclinical PAD model. Hypoxia serum starvation (HSS) was used as an in vitro PAD model. VEGF165b was inhibited/neutralized by an isoform-specific VEGF165b antibody. Results Systematic analysis of miR-17-92 cluster members (miR-17-18a-19a-19b-20a-92) in experimental-PAD models showed that VEGF165b-inhibition induces miRNA-17-20a (within miR-17-92 cluster) in HSS-ECs and HSS-bone marrow derived macrophages (BMDMs) vs. respective normal and/or isotype matched IgG controls to enhance perfusion-recovery. Consistent with the bioinformatics analysis that revealed RCAN3 as a common target of miR-17 and miR-20a, Argonaute-2 pull-down assays showed decreased miR-17-20a expression and higher RCAN3 expression in the RISC complex of HSS-ECs and HSS-BMDMs vs. the respective controls. Inhibiting miR-17-20a induced RCAN3 levels to decrease ischemic angiogenesis and promoted M1-like polarization to impair perfusion recovery. Finally, using STAT3 inhibitors, S100A8/A9 silencers and VEGFR1-deficient ECs and Møs, we show that VEGF165b inhibition activates the miR-17-20a-RCAN3 pathway independent of VEGFR1-STAT3 or VEGFR1-S100A8/A9 in ischemic ECs and ischemic Møs, respectively. Conclusion Our data revealed a hereunto unrecognized therapeutic 'miR-17-20a-RCAN3' pathway in the ischemic vasculature that is VEGFR1-STAT3/S100A8/A9 independent and is activated only upon VEGF165b inhibition in PAD.
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Affiliation(s)
- S Batan
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta-GA-30912
| | - S Kuppuswamy
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta-GA-30912
| | - M Wood
- Medical College of Georgia, Augusta University, Augusta-GA-30912
| | - M Reddy
- Medical College of Georgia, Augusta University, Augusta-GA-30912
| | - B H Annex
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta-GA-30912
| | - V C Ganta
- Vascular Biology Center, Department of Medicine, Augusta University, Augusta-GA-30912
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13
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Otsuka K, Nishiyama H, Kuriki D, Kawada N, Ochiya T. Connecting the dots in the associations between diet, obesity, cancer, and microRNAs. Semin Cancer Biol 2023; 93:52-69. [PMID: 37156343 DOI: 10.1016/j.semcancer.2023.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
The prevalence of obesity has reached pandemic levels worldwide, leading to a lower quality of life and higher health costs. Obesity is a major risk factor for noncommunicable diseases, including cancer, although obesity is one of the major preventable causes of cancer. Lifestyle factors, such as dietary quality and patterns, are also closely related to the onset and development of obesity and cancer. However, the mechanisms underlying the complex association between diet, obesity, and cancer remain unclear. In the past few decades, microRNAs (miRNAs), a class of small non-coding RNAs, have been demonstrated to play critical roles in biological processes such as cell differentiation, proliferation, and metabolism, highlighting their importance in disease development and suppression and as therapeutic targets. miRNA expression levels can be modulated by diet and are involved in cancer and obesity-related diseases. Circulating miRNAs can also mediate cell-to-cell communications. These multiple aspects of miRNAs present challenges in understanding and integrating their mechanism of action. Here, we introduce a general consideration of the associations between diet, obesity, and cancer and review the current knowledge of the molecular functions of miRNA in each context. A comprehensive understanding of the interplay between diet, obesity, and cancer could be valuable for the development of effective preventive and therapeutic strategies in future.
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Affiliation(s)
- Kurataka Otsuka
- Tokyo NODAI Research Institure, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan; R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan; Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan; Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiroshi Nishiyama
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Daisuke Kuriki
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Naoki Kawada
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan
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14
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Al-Sisan SM, Zihlif MA, Hammad HM. Differential miRNA expression of hypoxic MCF7 and PANC-1 cells. Front Endocrinol (Lausanne) 2023; 14:1110743. [PMID: 37583428 PMCID: PMC10424510 DOI: 10.3389/fendo.2023.1110743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 06/21/2023] [Indexed: 08/17/2023] Open
Abstract
Background Hypoxia plays a critical role in the tumor microenvironment by affecting cellular proliferation, metabolism, apoptosis, DNA repair, and chemoresistance. Since hypoxia provokes a distinct shift of microRNA, it is important to illustrate the relative contribution of each hypoxamiR to cancer progression. Aims The present study aims to shed light on the hypoxamiRs that are involved in pancreatic and breast cancer progression to highlight novel targets for the development of new therapies. Methods For 20 cycles, MCF7 breast cancer cells and PANC-1 pancreatic cancer cells were subjected to chronic cyclic hypoxia, which consisted of 72 hours of hypoxia followed by 24 hours of reoxygenation. After 10 and 20 cycles of hypoxia, miRNA expression alterations were profiled using RT-PCR array and further analyzed using a visual analytics platform. The MTT cell proliferation assay was used to determine hypoxic cells' chemoresistance to doxorubicin. Results Under chronic cyclic hypoxia, hypoxic PANC-1 cells have a comparable doubling time with their normoxic counterparts, whereas hypoxic MCF7 cells show a massive increase in doubling time when compared to their normoxic counterparts. Both hypoxic cell lines developed EMT-like phenotypes as well as doxorubicin resistance. According to the findings of miRNet, 6 and 10 miRNAs were shown to play an important role in enriching six hallmarks of pancreatic cancer in the 10th and 20th cycles of hypoxia, respectively, while 7 and 11 miRNAs were shown to play an important role in enriching the four hallmarks of breast cancer in the 10th and 20th cycles of hypoxia, respectively. Conclusions miR-221, miR-21, miR-155, and miR-34 were found to be involved in the potentiation of hypoxic PANC-1 hallmarks at both the 10th and 20th cycles, while miR-93, miR-20a, miR-15, and miR-17 were found to be involved in the potentiation of hypoxic MCF7 hallmarks at both the 10th and 20th cycles. This variation in miRNA expression was also connected to the emergence of an EMT-like phenotype, alterations in proliferation rates, and doxorubicin resistance. The chemosensitivity results revealed that chronic cyclic hypoxia is critical in the formation of chemoresistant phenotypes in pancreatic and breast cancer cells. miR-181a and let-7e expression disparities in PANC1, as well as miR-93, miR-34, and miR-27 expression disparities in MCF7, may be associated with the formation of chemoresistant MCF7 and PANC-1 cells following 20 cycles of chronic cyclic hypoxia. Indeed, further research is needed since the particular mechanisms that govern these processes are unknown.
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Affiliation(s)
- Sandy M. Al-Sisan
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Malek A. Zihlif
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Hana M. Hammad
- Department of Biological Sciences, School of Science, The University of Jordan, Amman, Jordan
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15
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Singh S, Saini H, Sharma A, Gupta S, Huddar VG, Tripathi R. Breast cancer: miRNAs monitoring chemoresistance and systemic therapy. Front Oncol 2023; 13:1155254. [PMID: 37397377 PMCID: PMC10312137 DOI: 10.3389/fonc.2023.1155254] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.
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Affiliation(s)
- Shivam Singh
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Heena Saini
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhash Gupta
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - V. G. Huddar
- Department of Kaya Chikitsa (Internal Medicine), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Richa Tripathi
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
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16
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Treeck O, Haerteis S, Ortmann O. Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer. Cancers (Basel) 2023; 15:cancers15061632. [PMID: 36980520 PMCID: PMC10046587 DOI: 10.3390/cancers15061632] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine therapy of ERα-positive breast cancer (BC) is a successful treatment approach, but resistance to this therapy is a major clinical problem. Therefore, a deeper understanding of resistance mechanisms is important to overcome this resistance. An increasing amount of evidence demonstrate that ncRNAs affect the response to endocrine therapy. Thus, ncRNAs are considered versatile biomarkers to predict or monitor therapy response. In this review article, we intend to give a summary and update on the effects of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) on estrogen signaling in BC cells, this pathway being the target of endocrine therapy, and their role in therapy resistance. For this purpose, we reviewed articles on these topics listed in the PubMed database. Finally, we provide an assessment regarding the clinical use of these ncRNA types, particularly their circulating forms, as predictive BC biomarkers and their potential role as therapy targets to overcome endocrine resistance.
