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1
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Sikder S, Bhattacharya A, Agrawal A, Sethi G, Kundu TK. Micro-RNAs in breast cancer progression and metastasis: A chromatin and metabolic perspective. Heliyon 2024; 10:e38193. [PMID: 39386816 PMCID: PMC11462366 DOI: 10.1016/j.heliyon.2024.e38193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 09/06/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Breast cancer is a highly complex disease with multiple subtypes. While many of the breast cancer cases are sporadic some can be familial or hereditary. Genomic integrity is closely monitored by several mechanisms, such as DNA damage machinery and mitotic checkpoints. Any defect in the key genes involved in the regulation of these mechanisms often results in genomic instability, predisposing the cells to malignancy. This results in altered expression of many coding and noncoding genes. The noncoding RNAs especially the long noncoding RNA (lncRNAs) and microRNA (miRNAs) act as key regulators of cancer gene networks. Some miRNAs repress the expression of the heterochromatin-associated proteins, inducing the formation of open chromatin, and promoting the expression of genes required for oncogenesis. Additionally, specific miRNAs may also favour cancer progression and metastasis by regulating the expression of genes that support the metabolic microenvironment essential for cancer cell growth and proliferation. Understanding how these noncoding RNAs contribute to breast cancer development opens potential avenues for therapeutic intervention, targeting their dysregulated activity.
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Affiliation(s)
- Sweta Sikder
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| | - Aditya Bhattacharya
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| | - Aayushi Agrawal
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, 117600, Singapore
| | - Tapas K. Kundu
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
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2
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Truong VA, Chang YH, Dang TQ, Tu Y, Tu J, Chang CW, Chang YH, Liu GS, Hu YC. Programmable editing of primary MicroRNA switches stem cell differentiation and improves tissue regeneration. Nat Commun 2024; 15:8358. [PMID: 39333549 PMCID: PMC11436717 DOI: 10.1038/s41467-024-52707-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 09/19/2024] [Indexed: 09/29/2024] Open
Abstract
Programmable RNA editing is harnessed for modifying mRNA. Besides mRNA, miRNA also regulates numerous biological activities, but current RNA editors have yet to be exploited for miRNA manipulation. To engineer primary miRNA (pri-miRNA), the miRNA precursor, we present a customizable editor REPRESS (RNA Editing of Pri-miRNA for Efficient Suppression of miRNA) and characterize critical parameters. The optimized REPRESS is distinct from other mRNA editing tools in design rationale, hence enabling editing of pri-miRNAs that are not editable by other RNA editing systems. We edit various pri-miRNAs in different cells including adipose-derived stem cells (ASCs), hence attenuating mature miRNA levels without disturbing host gene expression. We further develop an improved REPRESS (iREPRESS) that enhances and prolongs pri-miR-21 editing for at least 10 days, with minimal perturbation of transcriptome and miRNAome. iREPRESS reprograms ASCs differentiation, promotes in vitro cartilage formation and augments calvarial bone regeneration in rats, thus implicating its potentials for engineering miRNA and applications such as stem cell reprogramming and tissue regeneration.
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Affiliation(s)
- Vu Anh Truong
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-Han Chang
- Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Thuc Quyen Dang
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Yi Tu
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Jui Tu
- Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan
| | - Chin-Wei Chang
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Yi-Hao Chang
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Guei-Sheung Liu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Yu-Chen Hu
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
- Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
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3
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Noches V, Campos-Melo D, Droppelmann CA, Strong MJ. Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis. Front Mol Neurosci 2024; 17:1417961. [PMID: 39290830 PMCID: PMC11405384 DOI: 10.3389/fnmol.2024.1417961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.
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Affiliation(s)
- Veronica Noches
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Danae Campos-Melo
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Cristian A Droppelmann
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Michael J Strong
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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4
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Zhang R, Gao Y, Wang S, Pan J, Geng S, Li Z, Zhang K, Meng W. Detection of miRNA-378based on a catalytic hairpin self-assembly reaction combined with gold nanoparticle colorimetry. NANOTECHNOLOGY 2024; 35:355602. [PMID: 38821044 DOI: 10.1088/1361-6528/ad5297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 05/31/2024] [Indexed: 06/02/2024]
Abstract
Recent studies have shown that abnormalmiRNA-378expression is a rule, rather than an exception, in cervical cancer and can be used as a diagnostic and prognostic biomarker to assess tumor initiation. In this study, we developed a general, sensitive strategy for detectingmiRNA-378using catalytic hairpin self-assembly (CHA) combined with gold nanoparticles (AuNP) colorimetry. The presence ofmiRNA-378triggers the repeated self-assembly of two designed hairpin DNAs (H1 and H2) into dsDNA polymers, which leads to changes in the surface plasmon resonance absorption band and the macroscopic color of the AuNP colloids due to the formation of nanoparticle-DNA conjugates. This experimental phenomenon can be observed by ultraviolet-visible spectrometry or even with the naked eye. Using this method,miRNA-378could be quantitatively detected at the picomolar level (as low as 20.7 pM). Compared with traditional methods, such as quantitative polymerase chain reaction and RNA blotting, this strategy has a simple operation, low cost, and high sensitivity and selectivity, and thus, exhibits significant potential for miRNA detection.