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Affiliation(s)
- Oliver Treeck
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany
- Correspondence:
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany
| | - Olaf Ortmann
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany
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17
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MicroRNAs: A Link between Mammary Gland Development and Breast Cancer. Int J Mol Sci 2022; 23:ijms232415978. [PMID: 36555616 PMCID: PMC9786715 DOI: 10.3390/ijms232415978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Breast cancer is among the most common cancers in women, second to skin cancer. Mammary gland development can influence breast cancer development in later life. Processes such as proliferation, invasion, and migration during mammary gland development can often mirror processes found in breast cancer. MicroRNAs (miRNAs), small, non-coding RNAs, can repress post-transcriptional RNA expression and can regulate up to 80% of all genes. Expression of miRNAs play a key role in mammary gland development, and aberrant expression can initiate or promote breast cancer. Here, we review the role of miRNAs in mammary development and breast cancer, and potential parallel roles. A total of 32 miRNAs were found to be expressed in both mammary gland development and breast cancer. These miRNAs are involved in proliferation, metastasis, invasion, and apoptosis in both processes. Some miRNAs were found to have contradictory roles, possibly due to their ability to target many genes at once. Investigation of miRNAs and their role in mammary gland development may inform about their role in breast cancer. In particular, by studying miRNA in development, mechanisms and potential targets for breast cancer treatment may be elucidated.
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18
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Rajabi A, Kayedi M, Rahimi S, Dashti F, Mirazimi SMA, Homayoonfal M, Mahdian SMA, Hamblin MR, Tamtaji OR, Afrasiabi A, Jafari A, Mirzaei H. Non-coding RNAs and glioma: Focus on cancer stem cells. Mol Ther Oncolytics 2022; 27:100-123. [PMID: 36321132 PMCID: PMC9593299 DOI: 10.1016/j.omto.2022.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Glioblastoma and gliomas can have a wide range of histopathologic subtypes. These heterogeneous histologic phenotypes originate from tumor cells with the distinct functions of tumorigenesis and self-renewal, called glioma stem cells (GSCs). GSCs are characterized based on multi-layered epigenetic mechanisms, which control the expression of many genes. This epigenetic regulatory mechanism is often based on functional non-coding RNAs (ncRNAs). ncRNAs have become increasingly important in the pathogenesis of human cancer and work as oncogenes or tumor suppressors to regulate carcinogenesis and progression. These RNAs by being involved in chromatin remodeling and modification, transcriptional regulation, and alternative splicing of pre-mRNA, as well as mRNA stability and protein translation, play a key role in tumor development and progression. Numerous studies have been performed to try to understand the dysregulation pattern of these ncRNAs in tumors and cancer stem cells (CSCs), which show robust differentiation and self-regeneration capacity. This review provides recent findings on the role of ncRNAs in glioma development and progression, particularly their effects on CSCs, thus accelerating the clinical implementation of ncRNAs as promising tumor biomarkers and therapeutic targets.
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Affiliation(s)
- Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehrdad Kayedi
- Department of Radiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shiva Rahimi
- School of Medicine,Fasa University of Medical Sciences, Fasa, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mina Homayoonfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Omid Reza Tamtaji
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Afrasiabi
- Department of Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ameneh Jafari
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - 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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19
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Qiu J, Chen L, Yang J, Varier KM, Gajendran B, Yao Y, Liu W, Song J, Rao Q, Long Q, Yuan C, Hao X, Li Y. Garmultin-A Incites Apoptosis in CB3 Cells Through miR-17-5p by Attenuating Poly (ADP-Ribose) Polymerase-1. Dose Response 2022; 20:15593258221130681. [PMID: 36246167 PMCID: PMC9558886 DOI: 10.1177/15593258221130681] [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: 05/25/2022] [Revised: 08/15/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022] Open
Abstract
Background Leukemia accounts for a large number of deaths, worldwide, every year.
Treating this ailment is always a challenging job. Recently, oncogenic miRNA
leading to apoptosis are highly promising targets of many natural products.
In this study, Garmultin-A (GA), isolated from the bark of Garcinia
multiflora, was elucidated for its anti-leukemic effect in CB3
cells. Methods The effect of the compound on CB3 cell viability was detected by MTT assay
and apoptosis by FITC Annexin V/PI and Hochest 33258 staining. The western
blot analysis assessed the BAX, BCL2, cMYC, pERK, and PARP-1 protein levels.
Autodock analysis predicted the ligand–protein interactions. q-RT-PCR
quantified the miR-17-5p expression. Luciferase assay confirmed the
interaction between PARP-1 and miR-17-5p. Results We uncover that GA leads to apoptosis by inducing overexpression of miR-17-5p
and significantly downregulate PARP-1 protein levels in CB3 cells. The
overexpression of miR-17-5p promotes apoptosis, and the miR-17-5p antagomirs
restore GA-triggered apoptosis. Notably, we disclose that PARP-1 is a direct
target of miR-17-5p. Increased pro-apoptotic and reduced anti-apoptosis
protein levels were also observed in GA-treated CB3 cells. Conclusion These results provide critical insights that GA could induce apoptosis in CB3
cells through targeting miR-17-5p by attenuating PARP-1. Thus, GA could act
as a novel therapeutic agent for erythroleukemia.
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Affiliation(s)
- Jianfei Qiu
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China,Department of Immunology, College
of Basic Medical Sciences, Guizhou Medical
University, Guiyang, P.R. China
| | - Li Chen
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Jue Yang
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Krishnapriya M. Varier
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Babu Gajendran
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Yao Yao
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Wuling Liu
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Jingrui Song
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Qing Rao
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Qun Long
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China
| | - Chunmao Yuan
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China,Chunmao Yuan, Xiaojiang Hao and Yanmei Li,
State Key Laboratory for Functions and Applications of Medicinal Plants/School
of Pharmaceutical Sciences, Guizhou Medical University, Baiyun District, Guiyang
Guiyang, P.R. China. Emails: ;
;
| | - Xiaojiang Hao
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China,Chunmao Yuan, Xiaojiang Hao and Yanmei Li,
State Key Laboratory for Functions and Applications of Medicinal Plants/School
of Pharmaceutical Sciences, Guizhou Medical University, Baiyun District, Guiyang
Guiyang, P.R. China. Emails: ;
;
| | - Yanmei Li
- State Key Laboratory for Functions
and Applications of Medicinal Plants/School of Pharmaceutical Sciences,
Guizhou
Medical University, Guiyang, P.R.
China,The Key Laboratory of Chemistry for Natural
Products of Guizhou Province and Chinese Academic of
Sciences, Guiyang, P.R. China,Chunmao Yuan, Xiaojiang Hao and Yanmei Li,
State Key Laboratory for Functions and Applications of Medicinal Plants/School
of Pharmaceutical Sciences, Guizhou Medical University, Baiyun District, Guiyang
Guiyang, P.R. China. Emails: ;
;
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20
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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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Chiantore MV, Iuliano M, Mongiovì RM, Dutta S, Tommasino M, Di Bonito P, Accardi L, Mangino G, Romeo G. The E6 and E7 proteins of beta3 human papillomavirus 49 can deregulate both cellular and extracellular vesicles-carried microRNAs. Infect Agent Cancer 2022; 17:29. [PMID: 35705991 PMCID: PMC9199308 DOI: 10.1186/s13027-022-00445-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The β3 human papillomavirus (HPV)49 induces immortalization of primary keratinocytes through the action of E6 and E7 oncoproteins with an efficiency similar to alpha high risk (HR)-HPV16. Since HR-HPV oncoproteins are known to alter microRNA (miRNA) expression and extracellular vesicle (EV) production, we investigated the impact of HPV49 E6 and E7 proteins on miRNA profile and EV expression, and their involvement in the control of cell proliferation. METHODS The miRNA expression was evaluated by a miRNA array and validated by RT-qPCR in primary human keratinocytes immortalized by β3 HPV49 (K49) or α9 HR-HPV16 (K16), and in EVs from K49 and K16. The modulation of miRNA target proteins was investigated by immunoblotting analyses. RESULTS By comparing miRNA expression in K49 and K16 and the derived EVs, six miRNAs involved in HPV tumorigenesis were selected and validated. MiR-19a and -99a were found to be upregulated and miR-34a downregulated in both cell lines; miR-17 and -590-5p were upregulated in K49 and downmodulated in K16; miR-21 was downregulated only in K16. As for EV-carried miRNAs, the expression of miR-17, -19a, -21 and -99a was decreased and miR-34a was increased in K49 EVs. In K16 EVs, we revealed the same modulation of miR-19a, -34a, and -99a observed in producing cells, while miR-21 was upregulated. Cyclin D1, a common target of the selected miRNAs, was downmodulated in both cell lines, whereas cyclin-dependent kinase 4 was down-modulated in K49 but upregulated in K16. CONCLUSION These data suggest that E6 and E7 proteins of β3 HPV49 and α9 HR-HPV16 affect key factors of cell cycle control by indirect mechanisms based on miRNA modulation.