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Affiliation(s)
- Run Zhang
- Key Laboratory of Biomedical Functional Materials, School of Sciences, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Yahui Gao
- Key Laboratory of Biomedical Functional Materials, School of Sciences, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Shan Wang
- Key Laboratory of Biomedical Functional Materials, School of Sciences, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Jinru Pan
- Key Laboratory of Biomedical Functional Materials, School of Sciences, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Shuang Geng
- NO. 3 Middle School of Cangzhou, No. 126, Gongnong Road, Xinhua District, Cangzhou 061000, People's Republic of China
| | - Zhen Li
- Tongji Hospital Tongji Medical College of Hust, No. 501, Gaoxin Avenue, East Lake New Technology Development Zone, Wuhan 430030, People's Republic of China
| | - Kejie Zhang
- School of Materials Science and Engineering, Nanjing Institute of Technology, No. 1, Hongjing Road, Jiangning District, Nanjing 211167, People's Republic of China
| | - Wei Meng
- Key Laboratory of Biomedical Functional Materials, School of Sciences, China Pharmaceutical University, Nanjing 211198, People's Republic of China
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5
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Chen C, Demirkhanyan L, Gondi CS. The Multifaceted Role of miR-21 in Pancreatic Cancers. Cells 2024; 13:948. [PMID: 38891080 PMCID: PMC11172074 DOI: 10.3390/cells13110948] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
With the lack of specific signs and symptoms, pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at late metastatic stages, resulting in poor survival outcomes. Among various biomarkers, microRNA-21 (miR-21), a small non-coding RNA, is highly expressed in PDAC. By inhibiting regulatory proteins at the 3' untranslated regions (UTR), miR-21 holds significant roles in PDAC cell proliferation, epithelial-mesenchymal transition, angiogenesis, as well as cancer invasion, metastasis, and resistance therapy. We conducted a systematic search across major databases for articles on miR-21 and pancreatic cancer mainly published within the last decade, focusing on their diagnostic, prognostic, therapeutic, and biological roles. This rigorous approach ensured a comprehensive review of miR-21's multifaceted role in pancreatic cancers. In this review, we explore the current understandings and future directions regarding the regulation, diagnostic, prognostic, and therapeutic potential of targeting miR-21 in PDAC. This exhaustive review discusses the involvement of miR-21 in proliferation, epithelial-mesenchymal transition (EMT), apoptosis modulation, angiogenesis, and its role in therapy resistance. Also discussed in the review is the interplay between various molecular pathways that contribute to tumor progression, with specific reference to pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Clare Chen
- Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Lusine Demirkhanyan
- Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Internal Medicine and Surgery, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Christopher S. Gondi
- Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Internal Medicine and Surgery, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Internal Medicine, Surgery, and Health Science Education and Pathology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Health Care Engineering Systems Center, The Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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6
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Farahmand Y, Nabiuni M, Vafaei Mastanabad M, Sheibani M, Mahmood BS, Obayes AM, Asadi F, Davallou R. The exo-microRNA (miRNA) signaling pathways in pathogenesis and treatment of stroke diseases: Emphasize on mesenchymal stem cells (MSCs). Cell Biochem Funct 2024; 42:e3917. [PMID: 38379232 DOI: 10.1002/cbf.3917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/07/2023] [Accepted: 12/17/2023] [Indexed: 02/22/2024]
Abstract
A major factor in long-term impairment is stroke. Patients with persistent stroke and severe functional disabilities have few therapy choices. Long noncoding RNAs (lncRNAs) may contribute to the regulation of the pathophysiologic processes of ischemic stroke as shown by altered expression of lncRNAs and microRNA (miRNAs) in blood samples of acute ischemic stroke patients. On the other hand, multipotent mesenchymal stem cells (MSCs) increase neurogenesis, and angiogenesis, dampen neuroinflammation, and boost brain plasticity to improve functional recovery in experimental stroke models. MSCs can be procured from various sources such as the bone marrow, adipose tissue, and peripheral blood. Under the proper circumstances, MSCs can differentiate into a variety of mature cells, including neurons, astrocytes, and oligodendrocytes. Accordingly, the capability of MSCs to exert neuroprotection and also neurogenesis has recently attracted more attention. Nowadays, lncRNAs and miRNAs derived from MSCs have opened new avenues to alleviate stroke symptoms. Accordingly, in this review article, we examined various studies concerning the lncRNAs and miRNAs' role in stroke pathogenesis and delivered an overview of the therapeutic role of MSC-derived miRNAs and lncRNAs in stroke conditions.
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Affiliation(s)
- Yalda Farahmand
- School of Medicine, Terhan University of Medical Sciences, Tehran, Iran
| | - Mohsen Nabiuni
- Neurosurgery Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Vafaei Mastanabad
- Neurosurgery Department, Faculty of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Mehrnaz Sheibani
- Division of Pediatric Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - Ali Mohammed Obayes
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Fatemeh Asadi
- Department of Genetics, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran
- Department of Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Rosa Davallou
- Department of Neurology, Sayyad Shirazi Hospital, Golestan University of Medical Siences, Gorgan, Iran
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7
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Mathur A, Singh A, Hussain Y, Mishra A, Meena A, Mishra N, Luqman S. Regulating pri/pre-microRNA up/down expressed in cancer proliferation, angiogenesis and metastasis using selected potent triterpenoids. Int J Biol Macromol 2024; 257:127945. [PMID: 37951434 DOI: 10.1016/j.ijbiomac.2023.127945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/17/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023]
Abstract
MicroRNAs (miRNAs) play a crucial role in cancer progression by selectively inducing translational degradation of messenger RNA (mRNA) via sequence-specific interactions with the 3'-untranslated region (3'-UTR). The potential targeting of miRNA has been recognized as a significant avenue for investigating the biological progression of diverse cancer types. Consequently, targeting of pri-miRNA and pre-miRNA by phytochemicals emerges as a viable strategy in the realm of anticancer therapies. Among phytochemicals, triterpenoids have garnered significant recognition for their chemotherapeutic and chemopreventive capabilities in combating multiple cancers. To date, there is a dearth of literature about the molecular interactions between triterpenoids and miRNAs. The primary objective of this investigation is to discern the potential triterpenoids that can function as modulators for specific miRNAs, namely pri-miRNA-19b-2, pre-miR21, microRNA 20b, pri-miRNA-208a, pri-miRNA-378a, pri-miRNA-320b-2, and pri-miRNA-300, achieved through the use of in silico investigations. The study primarily focused on performing drug-likeness, computer-aided toxicity, and pharmacokinetic prediction studies for triterpenoids. Furthermore, molecular docking and simulation techniques were employed to investigate these compounds. The triterpenoids studied were shown to have drug-likeness characteristics, although asiatic acid, lupeol, and pristimerin were able to pass all toxicity tests. Among the triterpenoids that underwent docking, pristimerin had a significant binding energy of -10.9 kcal/mol during its interaction with pri-miR-378a. The stable interaction between the pristimerin and miRNA complex was demonstrated by molecular dynamics simulation. As a result, pristimerin has the potential to act as a modulator of carcinogenic miRNAs, making it a promising candidate for cancer prevention and treatment due to its tailored modulation of miRNA activity.
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Affiliation(s)
- Anurag Mathur
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Akanksha Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Yusuf Hussain
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Anamika Mishra
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Prayagraj 211012, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
| | - Nidhi Mishra
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Prayagraj 211012, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
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8
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Arabkari V, Barua D, Hossain MM, Webber M, Smith T, Gupta A, Gupta S. miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells. Int J Mol Sci 2023; 25:186. [PMID: 38203358 PMCID: PMC10778669 DOI: 10.3390/ijms25010186] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/13/2023] [Accepted: 12/16/2023] [Indexed: 01/12/2024] Open
Abstract
X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.
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Affiliation(s)
- Vahid Arabkari
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91TK33 Galway, Ireland; (V.A.); (D.B.); (M.M.H.); (M.W.)
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, 40530 Gothenburg, Sweden
| | - David Barua
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91TK33 Galway, Ireland; (V.A.); (D.B.); (M.M.H.); (M.W.)
| | - Muhammad Mosaraf Hossain
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91TK33 Galway, Ireland; (V.A.); (D.B.); (M.M.H.); (M.W.)
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Mark Webber
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91TK33 Galway, Ireland; (V.A.); (D.B.); (M.M.H.); (M.W.)
| | - Terry Smith
- Molecular Diagnostic Research Group, College of Science, University of Galway, H91TK33 Galway, Ireland;
| | - Ananya Gupta
- Discipline of Physiology, School of Medicine, University of Galway, H91TK33 Galway, Ireland;
| | - Sanjeev Gupta
- Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91TK33 Galway, Ireland; (V.A.); (D.B.); (M.M.H.); (M.W.)
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9
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Wang H, Shi J, Wang J, Hu Y. MicroRNA‑378: An important player in cardiovascular diseases (Review). Mol Med Rep 2023; 28:172. [PMID: 37503766 PMCID: PMC10436248 DOI: 10.3892/mmr.2023.13059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 05/31/2023] [Indexed: 07/29/2023] Open
Abstract
Cardiovascular disease (CVD) is a common chronic clinical condition and is the main cause of death in humans worldwide. Understanding the genetic and molecular mechanisms involved in the development of CVD is essential to develop effective prevention strategies and therapeutic measures. An increasing number of CVD‑related genetic studies have been conducted, including those on the potential roles of microRNAs (miRs). These studies have demonstrated that miR‑378 is involved in the pathological processes of CVD, including those of myocardial infarction, heart failure and coronary heart disease. Despite the potential importance of miR‑378 CVD, a comprehensive summary of the related literature is lacking. Thus, the present review aimed to summarize the findings of previous studies on the roles and mechanisms of miR‑378 in a variety of CVDs and provide an up‑to date basis for further r research targeting the prevention and treatment of CVDs.