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Affiliation(s)
| | - Marco Iuliano
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome - Polo Pontino, Latina, Italy
| | - Roberta Maria Mongiovì
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome - Polo Pontino, Latina, Italy
| | - Sankhadeep Dutta
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India
| | - Massimo Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France
- Present Address: Department of Pharmacy-Pharmaceutical Sciences, University of Bari A. Moro, Bari, Italy
| | - Paola Di Bonito
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Luisa Accardi
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Giorgio Mangino
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome - Polo Pontino, Latina, Italy
| | - Giovanna Romeo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome - Polo Pontino, Latina, Italy
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22
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Mallick AM, Tripathi A, Mishra S, Mukherjee A, Dutta C, Chatterjee A, Sinha Roy R. Emerging Approaches for Enabling RNAi Therapeutics. Chem Asian J 2022; 17:e202200451. [PMID: 35689534 DOI: 10.1002/asia.202200451] [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: 04/28/2022] [Revised: 06/04/2022] [Indexed: 11/07/2022]
Abstract
RNA interference (RNAi) is a primitive evolutionary mechanism developed to escape incorporation of foreign genetic material. siRNA has been instrumental in achieving the therapeutic potential of RNAi by theoretically silencing any gene of interest in a reversible and sequence-specific manner. Extrinsically administered siRNA generally needs a delivery vehicle to span across different physiological barriers and load into the RISC complex in the cytoplasm in its functional form to show its efficacy. This review discusses the designing principles and examples of different classes of delivery vehicles that have proved to be efficient in RNAi therapeutics. We also briefly discuss the role of RNAi therapeutics in genetic and rare diseases, epigenetic modifications, immunomodulation and combination modality to inch closer in creating a personalized therapy for metastatic cancer. At the end, we present, strategies and look into the opportunities to develop efficient delivery vehicles for RNAi which can be translated into clinics.
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Affiliation(s)
- Argha M Mallick
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Archana Tripathi
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Sukumar Mishra
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Asmita Mukherjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Chiranjit Dutta
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India.,Present address:Department of Biological Sciences, NUS Environmental Research Institute (NERI), National University of Singapore (NUS), Block S2 #05-01, 16 Science Drive 4, Singapore, 117558, Singapore
| | - Ananya Chatterjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Rituparna Sinha Roy
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India.,Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India.,Centre for Climate and Environmental Studies, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
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23
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The effect of mesenchymal stromal cells ın the microenvironment on cancer development. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:114. [PMID: 35674854 DOI: 10.1007/s12032-022-01703-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/01/2022] [Indexed: 10/18/2022]
Abstract
Inflammatory signals secreted from the tumor microenvironment are thought to promote tumor growth and survival. It has been reported that stromal cells in the tumor microenvironment have similar characteristics to tumor-associated cells. In addition miRNAs play critical roles in various diseases, including cancer. In this study, we aimed to investigate the effects of co-culture of cancer cells and stromal cells isolated from normal and malignant breast tissue on each other and the possible effects of miRNAs on these interactions. The characterized stromal cells were co-cultured with an MDA-MB-231 cancer cell line. The proliferation capacity of the experimental groups was evaluated using the WST-1 assay. The expression of breast cancer-specific miRNAs and related genes were assessed by real-time PCR. ELISA assay was performed to determine the concentration of some cytokines and chemokines. We found that the microenvironment plays an important role in the development of cancer, confirming the changes in the expression of oncogenic and tumor suppressor miRNA and their target genes after co-culture with malignant stromal cells. As a result of the studies, specific gene expressions of related signaling pathways were detected in correlation with miRNA changes and the effects of tumor microenvironment on tumorigenesis were revealed in detail. miRNAs have been shown to play an important role in cancer development in recent studies. The idea that these small molecules can be used in diagnosis and treatment is becoming stronger day by day. We believe that new treatment approaches involving the tumor microenvironment and using miRNAs as markers are promising.
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24
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Fan X, Zou X, Liu C, Peng S, Zhang S, Zhou X, Wang T, Zhu W. Global analysis of miRNA-mRNA regulation pair in bladder cancer. World J Surg Oncol 2022; 20:66. [PMID: 35241117 PMCID: PMC8896384 DOI: 10.1186/s12957-022-02538-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 02/21/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose MicroRNA (miRNA) is a class of short non-coding RNA molecules that functions in RNA silencing and post-transcriptional regulation of gene expression. This study aims to identify critical miRNA-mRNA regulation pairs contributing to bladder cancer (BLCA) pathogenesis. Patients and methods MiRNA and mRNA microarray and RNA-sequencing datasets were downloaded from gene expression omnibus (GEO) and the cancer genome atlas (TCGA) databases. The tool of GEO2R and R packages were used to screen differential miRNAs (DE-miRNAs) and mRNAs (DE-mRNAs) and DAVID, DIANA, and Hiplot tools were used to perform gene enrichment analysis. The miRNA-mRNA regulation pair were screened from the experimentally validated miRNA-target interactions databases (miRTarbase and TarBase). Twenty-eight pairs of BLCA tissues were used to further verify the screened DE-miRNAs and DE-mRNAs by quantitative reverse transcription and polymerase chain reaction (qRT-PCR). The diagnostic value of the miRNA-mRNA regulation pairs was evaluated by receiver operating characteristic curve (ROC) and decision curve analysis (DCA). The correlation analysis between the selected miRNA-mRNAs regulation pair and clinical, survival and tumor-related phenotypes was performed in this study. Results After miRTarBase, the analysis of 2 miRNA datasets, 6 mRNA datasets, and TCGA-BLCA dataset, a total of 13 miRNAs (5 downregulated and 8 upregulated in BLCA tissues) and 181 mRNAs (72 upregulated and 109 downregulated in BLCA tissues) were screened out. The pairs of miR-17-5p (upregulated in BLCA tissues) and TGFBR2 (downregulated in BLCA tissues) were verified in the external validation cohort (28 BLCA vs. 28 NC) using qRT-PCR. Areas under the ROC curve of the miRNA-mRNA regulation pair panel were 0.929 (95% CI: 0.885–0.972, p < 0.0001) in TCGA-BLCA and 0.767 (95% CI: 0.643–0.891, p = 0.001) in the external validation. The DCA also showed that the miRNA-mRNA regulation pairs had an excellent diagnostic performance distinguishing BLCA from normal controls. Correlation analysis showed that miR-17-5p and TGFBR2 correlated with tumor immunity. Conclusions The research identified potential miRNA-mRNA regulation pairs, providing a new idea for exploring the genesis and development of BLCA. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02538-w.
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Affiliation(s)
- Xingchen Fan
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Xuan Zou
- First Clinical College of Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People's Republic of China
| | - Cheng Liu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Shuang Peng
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Shiyu Zhang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.