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Affiliation(s)
- Huan Wang
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Jingjing Shi
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Jiuchong Wang
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Yuanhui Hu
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
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10
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Wang Z, Tan W, Li B, Zou J, Li Y, Xiao Y, He Y, Yoshida S, Zhou Y. Exosomal non-coding RNAs in angiogenesis: Functions, mechanisms and potential clinical applications. Heliyon 2023; 9:e18626. [PMID: 37560684 PMCID: PMC10407155 DOI: 10.1016/j.heliyon.2023.e18626] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 08/11/2023] Open
Abstract
Exosomes are extracellular vesicles that can be produced by most cells. Exosomes act as important intermediaries in intercellular communication, and participate in a variety of biological activities between cells. Non-coding RNAs (ncRNAs) usually refer to RNAs that do not encode proteins. Although ncRNAs have no protein-coding capacity, they are able to regulate gene expression at multiple levels. Angiogenesis is the formation of new blood vessels from pre-existing vessels, which is an important physiological process. However, abnormal angiogenesis could induce many diseases such as atherosclerosis, diabetic retinopathy and cancer. Many studies have shown that ncRNAs can stably exist in exosomes and play a wide range of physiological and pathological roles including regulation of angiogenesis. In brief, some specific ncRNAs can be enriched in exosomes secreted by cells and absorbed by recipient cells through the exosome pathway, thus activating relevant signaling pathways in target cells and playing a role in regulating angiogenesis. In this review, we describe the physiological and pathological functions of exosomal ncRNAs in angiogenesis, summarize their role in angiogenesis-related diseases, and illustrate potential clinical applications like novel drug therapy strategies and diagnostic markers in exosome research as inspiration for future investigations.
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Affiliation(s)
- Zicong Wang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Wei Tan
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Bingyan Li
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Jingling Zou
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yun Li
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yangyan Xiao
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yan He
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Shigeo Yoshida
- Department of Ophthalmology, Kurume University School of Medicine, Fukuoka, 830-0011, Japan
| | - Yedi Zhou
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
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11
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Zhao K, Kong C, Shi N, Jiang J, Li P. Potential angiogenic, immunomodulatory, and antifibrotic effects of mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis. Front Immunol 2023; 14:1125257. [PMID: 37251412 PMCID: PMC10213547 DOI: 10.3389/fimmu.2023.1125257] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/24/2023] [Indexed: 05/31/2023] Open
Abstract
Systemic sclerosis (SSc) is an intricate systemic autoimmune disease with pathological features such as vascular injury, immune dysregulation, and extensive fibrosis of the skin and multiple organs. Treatment options are limited; however, recently, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been acknowledged in preclinical and clinical trials as being useful in treating autoimmune diseases and are likely superior to MSCs alone. Recent research has also shown that MSC-EVs can ameliorate SSc and the pathological changes in vasculopathy, immune dysfunction, and fibrosis. This review summarizes the therapeutic effects of MSC-EVs on SSc and the mechanisms that have been discovered to provide a theoretical basis for future studies on the role of MSC-EVs in treating SSc.
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Affiliation(s)
- Kelin Zhao
- Department of Rheumatology and Immunology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Chenfei Kong
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Naixu Shi
- Department of Stomatology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Ping Li
- Department of Rheumatology and Immunology, China-Japan Union Hospital, Jilin University, Changchun, China
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12
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Arrigo A, Regua AT, Najjar MK, Lo HW. Tumor Suppressor Candidate 2 (TUSC2): Discovery, Functions, and Cancer Therapy. Cancers (Basel) 2023; 15:2455. [PMID: 37173921 PMCID: PMC10177220 DOI: 10.3390/cancers15092455] [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: 03/24/2023] [Revised: 04/20/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
Tumor Suppressor Candidate 2 (TUSC2) was first discovered as a potential tumor suppressor gene residing in the frequently deleted 3p21.3 chromosomal region. Since its discovery, TUSC2 has been found to play vital roles in normal immune function, and TUSC2 loss is associated with the development of autoimmune diseases as well as impaired responses within the innate immune system. TUSC2 also plays a vital role in regulating normal cellular mitochondrial calcium movement and homeostasis. Moreover, TUSC2 serves as an important factor in premature aging. In addition to TUSC2's normal cellular functions, TUSC2 has been studied as a tumor suppressor gene that is frequently deleted or lost in a multitude of cancers, including glioma, sarcoma, and cancers of the lung, breast, ovaries, and thyroid. TUSC2 is frequently lost in cancer due to somatic deletion within the 3p21.3 region, transcriptional inactivation via TUSC2 promoter methylation, post-transcriptional regulation via microRNAs, and post-translational regulation via polyubiquitination and proteasomal degradation. Additionally, restoration of TUSC2 expression promotes tumor suppression, eventuating in decreased cell proliferation, stemness, and tumor growth, as well as increased apoptosis. Consequently, TUSC2 gene therapy has been tested in patients with non-small cell lung cancer. This review will focus on the current understanding of TUSC2 functions in both normal and cancerous tissues, mechanisms of TUSC2 loss, TUSC2 cancer therapeutics, open questions, and future directions.
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Affiliation(s)
- Austin Arrigo
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA (A.T.R.); (M.K.N.)
- Graduate School of Arts and Sciences, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Angelina T. Regua
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA (A.T.R.); (M.K.N.)
| | - Mariana K. Najjar
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA (A.T.R.); (M.K.N.)
- Graduate School of Arts and Sciences, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Hui-Wen Lo
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA (A.T.R.); (M.K.N.)