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25
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Wan X, Yan Z, Tan Z, Cai Z, Qi Y, Lu L, Xu Y, Chen J, Lei T. MicroRNAs in Dopamine Agonist-Resistant Prolactinoma. Neuroendocrinology 2022; 112:417-426. [PMID: 34034260 DOI: 10.1159/000517356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/23/2021] [Indexed: 11/19/2022]
Abstract
Dopamine agonists (DAs) are preferred for the treatment of prolactinomas and are usually very effective. Nonetheless, 20-30% of bromocriptine- and approximately 10% of cabergoline-treated individuals exhibit resistance to DAs. In addition, the mechanism underlying this phenomenon remains elusive. In this study, we summarize the major findings regarding the role of microRNAs (miRNAs) in the pathogenesis of DA-resistant prolactinoma (DARP). Currently available evidence suggests that miRNAs are usually dysregulated in DARP and that, although controversial, the dysregulated miRNAs target the transforming growth factor (TGF)-β, dopamine 2 receptor (D2R), or estradiol (E2)/estrogen receptor (ER) signaling pathways to mediate the therapeutic effect of DAs. These findings provide new incentives for research on innovative strategies for predicting patients' responsiveness to dopamine therapies and for developing treatment approaches. Unfortunately, recent studies tended to focus exclusively on the differential miRNA expression profiles between DARP and dopamine-sensitive prolactinoma, and no definitive consensus has been reached regarding the role of these miRNAs in the modulation mechanism. Therefore, current and future efforts should be directed toward the exploration of the mechanism underlying the dysregulation of miRNAs as well as of the target proteins that are affected by the dysregulated miRNAs. Furthermore, the modulation of the expression of dysregulated miRNAs, which target the D2R, TGF-β, or E2/ER signaling pathways, might be a promising alternative to treat patients with DARP and improve their prognosis.
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Affiliation(s)
- Xueyan Wan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zisheng Yan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhoubin Tan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi Cai
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiwei Qi
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Lu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Xu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Lei
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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26
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Winter E, Cisilotto J, Silva AH, Rosolen D, Fabichak AP, Rode MP, Creczynski-Pasa TB. MicroRNAs: Potential biomarkers for reproduction, diagnosis, prognosis, and therapeutic in domestic animals. Res Vet Sci 2021; 142:117-132. [PMID: 34942556 DOI: 10.1016/j.rvsc.2021.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 11/02/2021] [Accepted: 12/01/2021] [Indexed: 10/19/2022]
Abstract
MicroRNA (miRNAs) are small non-coding RNA molecules involved in a wide range of biological processes through the post-transcriptional regulation of gene expression. Most studies evaluated microRNA expression in human, and despite fewer studies in veterinary medicine, this topic is one of the most exciting areas of modern veterinary medicine. miRNAs showed to be part of the pathogenesis of diseases and reproduction physiology in animals, making them biomarkers candidates. This review provides an overview of the current knowledge regarding miRNAs' role in reproduction and animal diseases, diagnostic and therapy.
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Affiliation(s)
- Evelyn Winter
- Department of Agriculture, Biodiversity and Forests, Federal University of Santa Catarina, Curitibanos, 89520000, SC, Brazil.
| | - Júlia Cisilotto
- Postgraduate Program in Pharmacy, Federal University of Santa Catarina, Florianopolis, 88040-900, SC, Brazil
| | - Adny Henrique Silva
- Postgraduate Program in Pharmacy, Federal University of Santa Catarina, Florianopolis, 88040-900, SC, Brazil
| | - Daiane Rosolen
- Postgraduate Program in Pharmacy, Federal University of Santa Catarina, Florianopolis, 88040-900, SC, Brazil
| | - Ana Paula Fabichak
- Department of Agriculture, Biodiversity and Forests, Federal University of Santa Catarina, Curitibanos, 89520000, SC, Brazil
| | - Michele Patricia Rode
- Postgraduate Program in Pharmacy, Federal University of Santa Catarina, Florianopolis, 88040-900, SC, Brazil
| | - Tânia Beatriz Creczynski-Pasa
- Postgraduate Program in Pharmacy, Federal University of Santa Catarina, Florianopolis, 88040-900, SC, Brazil; Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, 88040-900, SC, Brazil
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27
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Andreeva OE, Sorokin DV, Mikhaevich EI, Bure IV, Shchegolev YY, Nemtsova MV, Gudkova MV, Scherbakov AM, Krasil’nikov MA. Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance. Molecules 2021; 26:molecules26216661. [PMID: 34771077 PMCID: PMC8588049 DOI: 10.3390/molecules26216661] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/26/2021] [Accepted: 10/30/2021] [Indexed: 01/09/2023] Open
Abstract
Hormone therapy is one of the most effective breast cancer treatments, however, its application is limited by the progression of hormonal resistance, both primary or acquired. The development of hormonal resistance is caused either by an irreversible block of hormonal signalling (suppression of the activity or synthesis of hormone receptors), or by activation of oestrogen-independent signalling pathways. Recently the effect of exosome-mediated intercellular transfer of hormonal resistance was revealed, however, the molecular mechanism of this effect is still unknown. Here, the role of exosomal miRNAs (microRNAs) in the transferring of hormonal resistance in breast cancer cells has been studied. The methods used in the work include extraction, purification and RNAseq of miRNAs, transfection of miRNA mimetics, immunoblotting, reporter analysis and the MTT test. Using MCF7 breast cancer cells and MCF7/T tamoxifen-resistant sub-line, we have found that some miRNAs, suppressors of oestrogen receptor signalling, are overexpressed in the exosomes of the resistant breast cancer cells. The multiple (but not single) transfection of one of the identified miRNA, miR-181a-2, into oestrogen-dependent MCF7 cells induced the irreversible tamoxifen resistance associated with the continuous block of the oestrogen receptor signalling and the activation of PI3K/Akt pathway. We suppose that the miRNAs-ERα suppressors may act as trigger agents inducing the block of oestrogen receptor signalling and breast cancer cell transition to an aggressive oestrogen-independent state.
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Affiliation(s)
- Olga E. Andreeva
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
| | - Danila V. Sorokin
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
| | - Ekaterina I. Mikhaevich
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
| | - Irina V. Bure
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (I.V.B.); (M.V.N.)
| | - Yuri Y. Shchegolev
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
| | - Marina V. Nemtsova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (I.V.B.); (M.V.N.)
| | - Margarita V. Gudkova
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
| | - Alexander M. Scherbakov
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
- Correspondence: or
| | - Mikhail A. Krasil’nikov
- Department of Experimental Tumour Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia; (O.E.A.); (D.V.S.); (E.I.M.); (Y.Y.S.); (M.V.G.); (M.A.K.)
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28
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Raigon Ponferrada A, Guerrero Orriach JL, Molina Ruiz JC, Romero Molina S, Gómez Luque A, Cruz Mañas J. Breast Cancer and Anaesthesia: Genetic Influence. Int J Mol Sci 2021; 22:7653. [PMID: 34299272 PMCID: PMC8307639 DOI: 10.3390/ijms22147653] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022] Open
Abstract
Breast cancer is the leading cause of mortality in women. It is a heterogeneous disease with a high degree of inter-subject variability even in patients with the same type of tumor, with individualized medicine having acquired significant relevance in this field. The clinical and morphological heterogeneity of the different types of breast tumors has led to a diversity of staging and classification systems. Thus, these tumors show wide variability in genetic expression and prognostic biomarkers. Surgical treatment is essential in the management of these patients. However, the perioperative period has been found to significantly influence survival and cancer recurrence. There is growing interest in the pro-tumoral effect of different anaesthetic and analgesic agents used intraoperatively and their relationship with metastatic progression. There is cumulative evidence of the influence of anaesthetic techniques on the physiopathological mechanisms of survival and growth of the residual neoplastic cells released during surgery. Prospective randomized clinical trials are needed to obtain quality evidence on the relationship between cancer and anaesthesia. This document summarizes the evidence currently available about the effects of the anaesthetic agents and techniques used in primary cancer surgery and long-term oncologic outcomes, and the biomolecular mechanisms involved in their interaction.
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Affiliation(s)
- Aida Raigon Ponferrada
- Institute of Biomedical Research in Malaga (IBIMA), 29010 Malaga, Spain; (A.R.P.); (A.G.L.)