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13
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Feng Z, Bao S, Kong L, Chen X. MicroRNA-378 inhibits hepatocyte apoptosis during acute liver failure by targeting caspase-9 in mice. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:124-134. [PMID: 35964807 DOI: 10.1016/j.gastrohep.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 06/18/2022] [Accepted: 07/16/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. It has been demonstrated that micro ribonucleic acids (miRNAs) are crucial mediators of nearly all pathological processes, including liver disease. OBJECTIVE The present study investigates the role of miR-378 in ALF. An ALF mouse model was induced using intraperitoneal injections of d-galactosamine/lipopolysaccharide (d-GalN/LPS). A hepatocyte cell line and miR-378 analogue were used in vitro to investigate the possible roles of miR-378 in ALF. METHODS The expressions of miR-378 and predicted target genes were measured via reverse transcription-quantitative polymerase chain reaction and western blotting, and cell apoptosis was assayed using flow cytometry. RESULTS Compared with mice in the control group, the mice challenged with d-GalN/LPS showed higher levels of alanine aminotransferase, aspartate aminotransferase, tumour necrosis factor-alpha and interleukin-6, more severe liver damage and increased numbers of apoptotic hepatocytes. Hepatic miR-378 was distinctly downregulated, while messenger RNA and protein levels of cysteinyl aspartate specific proteinase 9 (caspase-9) were upregulated in the ALF model. Furthermore, miR-378 was downregulated in d-GalN/TNF-induced hepatocyte cells, and miR-378 was found to inhibit hepatocyte apoptosis by targeting caspase-9. CONCLUSION Together, the present results indicate that miR-378 is a previously unrecognised post-ALF hepatocyte apoptosis regulator and may be a potential therapeutic target in the context of ALF.
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Affiliation(s)
- Zhiwen Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
| | - Shenghua Bao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
| | - Lianbao Kong
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaopeng Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
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14
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Souza VGP, de Araújo RP, Santesso MR, Seneda AL, Minutentag IW, Felix TF, Hamamoto Filho PT, Pewarchuk ME, Brockley LJ, Marchi FA, Lam WL, Drigo SA, Reis PP. Advances in the Molecular Landscape of Lung Cancer Brain Metastasis. Cancers (Basel) 2023; 15:722. [PMID: 36765679 PMCID: PMC9913505 DOI: 10.3390/cancers15030722] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC.
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Affiliation(s)
- Vanessa G. P. Souza
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
| | - Rachel Paes de Araújo
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Mariana R. Santesso
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Ana Laura Seneda
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Iael W. Minutentag
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Tainara Francini Felix
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Pedro Tadao Hamamoto Filho
- Department of Neurology, Psychology and Psychiatry, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | | | - Liam J. Brockley
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
| | - Fábio A. Marchi
- Faculty of Medicine, University of São Paulo, São Paulo 01246-903, Brazil
| | - Wan L. Lam
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
| | - Sandra A. Drigo
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Patricia P. Reis
- Molecular Oncology Laboratory, Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
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15
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Ju YK, Fang BR. [Research advances on the mechanism of extracellular vesicles of adipose-derived mesenchymal stem cells in promoting wound angiogenesis]. ZHONGHUA SHAO SHANG YU CHUANG MIAN XIU FU ZA ZHI 2023; 39:85-90. [PMID: 36740432 DOI: 10.3760/cma.j.cn501225-20220322-00080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Wound healing involves complex pathophysiological mechanism, among which angiogenesis is considered as one of the key steps in wound healing, and promoting wound angiogenesis can accelerate wound healing. In recent years, mesenchymal stem cell-derived extracellular vesicles have been proven to produce equivalent effects of wound healing promotion comparable to stem cell therapy, with the advantages of low antigenicity and high biocompatibility. The specific mechanism by which extracellular vesicles facilitate wound healing is still not fully understood and is thought to involve all stages of wound healing. This article focuses on the possible mechanism of extracellular vesicles of adipose-derived mesenchymal stem cells in promoting wound angiogenesis, so as to provide ideas for further study on the mechanism of extracellular vesicles to promote wound healing.
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Affiliation(s)
- Y K Ju
- Department of Plastic and Aesthetic (Burn) Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - B R Fang
- Department of Plastic and Aesthetic (Burn) Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, China
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16
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Sola IM, Karin-Kujundzic V, Paic F, Lijovic L, Glibo M, Serman N, Duic T, Skrtic A, Kuna K, Vranic S, Serman L. WNT5A, β‑catenin and SUFU expression patterns, and the significance of microRNA deregulation in placentas with intrauterine growth restriction. Mol Med Rep 2022; 27:28. [PMID: 36524356 PMCID: PMC9813565 DOI: 10.3892/mmr.2022.12914] [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: 07/07/2022] [Accepted: 10/05/2022] [Indexed: 12/15/2022] Open
Abstract
Placental insufficiency is a common cause of intrauterine growth restriction (IUGR). It affects ~10% of pregnancies and increases fetal and neonatal morbidity and mortality. Although Wnt and Hh pathways are crucial for embryonic development and placentation, their role in the pathology of IUGR is still not sufficiently explored. The present study analyzed the expression of positive regulators of the Wnt pathway, WNT5A and β‑catenin, and the expression of the Hh pathway negative regulator suppressor of fused (SUFU). Immunohistochemical and reverse transcription‑quantitative PCR (RT‑qPCR) assays were performed on 34 IUGR and 18 placental tissue samples from physiologic singleton‑term pregnancies. Epigenetic mechanisms of SUFU gene regulation were also investigated by methylation‑specific PCR analysis of its promoter and RT‑qPCR analysis of miR‑214‑3p and miR‑378a‑5p expression. WNT5A protein expression was higher in endothelial cells of placental villi from IUGR compared with control tissues. That was also the case for β‑catenin protein expression in trophoblasts and endothelial cells and SUFU protein expression in trophoblasts from IUGR placentas. The SUFU gene promoter remained unmethylated in all tissue samples, while miR‑214‑3p and miR‑378a‑5p were downregulated in IUGR. The present results suggested altered Wnt and Hh signaling in IUGR. DNA methylation did not appear to be a mechanism of SUFU regulation in the pathogenesis of IUGR, but its expression could be regulated by miRNA targeting.