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
| | - Jose Luis Guerrero Orriach
- Institute of Biomedical Research in Malaga (IBIMA), 29010 Malaga, Spain; (A.R.P.); (A.G.L.)
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
- Department of Pharmacology and Pediatrics, School of Medicine, University of Malaga, 29010 Malaga, Spain
| | - Juan Carlos Molina Ruiz
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
| | - Salvador Romero Molina
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
| | - Aurelio Gómez Luque
- Institute of Biomedical Research in Malaga (IBIMA), 29010 Malaga, Spain; (A.R.P.); (A.G.L.)
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
- Department of Pharmacology and Pediatrics, School of Medicine, University of Malaga, 29010 Malaga, Spain
| | - Jose Cruz Mañas
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
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Khalaf K, Hana D, Chou JTT, Singh C, Mackiewicz A, Kaczmarek M. Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Front Immunol 2021; 12:656364. [PMID: 34122412 PMCID: PMC8190405 DOI: 10.3389/fimmu.2021.656364] [Citation(s) in RCA: 262] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/27/2021] [Indexed: 12/11/2022] Open
Abstract
The tumor microenvironment (TME) is a complex and ever-changing "rogue organ" composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.
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Affiliation(s)
- Khalil Khalaf
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Doris Hana
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Jadzia Tin-Tsen Chou
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Chandpreet Singh
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Andrzej Mackiewicz
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
| | - Mariusz Kaczmarek
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Center, Poznań, Poland
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland
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SRC-3, a Steroid Receptor Coactivator: Implication in Cancer. Int J Mol Sci 2021; 22:ijms22094760. [PMID: 33946224 PMCID: PMC8124743 DOI: 10.3390/ijms22094760] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
Steroid receptor coactivator-3 (SRC-3), also known as amplified in breast cancer 1 (AIB1), is a member of the SRC family. SRC-3 regulates not only the transcriptional activity of nuclear receptors but also many other transcription factors. Besides the essential role of SRC-3 in physiological functions, it also acts as an oncogene to promote multiple aspects of cancer. This review updates the important progress of SRC-3 in carcinogenesis and summarizes its mode of action, which provides clues for cancer therapy.
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Berberine suppresses bladder cancer cell proliferation by inhibiting JAK1-STAT3 signaling via upregulation of miR-17-5p. Biochem Pharmacol 2021; 188:114575. [PMID: 33887260 DOI: 10.1016/j.bcp.2021.114575] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023]
Abstract
Hyperactivation of signal transducer and activator of transcription 3 (STAT3) is strongly associated with cancer initiation, progression, metastasis, chemoresistance, and immune evasion; thus, STAT3 has been intensely studied as a therapeutic target for cancer treatment. Berberine (BBR), an active component extracted from Coptis chinensis, has shown anti-tumor effects in multiple tumors. However, its underlying mechanisms have not yet been fully elucidated. In this study, we investigated the effects and the underlying mechanisms of BBR on bladder cancer (BCa) cells. We found that BBR showed significant cytotoxic effects against BCa cell lines both in vivo and in vitro, with much lower cytotoxic effects on the human normal urothelial cell line SV-HUC-1. BBR treatment induced DNA replication defects and cell cycle arrest, resulting in apoptosis or cell senescence, depending on p53 status, in BCa cells. Mechanistically, BBR exerted anti-tumor effects on BCa cells by inhibiting Janus kinase 1 (JAK1)-STAT3 signaling through the upregulation of miR-17-5p, which directly binds to the 3'UTR of JAK1 and STAT3, downregulating their expressions. Collectively, our results demonstrate that BBR exerts anti-tumor effects by perturbing JAK1-STAT3 signaling through the upregulation of miR-17-5p in BCa cells, and that BBR may serve as a potential therapeutic option for BCa treatment.
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Singh M, Kumar V, Sehrawat N, Yadav M, Chaudhary M, Upadhyay SK, Kumar S, Sharma V, Kumar S, Dilbaghi N, Sharma AK. Current paradigms in epigenetic anticancer therapeutics and future challenges. Semin Cancer Biol 2021; 83:422-440. [PMID: 33766649 DOI: 10.1016/j.semcancer.2021.03.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/14/2020] [Accepted: 03/16/2021] [Indexed: 12/16/2022]
Abstract
Any alteration at the genetic or epigenetic level, may result in multiplex of diseases including tumorigenesis which ultimately results in the cancer development. Restoration of the normal epigenome by reversing the epigenetic alterations have been reported in tumors paving the way for development of an effective epigenetic treatment in cancer. However, delineating various epigenetic events has been a challenging task so far despite substantial progress in understanding DNA methylation and histone modifications during transcription of genes. Many inhibitors in the form of epigenetic drugs mostly targeting chromatin and histone modifying enzymes including DNA methyltransferase (DNMT) enzyme inhibitors and a histone deacetylases (HDACs) inhibitor, have been in use subsequent to the approval by FDA for cancer treatment. Similarly, other inhibitory drugs, such as FK228, suberoylanilide hydroxamic acid (SAHA) and MS-275, have been successfully tested in clinical studies. Despite all these advancements, still we see a hazy view as far as a promising epigenetic anticancer therapy is concerned. The challenges are to have more specific and effective inhibitors with negligible side effects. Moreover, the alterations seen in tumors are not well understood for which one has to gain deeper insight into the tumor pathology as well. Current review focusses on such epigenetic alterations occurring in cancer and the effective strategies to utilize such alterations for potential therapeutic use and treatment in cancer.
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Affiliation(s)
- Manoj Singh
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Vikas Kumar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Nirmala Sehrawat
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Mukesh Yadav
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Mayank Chaudhary
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Sushil K Upadhyay
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Sunil Kumar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Varruchi Sharma
- Department of Biotechnology, Sri Guru Gobind Singh College Sector-26, Chandigarh, UT, 160019, India
| | - Sandeep Kumar
- Department of Bio& Nanotechnology, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, 125001, India
| | - Neeraj Dilbaghi
- Department of Bio& Nanotechnology, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, 125001, India
| | - Anil K Sharma
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India.
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López-Jiménez E, Andrés-León E. The Implications of ncRNAs in the Development of Human Diseases. Noncoding RNA 2021; 7:17. [PMID: 33668203 PMCID: PMC8006041 DOI: 10.3390/ncrna7010017] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/14/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
The mammalian genome comprehends a small minority of genes that encode for proteins (barely 2% of the total genome in humans) and an immense majority of genes that are transcribed into RNA but not encoded for proteins (ncRNAs). These non-coding genes are intimately related to the expression regulation of protein-coding genes. The ncRNAs subtypes differ in their size, so there are long non-coding genes (lncRNAs) and other smaller ones, like microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs). Due to their important role in the maintenance of cellular functioning, any deregulation of the expression profiles of these ncRNAs can dissemble in the development of different types of diseases. Among them, we can highlight some of high incidence in the population, such as cancer, neurodegenerative, or cardiovascular disorders. In addition, thanks to the enormous advances in the field of medical genomics, these same ncRNAs are starting to be used as possible drugs, approved by the FDA, as an effective treatment for diseases.
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Affiliation(s)
- Elena López-Jiménez
- Centre for Haematology, Immunology and Inflammation Department, Faculty of Medicine, Imperial College London, London W12 0NN, UK
| | - Eduardo Andrés-León
- Unidad de Bioinformática, Instituto de Parasitología y Biomedicina “López-Neyra”, Consejo Superior de Investigaciones Científicas, 18016 Granada, Spain
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Twist activates miR-22 to suppress estrogen receptor alpha in breast cancer. Mol Cell Biochem 2021; 476:2295-2306. [PMID: 33582945 DOI: 10.1007/s11010-021-04065-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022]
Abstract
TWIST1 (Twist) is a basic helix-loop-helix transcription factor that is overexpressed in many cancers and promotes tumor cell invasion, metastasis, and recurrence. In this study, we demonstrate that Twist upregulates expression of microRNA 22 (miR-22) which, in turn, downregulates estrogen receptor alpha (ER) expression in breast cancer. Initial analysis of miR-22 and Twist expression in a panel of breast cancer cell lines showed a direct correlation between Twist and miR-22 levels with miR-22 being highly expressed in ER negative cell lines. Overexpressing Twist caused increased miR-22 levels while downregulating it led to decreased miR-22 expression. To characterize the upstream promoter region of miR-22, we utilized rapid amplification of cDNA ends and identified the transcription start site and the putative promoter region of miR-22. Mechanistically, we determined that Twist, in combination with HDAC1 and DNMT3B, transcriptionally upregulates miR-22 expression by binding to E-boxes in the proximal miR-22 promoter. We also established that miR-22 causes an increase in growth in 3D but not 2D cultures. Importantly, we observed a direct correlation between increased breast cancer grade and Twist and miR-22 expression. We also identified two potential miR-22 binding sites in the 3'-UTR region of ER and confirmed by promoter assays that miR-22 regulates ER expression by binding to both target sites. These results reveal a novel pathway of ER suppression by Twist through miR-22 activation that could potentially promote the ER negative phenotype in breast cancers.