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Affiliation(s)
- Ida Marija Sola
- Department of Obstetrics and Gynecology, University Hospital Sestre Milosrdnice, 10000 Zagreb, Croatia
| | - Valentina Karin-Kujundzic
- Department of Biology, University of Zagreb, 10000 Zagreb, Croatia,Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia,Correspondence to: Dr Valentina Karin-Kujundzic, Department of Biology, School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia, E-mail:
| | - Frane Paic
- Department of Biology, University of Zagreb, 10000 Zagreb, Croatia
| | - Lada Lijovic
- Department of Anesthesiology and Critical Care, General Hospital Fra Mihovil Sučić, 80101 Livno, Bosnia and Herzegovina
| | - Mislav Glibo
- Department of Biology, University of Zagreb, 10000 Zagreb, Croatia
| | - Nikola Serman
- Zagreb Emergency Medicine Service, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Tihana Duic
- Department of Biology, University of Zagreb, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia,Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia,Department of Pathology, University Hospital Merkur, 10000 Zagreb, Croatia
| | - Krunoslav Kuna
- Department of Obstetrics and Gynecology, University Hospital Sestre Milosrdnice, 10000 Zagreb, Croatia
| | - Semir Vranic
- College of Medicine, QU Health, Qatar University, 2713 Doha, Qatar
| | - Ljiljana Serman
- Department of Biology, University of Zagreb, 10000 Zagreb, Croatia,Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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17
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Jiang Y, Wang R, Wang C, Guo Y, Xu T, Zhang Z, Yang GY, Xu H, Tang Y. Brain Microenvironment Responsive and Pro-Angiogenic Extracellular Vesicle-Hydrogel for Promoting Neurobehavioral Recovery in Type 2 Diabetic Mice After Stroke. Adv Healthc Mater 2022; 11:e2201150. [PMID: 36074801 DOI: 10.1002/adhm.202201150] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 08/26/2022] [Indexed: 01/28/2023]
Abstract
Stroke patients with diabetes have worse neurological outcomes than non-diabetic stroke patients, and treatments beneficial for non-diabetic stroke patients are not necessarily effective for diabetic stroke patients. While stem cell-derived extracellular vesicles (EVs) show potential for treating stroke, the results remain unsatisfactory due to the lack of approaches for retaining and controlling EVs released into the brain. Herein, a glucose/reactive oxygen species dual-responsive hydrogel showing excellent injectability, biocompatibility, and self-healing capability is introduced as an EVs-loading vehicle and an intelligent EVs sustained releasing system in the brain. These EVs-hydrogels are developed via crosslinking of phenylboronic acid-modified hyaluronic acid and Poly vinyl alcohol, and fusion with neural stem cell-derived EVs. The results show EVs are stably incorporated into the hydrogels and can be controllably released in response to the brain microenvironment after stroke in type 2 diabetic mice. The EVs-hydrogels exert an excellent angiogenic effect, increasing the migration and tube formation of human umbilical vein endothelial cells. In addition, injection of EVs-hydrogels into the ischemic mouse brain enhances EVs retention and facilitates sustained release, promotes angiogenesis, and improves neurobehavioral recovery. These results suggest such a microenvironment responsive and sustained release EVs-hydrogel system offers a safe, and efficient therapy for diabetic stroke.
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Affiliation(s)
- Yixu Jiang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
| | - Ruiqi Wang
- College of Chemistry and Materials Sciences, Shanghai Normal University, No.100 Guilin Road, Shanghai, 200234, China
| | - Cheng Wang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
| | - Yiyan Guo
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
| | - Tongtong Xu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
| | - Zhijun Zhang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
| | - Guo-Yuan Yang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
| | - He Xu
- College of Chemistry and Materials Sciences, Shanghai Normal University, No.100 Guilin Road, Shanghai, 200234, China
| | - Yaohui Tang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai, 200030, China
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18
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Qin Y, Liang R, Lu P, Lai L, Zhu X. Depicting the Implication of miR-378a in Cancers. Technol Cancer Res Treat 2022; 21:15330338221134385. [PMID: 36285472 PMCID: PMC9608056 DOI: 10.1177/15330338221134385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
MicroRNA-378a (miR-378a), including miR-378a-3p and miR-378a-5p, are encoded in PPARGC1B gene. miR-378a is essential for tumorigenesis and is an independent prognostic biomarker for various malignant tumors. Aberrant expression of miR-378a affects several physiological and pathological processes, including proliferation, apoptosis, tumorigenesis, cancer invasion, metastasis, and therapeutic resistance. Interestingly, miR-378a has a dual functional role in either promoting or inhibiting tumorigenesis, independent of the cancer type. In this review, we comprehensively summarized the role and regulatory mechanisms of miR-378a in cancer development, hoping to provide a direction for its potential use in cancer therapy.
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Affiliation(s)
- Yuelan Qin
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Renba Liang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Pingan Lu
- Faculty of Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Lin Lai
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Xiaodong Zhu
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China,Affiliated Wuming Hospital of Guangxi Medical University, Nanning, People's Republic of China,Key Laboratory of Early Prevention and Treatment for Regional High-Incidence-Tumor, Guangxi Medical University, Ministry of Education, Nanning, People's Republic of China,Xiaodong Zhu, Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, 22 Shuang Yong Road, Nanning 530021, People's Republic of China.
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19
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Sufianov A, Begliarzade S, Kudriashov V, Nafikova R, Ilyasova T, Liang Y. Role of miRNAs in vascular development. Noncoding RNA Res 2022; 8:1-7. [PMID: 36262425 PMCID: PMC9552023 DOI: 10.1016/j.ncrna.2022.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/27/2022] Open
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20
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Serum MicroRNAs: -28-3p, -31-5p, -378a-3p, and -382-5p as novel potential biomarkers in acute lymphoblastic leukemia. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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21
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DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma. Cell Death Dis 2022; 13:456. [PMID: 35562342 PMCID: PMC9106801 DOI: 10.1038/s41419-022-04898-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 04/22/2022] [Accepted: 04/29/2022] [Indexed: 12/14/2022]
Abstract
Clear cell renal cell carcinoma (ccRCC) patients are highly angiogenic and treated by targeted therapies against VEGFA/VEGFR signaling pathway. However, tumors with such targeted therapies remain a significant clinic challenge. Understanding the underlying mechanism against angiogenesis is highly desired. Here, we demonstrated that the lncRNA DMDRMR serves as a sponge of miR-378a-5p to increase EZH2 and SMURF1 expression, thus promoting EZH2-mediated transcriptional repression of DAB2IP and SMURF1-mediated degradation of DAB2IP. Consequently, this axis activates VEGFA/VEGFR2 signaling pathway, resulting in angiogenesis and resistance of tumor cells to sunitinib in ccRCC. Moreover, the competing endogenous RNA regulatory axis of DMDRMR is clinically relevant to ccRCC pathogenesis and prognosis of patients with ccRCC. Our results support that the DMDRMR/miR-378a-5p/DAB2IP axis may serve as a novel target for combination diagnosis or therapy of ccRCC patients. Our findings may have highly clinical relevance for future translation to develop the targeted therapies for patients with ccRCC.
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22
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Al Kawas H, Saaid I, Jank P, Westhoff CC, Denkert C, Pross T, Weiler KBS, Karsten MM. How VEGF-A and its splice variants affect breast cancer development - clinical implications. Cell Oncol (Dordr) 2022; 45:227-239. [PMID: 35303290 PMCID: PMC9050780 DOI: 10.1007/s13402-022-00665-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2022] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Altered expression levels and structural variations in the vascular endothelial growth factor (VEGF) have been found to play important roles in cancer development and to be associated with the overall survival and therapy response of cancer patients. Particularly VEGF-A and its splice variants have been found to affect physiological and pathological angiogenic processes, including tumor angiogenesis, correlating with tumor progression, mostly caused by overexpression. This review focuses on the expression and impact of VEGF-A splice variants under physiologic conditions and in tumors and, in particular, the distribution and role of isoform VEGF165b in breast cancer. CONCLUSIONS AND PERSPECTIVES Many publications already highlighted the importance of VEGF-A and its splice variants in tumor therapy, especially in breast cancer, which are summarized in this review. Furthermore, we were able to demonstrate that cytoplasmatic VEGFA/165b expression is higher in invasive breast cancer tumor cells than in normal tissues or stroma. These examples show that the detection of VEGF splice variants can be performed also on the protein level in formalin fixed tissues. Although no quantitative conclusions can be drawn, these results may be the starting point for further studies at a quantitative level, which can be a major step towards the design of targeted antibody-based (breast) cancer therapies.
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Affiliation(s)
- Hivin Al Kawas
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Inas Saaid
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Paul Jank
- Institute of Pathology, Philipps-Universität Marburg, 35043, Marburg, Germany
| | | | - Carsten Denkert
- Institute of Pathology, Philipps-Universität Marburg, 35043, Marburg, Germany
| | - Therese Pross
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | | | - Maria Margarete Karsten
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
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23
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Floriano JF, Emanueli C, Vega S, Barbosa AMP, Oliveira RGD, Floriano EAF, Graeff CFDO, Abbade JF, Herculano RD, Sobrevia L, Rudge MVC. Pro-angiogenic approach for skeletal muscle regeneration. Biochim Biophys Acta Gen Subj 2022; 1866:130059. [PMID: 34793875 DOI: 10.1016/j.bbagen.2021.130059] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
The angiogenesis process is a phenomenon in which numerous molecules participate in the stimulation of the new vessels' formation from pre-existing vessels. Angiogenesis is a crucial step in tissue regeneration and recovery of organ and tissue function. Muscle diseases affect millions of people worldwide overcome the ability of skeletal muscle to self-repair. Pro-angiogenic therapies are key in skeletal muscle regeneration where both myogenesis and angiogenesis occur. These therapies have been based on mesenchymal stem cells (MSCs), exosomes, microRNAs (miRs) and delivery of biological factors. The use of different calls of biomaterials is another approach, including ceramics, composites, and polymers. Natural polymers are use due its bioactivity and biocompatibility in addition to its use as scaffolds and in drug delivery systems. One of these polymers is the natural rubber latex (NRL) which is biocompatible, bioactive, versatile, low-costing, and capable of promoting tissue regeneration and angiogenesis. In this review, the advances in the field of pro-angiogenic therapies are discussed.