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GPER1 and microRNA: Two Players in Breast Cancer Progression. Int J Mol Sci 2020; 22:ijms22010098. [PMID: 33374170 PMCID: PMC7795792 DOI: 10.3390/ijms22010098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is the main cause of morbidity and mortality in women worldwide. However, the molecular pathogenesis of breast cancer remains poorly defined due to its heterogeneity. Several studies have reported that G Protein-Coupled Estrogen Receptor 1 (GPER1) plays a crucial role in breast cancer progression, by binding to estrogens or synthetic agonists, like G-1, thus modulating genes involved in diverse biological events, such as cell proliferation, migration, apoptosis, and metastasis. In addition, it has been established that the dysregulation of short sequences of non-coding RNA, named microRNAs (miRNAs), is involved in various pathophysiological conditions, including breast cancer. Recent evidence has indicated that estrogens may regulate miRNA expression and therefore modulate the levels of their target genes, not only through the classical estrogen receptors (ERs), but also activating GPER1 signalling, hence suggesting an alternative molecular pathway involved in breast tumor progression. Here, the current knowledge about GPER1 and miRNA action in breast cancer is recapitulated, reporting recent evidence on the liaison of these two players in triggering breast tumorogenic effects. Elucidating the role of GPER1 and miRNAs in breast cancer might provide new tools for innovative approaches in anti-cancer therapy.
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Kandettu A, Radhakrishnan R, Chakrabarty S, Sriharikrishnaa S, Kabekkodu SP. The emerging role of miRNA clusters in breast cancer progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188413. [PMID: 32827583 DOI: 10.1016/j.bbcan.2020.188413] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/01/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
Micro RNAs (miRNAs) are small non-coding RNAs that are essential for regulation of gene expression of the target genes. Large number of miRNAs are organized into defined units known as miRNA clusters (MCs). The MCs consist of two or more than two miRNA encoding genes driven by a single promoter, transcribed together in the same orientation, that are not separated from each other by a transcription unit. Aberrant miRNA clusters expression is reported in breast cancer (BC), exhibiting both pro-tumorogenic and anti-tumorigenic role. Altered MCs expression facilitates to breast carcinogenesis by promoting the breast cells to acquire the various hallmarks of the cancer. Since miRNA clusters contain multiple miRNA encoding genes, targeting cluster may be more attractive than targeting individual miRNAs. Besides targeting dysregulated miRNA clusters in BC, studies have focused on the mechanism of action, and its contribution to the progression of the BC. The present review provides a comprehensive overview of dysregulated miRNA clusters and its role in the acquisition of cancer hallmarks in BC. More specifically, we have presented the regulation, differential expression, classification, targets, mechanism of action, and signaling pathways of miRNA clusters in BC. Additionally, we have also discussed the potential utility of the miRNA cluster as a diagnostic and prognostic indicator in BC.
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Affiliation(s)
- Amoolya Kandettu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - S Sriharikrishnaa
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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Upregulation of miRNA-23a-3p rescues high glucose-induced cell apoptosis and proliferation inhibition in cardiomyocytes. In Vitro Cell Dev Biol Anim 2020; 56:866-877. [PMID: 33197036 PMCID: PMC7723946 DOI: 10.1007/s11626-020-00518-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
Abstract
Maternal hyperglycemia potentially inhibits the development of the fetal heart by suppressing cardiomyocyte proliferation and promoting apoptosis. Different studies have indicated that miRNAs are key regulators of cardiomyocyte proliferation, differentiation, and apoptosis and play a protective role in a variety of cardiovascular diseases. However, the biological function of miRNA-23a in hyperglycemia-related cardiomyocyte injury is not fully understood. The present study investigated the effect of miRNA-23a-3p on cell proliferation and apoptosis in a myocardial injury model induced by high glucose. H9c2 cardiomyocytes were exposed to high glucose to establish an in vitro myocardial injury model and then transfected with miRNA-23a-3p mimics. After miRNA-23a-3p transfection, lens-free microscopy was used to dynamically monitor cell numbers and confluence and calculate the cell cycle duration. CCK-8 and EdU incorporation assays were performed to detect cell proliferation. Flow cytometry was used to measured cell apoptosis. Upregulation of miRNA-23a-3p significantly alleviated high glucose-induced cell apoptosis and cell proliferation inhibition (p < 0.01 and p < 0.0001, respectively). The cell cycle of the miRNA-23a-3p mimics group was significantly shorter than that of the negative control group (p < 0.01). The expression of cell cycle–activating and apoptosis inhibition-associated factors Ccna2, Ccne1, and Bcl-2 was downregulated by high glucose and upregulated by miRNA-23a-3p overexpression in high glucose-injured H9c2 cells. miRNA-23a-3p mimics transfection before high glucose treatment had a significantly greater benefit than transfection after high glucose treatment (p < 0.0001), and the rescue effect of miRNA-23a-3p increased as the concentration increased. This study suggests that miRNA-23a-3p exerted a dose- and time-dependent protective effect on high glucose-induced H9c2 cardiomyocyte injury.
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38
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Levy-Jurgenson A, Tekpli X, Kristensen VN, Yakhini Z. Spatial transcriptomics inferred from pathology whole-slide images links tumor heterogeneity to survival in breast and lung cancer. Sci Rep 2020; 10:18802. [PMID: 33139755 PMCID: PMC7606448 DOI: 10.1038/s41598-020-75708-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
Digital analysis of pathology whole-slide images is fast becoming a game changer in cancer diagnosis and treatment. Specifically, deep learning methods have shown great potential to support pathology analysis, with recent studies identifying molecular traits that were not previously recognized in pathology H&E whole-slide images. Simultaneous to these developments, it is becoming increasingly evident that tumor heterogeneity is an important determinant of cancer prognosis and susceptibility to treatment, and should therefore play a role in the evolving practices of matching treatment protocols to patients. State of the art diagnostic procedures, however, do not provide automated methods for characterizing and/or quantifying tumor heterogeneity, certainly not in a spatial context. Further, existing methods for analyzing pathology whole-slide images from bulk measurements require many training samples and complex pipelines. Our work addresses these two challenges. First, we train deep learning models to spatially resolve bulk mRNA and miRNA expression levels on pathology whole-slide images (WSIs). Our models reach up to 0.95 AUC on held-out test sets from two cancer cohorts using a simple training pipeline and a small number of training samples. Using the inferred gene expression levels, we further develop a method to spatially characterize tumor heterogeneity. Specifically, we produce tumor molecular cartographies and heterogeneity maps of WSIs and formulate a heterogeneity index (HTI) that quantifies the level of heterogeneity within these maps. Applying our methods to breast and lung cancer slides, we show a significant statistical link between heterogeneity and survival. Our methods potentially open a new and accessible approach to investigating tumor heterogeneity and other spatial molecular properties and their link to clinical characteristics, including treatment susceptibility and survival.
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Affiliation(s)
- Alona Levy-Jurgenson
- Department of Computer Science, Technion - Israel Institute of Technology, Haifa, 32000, Israel.
| | - Xavier Tekpli
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway
| | - Vessela N Kristensen
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway
- Division of Medicine, Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Lørenskog, Norway
| | - Zohar Yakhini
- Department of Computer Science, Technion - Israel Institute of Technology, Haifa, 32000, Israel.
- Interdisciplinary Center, Arazi School of Computer Science, Herzliya, 4610101, Israel.
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Differential expression, function and prognostic value of miR-17-92 cluster in ER-positive and triple-negative breast cancer. Cancer Treat Res Commun 2020; 25:100224. [PMID: 33096318 DOI: 10.1016/j.ctarc.2020.100224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/02/2020] [Accepted: 10/11/2020] [Indexed: 12/19/2022]
Abstract
Recent evidence has shown that the miR-17-92 cluster can function either as oncogene or tumor suppressor in human cancers. The function of miR-17-92 in subtypes of breast cancer remains largely unknown. The expression of miR-17-92 is elevated in triple negative breast cancer (TNBC) but reduced in estrogen receptor (ER)-positive breast cancer (ERPBC). We show that increased expression of miRNAs belonging to the miR-17-92 cluster is associated with poor outcome in TNBC, whereas the expression of miR-17-92 miRNAs is with good outcome in ERPBC. We show that ectopic expression of miR-17-92 inhibited cell growth and invasion of ER-positive and HER2-enriched cells. On the contrary, miR-17-92 expression enhanced cell growth and invasion of TNBC cells. Further, we found that miR-17-92 expression sensitized MCF7 cells to chemotherapeutic compounds, whereas it rendered SKBR3 cells resistant to them. We found that expression of ADORA1 was reduced by miR-17-92-expressing breast cancer cells, specifically in ERPBC. We observed an inverse correlation between the expression of ADORA1 and miR-17-92 in human breast cancer. Treatment with DPCPX, a selective ADORA1 antagonist, abolished the difference in the growth of control and miR-17-92 overexpressing MCF7 cells and identified ADORA1 as a key functional target of miR-17-92 in ERPBC. Furthermore, increased expression of ADORA1 in ERPBC is associated with a poor outcome. Our observations underscore the context-dependent role of miR-17-92 in breast cancer subtypes and suggest that miR-17-92 could serve as novel prognostic markers in breast cancer.
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Saikia M, Paul S, Chakraborty S. Role of microRNA in forming breast carcinoma. Life Sci 2020; 259:118256. [DOI: 10.1016/j.lfs.2020.118256] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/31/2020] [Accepted: 08/08/2020] [Indexed: 12/19/2022]
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Chatterjee B, Saha P, Bose S, Shukla D, Chatterjee N, Kumar S, Tripathi PP, Srivastava AK. MicroRNAs: As Critical Regulators of Tumor- Associated Macrophages. Int J Mol Sci 2020; 21:ijms21197117. [PMID: 32992449 PMCID: PMC7582892 DOI: 10.3390/ijms21197117] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022] Open
Abstract
Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer.
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Affiliation(s)
- Bilash Chatterjee
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Priyanka Saha
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Subhankar Bose
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Devendra Shukla
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
| | - Nabanita Chatterjee
- Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, WB 700026, India;
| | - Sanjay Kumar
- Division of Biology, Indian Institute of Science Education & Research, Tirupati, Andhra Pradesh 517507, India;
| | - Prem Prakash Tripathi
- Cell Biology & Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India;
| | - Amit Kumar Srivastava
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB 700032, India; (B.C.); (P.S.); (S.B.); (D.S.)
- Correspondence:
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Lv M, Li J, Gao X, Hao Y, Zhao F. Decreased expression of microRNA-17 in hippocampal tissues and blood from mice with depression up-regulates the expression of PAI-1 mRNA and protein. Braz J Med Biol Res 2020; 53:e8826. [PMID: 32901686 PMCID: PMC7485310 DOI: 10.1590/1414-431x20208826] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 05/22/2020] [Indexed: 01/19/2023] Open
Abstract
This study determined the expression of plasminogen activator inhibitor-1 (PAI-1) and microRNA (miR)-17 in a mouse depression model. Forty male mice were divided evenly into control and depression groups. A chronic unpredictable mild stress (CUMS) model was constructed. qRT-PCR was used to determine the expression of PAI-1 mRNA and miR-17. Western blotting and ELISA were used to determine expression of PAI-1 protein. Dual luciferase reporter assay was carried out to identify direct interaction between miR-17 and PAI-1 mRNA. The mice with depression had elevated PAI-1 mRNA and protein in hippocampal tissues and blood. Expression of miR-17 was decreased in hippocampal tissues and blood from mice with depression. miR-17 bound with the 3'-UTR of PAI-1 mRNA to regulate its expression. This study demonstrated that miR-17 expression in hippocampal tissues and blood from mice with depression was decreased while expression of PAI-1 mRNA and protein was up-regulated. miR-17 participated in depression in mice by regulating PAI-1.
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Affiliation(s)
- Min Lv
- Department of Psychology, The Second Children and Women's Healthcare of Jinan City, Jinan, China
| | - Jing Li
- Department of Gynecology, The Second Children and Women's Healthcare of Jinan City, Jinan, China
| | - Xinxue Gao
- Department of Psychiatry, Jining Psychiatry Hospital, Jining, China
| | - Yurong Hao
- Department of Psychiatry, Jining Psychiatry Hospital, Jining, China
| | - Fengxia Zhao
- Cardiac Intensive Care Unit, Affiliated Hospital of Jining Medical University, Jining, China
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MiR-93 suppresses tumorigenesis and enhances chemosensitivity of breast cancer via dual targeting E2F1 and CCND1. Cell Death Dis 2020; 11:618. [PMID: 32796817 PMCID: PMC7428045 DOI: 10.1038/s41419-020-02855-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 07/29/2020] [Accepted: 07/29/2020] [Indexed: 01/19/2023]
Abstract
Chemoresistance of tumors often leads to treatment failure in clinical practice, which underscores pivotal needs to uncover novel therapeutic strategies. Accumulating evidences show that microRNAs (miRNAs) are widely involved in carcinogenesis, but their function on chemoresistance remains largely unexplored. In this study, we found that miR-93-5p (miR-93) significantly inhibited cell proliferation, induced G1/S cell cycle arrest and increased chemosensitivity to paclitaxel (PTX) in vitro and in vivo. Moreover, two well-established oncogenes, E2F1 and CCND1, were identified as dual targets of miR-93. Knockdown of E2F1 and CCND1 reduced cell proliferation and PTX-sensitivity, whereas overexpression of them had the opposite effect. More importantly, overexpression of E2F1 and CCND1 antagonized miR-93-mediated cell cycle arrest and apoptosis. Further mechanistic study revealed that miR-93 exhibited its inhibitory role by directly targeting E2F1 and CCND1 to inactivate pRB/E2F1 pathway and AKT phosphorylation. Taken together, our findings suggested that miR-93 greatly improved chemosensitivity and potentially served as a novel therapeutic target for breast cancer treatment.
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Association of the Expression Level of miR-16 with Prognosis of Solid Cancer Patients: A Meta-Analysis and Bioinformatic Analysis. DISEASE MARKERS 2020; 2020:8815270. [PMID: 32774515 PMCID: PMC7397416 DOI: 10.1155/2020/8815270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/19/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
Objective To assess the association between the expression level of miR-16 and prognosis of solid cancer patients by meta-analysis and bioinformatic analysis. Methods PubMed, Web of Science, and Embase databases were searched until October 31, 2019, to identify eligible studies reporting the association of the miR-16 status with the prognosis of solid cancer patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled, and a heterogeneity test was conducted. Sensitivity analysis and a publication bias test were also carried out. Furthermore, the miRpower database was used to validate the association. Results Thirteen articles with 2303 solid cancer patients were included in the meta-analysis. Solid cancer patients with low expression level of miR-16 had shorter survival time (I2 = 84.0%, HR = 1.47, 95% CI: 1.13-1.91, P = 0.004). In the subgroup analyses of cancer sites, low miR-16 expression level was associated with poor prognosis in the reproductive system cancers (I2 = 33.3%, HR = 1.24, 95% CI: 1.06-1.45, P = 0.008). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Begg's test and Egger's test revealed no publication bias in the meta-analysis. In bioinformatic analysis, the significant association between miR-16 level and prognosis of patients with reproductive system cancers was further confirmed (HR = 1.21, 95% CI: 1.03-1.42, P = 0.017). Conclusion Low expression level of miR-16 is an indicator for poor prognosis of solid cancer patients, particularly in reproductive system cancers.
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Shafi S, Khan S, Hoda F, Fayaz F, Singh A, Khan MA, Ali R, Pottoo FH, Tariq S, Najmi AK. Decoding Novel Mechanisms and Emerging Therapeutic Strategies in Breast Cancer Resistance. Curr Drug Metab 2020; 21:199-210. [DOI: 10.2174/1389200221666200303124946] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 12/12/2019] [Accepted: 12/30/2019] [Indexed: 12/24/2022]
Abstract
Breast cancer (BC), an intricate and highly heterogeneous disorder, has presently afflicted 2.09 million females globally. Chemoresistance remains a paramount challenge in the treatment of BC. Owing to its assorted nature, the chemoresistant mechanisms of BC still need intensive research. Accumulating evidence suggests that abnormalities related to the biogenesis of cancer stem cells (CSCs) and microRNAs (miRNAs) are associated with BC progression and chemoresistance. The presently available interventions are inadequate to target chemoresistance, therefore more efficient alternatives are urgently needed to improvise existing therapeutic regimens. A myriad of strategies is being explored, such as immunotherapy, gene therapy, and combination treatment to surmount chemoresistance. Additionally, nanoparticles as chemotherapeutic carriers put forward the options to encapsulate numerous drugs, alone as well as in combination for cancer theranostics. This review summarizes the chemoresistance mechanisms of miRNAs and CSCs as well as the most recently documented therapeutic approaches for the treatment of chemoresistance in BC. By unraveling the underpinning mechanism of BC chemoresistance, researchers could possibly develop more efficient treatment strategies towards BC.
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Affiliation(s)
- Sadat Shafi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Sana Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Farazul Hoda
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Faizana Fayaz
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-3, MB Road, Pushp Vihar, New Delhi 110017, India
| | - Archu Singh
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Ruhi Ali
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-3, MB Road, Pushp Vihar, New Delhi 110017, India
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Sana Tariq
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-3, MB Road, Pushp Vihar, New Delhi 110017, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
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Shen P, Sun G, Zhao P, Dai J, Zhang X, Zhao J, Zhu S, Chen J, Tao R, Yang J, Zeng H. MicroRNA-106a suppresses prostate cancer proliferation, migration and invasion by targeting tumor-derived IL-8. Transl Cancer Res 2020; 9:3507-3517. [PMID: 35117716 PMCID: PMC8799044 DOI: 10.21037/tcr.2020.03.70] [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: 06/14/2019] [Accepted: 01/03/2020] [Indexed: 12/02/2022]
Abstract
BACKGROUND Tumor-derived interleukin-8 (IL-8) promotes tumorigenesis and progression of prostate cancer (PCa). MicroRNAs (miRNAs) are noncoding regulatory RNAs and their dysregulation is known to be implicated in carcinogenesis. However, the post-transcriptional mechanism of IL-8 via miRNAs is not fully understood. This study was intended to investigate whether miR-106a could affect the progression of PCa via targeting IL-8 or not. METHODS Using bioinformatics analysis, we postulated that IL-8 might be post-transcriptionally regulated by miR-106a. This was validated by dual reporter gene assays that miR-106a could bind to the predicted site of IL-8 mRNA. To determine the biological effects of miR-106a on PCa cells (PC-3 and DU145), MTT, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), migration and invasion assays were performed. RESULTS We found that miR-106a was barely expressed in PCa cells, whereas IL-8 was aberrantly upregulated. Elevated miR-106a could reduce IL-8 expression by directly binding the 3'-UTR of IL-8. Overexpression of miR-106a in PCa cells triggered cell apoptosis and suppressed cell proliferation, migration, and invasion. CONCLUSIONS This research showed that miR-106a could function as a tumor-suppressor by decreasing IL-8 levels in PCa.
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Affiliation(s)
- Pengfei Shen
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guangxi Sun
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Peng Zhao
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jindong Dai
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xingming Zhang
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jinge Zhao
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Sha Zhu
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Junru Chen
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ronggui Tao
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiyu Yang
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hao Zeng
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
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Zhou Y, Wang Z, Chen X, Zhang J, Yang L, Liu S, Liu Y. Identification of differentially expressed miRNAs and mRNAs in synovial of osteoarthritis via RNA-sequencing. BMC MEDICAL GENETICS 2020; 21:46. [PMID: 32122327 PMCID: PMC7053084 DOI: 10.1186/s12881-020-0978-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 02/19/2020] [Indexed: 01/02/2023]
Abstract
Background Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. This study attempted to investigate the key mRNAs and miRNAs related to OA. Patients and methods From April 17th, 2018 to May 17th, 2018, five patients with OA and three normal controls were enrolled in this present study. To identify the differentially expressed mRNAs (DEmRNAs) and miRNAs (DEmiRNAs) between patients with OA and normal controls, RNA-sequencing was performed. Then, DEmiRNA-target DEmRNAs analysis and functional annotation of DEmiRNA-target DEmRNAs were performed. To validate the RNA-sequencing results, quantitative real time-PCR (RT-PCR) and western blot analysis were performed as well. Results A total of 1068 DEmRNAs, 21 DEmiRNAs and 395 DEmiRNA-DEmRNA pairs were identified in synovial tissues of patients with OA. The functional annotation of DEmiRNA-target DEmRNAs revealed that Pathways in cancer and PI3K-Akt signaling pathway were significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. QRT-PCR and western blot results revealed that except for TLR7, the expression level of the others was consistent with the RNA-sequencing results, generally. Conclusion The findings of this present study may provide new clues for the roles of DEmRNAs and DEmiRNAs in the pathogenesis of OA.
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Affiliation(s)
- Yu Zhou
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China
| | - Zhicong Wang
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China
| | - Xi Chen
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China.
| | - Jianjun Zhang
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China
| | - Ling Yang
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China
| | - Shuping Liu
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China
| | - Yuehong Liu
- Department of Orthopedics, People's Hospital of Deyang City, No. 173, Taishan North Road, Jingyang District, Deyang, 618000, Sichuan, China.
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Mazurek M, Litak J, Kamieniak P, Osuchowska I, Maciejewski R, Roliński J, Grajkowska W, Grochowski C. Micro RNA Molecules as Modulators of Treatment Resistance, Immune Checkpoints Controllers and Sensitive Biomarkers in Glioblastoma Multiforme. Int J Mol Sci 2020; 21:ijms21041507. [PMID: 32098401 PMCID: PMC7073212 DOI: 10.3390/ijms21041507] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/11/2020] [Accepted: 02/18/2020] [Indexed: 12/18/2022] Open
Abstract
Based on genome sequencing, it is estimated that over 90% of genes stored in human genetic material are transcribed, but only 3% of them contain the information needed for the production of body proteins. This group also includes micro RNAs representing about 1%–3% of the human genome. Recent studies confirmed the hypothesis that targeting molecules called Immune Checkpoint (IC) open new opportunities to take control over glioblastoma multiforme (GBM). Detection of markers that indicate the presence of the cancer occupies a very important place in modern oncology. This function can be performed by both the cancer cells themselves as well as their components and other substances detected in the patients’ bodies. Efforts have been made for many years to find a suitable marker useful in the diagnosis and monitoring of gliomas, including glioblastoma.
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Affiliation(s)
- Marek Mazurek
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.)
| | - Jakub Litak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.)
- Department of Immunology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland;
| | - Piotr Kamieniak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.)
| | - Ida Osuchowska
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (I.O.); (R.M.)
| | - Ryszard Maciejewski
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (I.O.); (R.M.)
| | - Jacek Roliński
- Department of Immunology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland;
| | - Wiesława Grajkowska
- Department of Oncopathology and Biostructure, „Pomnik-Centrum Zdrowia Dziecka” Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland;
| | - Cezary Grochowski
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (I.O.); (R.M.)
- Laboratory of Virtual Man, Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland
- Correspondence:
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