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Affiliation(s)
- Juliana Ferreira Floriano
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil; National Heart and Lung Institute, Imperial College London, London, UK.
| | - Costanza Emanueli
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Sofia Vega
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil; Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | | | | | | | | | - Joelcio Francisco Abbade
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil
| | | | - Luis Sobrevia
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil; Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland, Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD, 4029, Queensland, Australia; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, the Netherlands.
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24
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Rimkus TK, Arrigo AB, Zhu D, Carpenter RL, Sirkisoon S, Doheny D, Regua AT, Wong GL, Manore S, Wagner C, Lin HK, Jin G, Ruiz J, Chan M, Debinski W, Lo HW. NEDD4 degrades TUSC2 to promote glioblastoma progression. Cancer Lett 2022; 531:124-135. [PMID: 35167936 PMCID: PMC8920049 DOI: 10.1016/j.canlet.2022.01.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/15/2022]
Abstract
Whether tumor suppressor candidate 2 (TUSC2) plays an important role in glioblastoma (GBM) progression is largely unknown. Whether TUSC2 undergoes polyubiquitination is unknown. Herein, we report that TUSC2 protein expression is reduced/lost in GBM compared to normal brain due to protein destabilization; TUSC2 mRNA is equally expressed in both tissues. NEDD4 E3 ubiquitin ligase polyubiquitinates TUSC2 at residue K71, and the TUSC2-K71R mutant is resistant to NEDD4-mediated proteasomal degradation. Analysis of GBM specimens showed NEDD4 protein is highly expressed in GBM and the level is inversely correlated with TUSC2 protein levels. Furthermore, TUSC2 restoration induces apoptosis and inhibits patient-derived glioma stem cells (PD-GSCs) in vitro and in vivo. Conversely, TUSC2-knockout promotes PD-GSCs in vitro and in vivo. RNA-Seq analysis and subsequent validations showed GBM cells with TUSC2-knockout expressed increased Bcl-xL and were more resistant to apoptosis induced by a Bcl-xL-specific BH3 mimetic. A TUSC2-knockout gene signature created from the RNA-seq data predicts poor patient survival. Together, these findings establish that NEDD4-mediated polyubiquitination is a novel mechanism for TUSC2 degradation in GBM and that TUSC2 loss promotes GBM progression in part through Bcl-xL upregulation.
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25
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Singh S, Srivastava PN, Meena A, Luqman S. Dietary flavonoid narirutin as a prospective antagonist of oncogenic pri/pre-microRNAs. Phytother Res 2022; 36:963-983. [PMID: 35040205 DOI: 10.1002/ptr.7367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 12/02/2021] [Accepted: 12/11/2021] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are involved in cancer progression via translational degradation in a sequence-specific manner of the 3'-untranslated region (3'UTR) of messenger RNA (mRNA). The involvement of miRNA in the biological progression of various cancer types is considered to be a potential target. Primary miRNA (pri-miRNA) and precursor-miRNA (pre-miRNA) synthesize the miRNA by dicer-catalyzed processes thus targeting pri/pre-miRNA by phytochemicals is amongst the appropriate approaches for anticancer therapies. Flavonoids category of phytochemicals is well-known for its chemotherapeutic and chemopreventive potential against multiple cancer types. However, the molecular interactions of flavonoids with miRNAs are not reported so far. Thus, this study aims to identify the promising flavonoids as the antagonist of miRNAs (pre-miR21, pri-miR-208a, pri-miR-378a, pri-miR320b, pri-miR-300, pri-miR-19b, and pre-miR-20b) using molecular docking simulations studies. Among the tested flavonoids, narirutin showed highest binding energy (-11.7 kcal/mol) against pri-miR19b followed by pri-miR-378a (-11.4 kcal/mol) > pri-miR320b (-11.2 kcal/mol) = pri-miR-300 (-11.2 kcal/mol) > pri-miR-208a (-9.0 kcal/mol) > pre-miR-20b (- 8.3 kcal/mol). The molecular dynamic simulation experiment confirmed that narirutin destabilizes the tertiary structure of pri-miRNA in comparison to apo-RNA. The finding indicates that narirutin binding with pre-miRNA causes disruption of pri-RNA structure that creates a loss of DICER-pre-miRNA interactions by hindering the pre-miRNA synthesis, thereby affecting miRNA processing. Further pharmacokinetics and toxicity prediction revealed that it is non-carcinogenic, non-mutagenic, and does not inhibit the CYPs activity. Thus, narirutin could be a possible antagonist of oncogenic miRNAs, therefore could be useful for miRNA-targeted cancer prevention and treatment.
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Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Pratik Narain Srivastava
- Molecular Microbiology and Immunology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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26
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Mao J, Zhang Z, Chen Y, Wu T, Fersht V, Jin Y, Meng J, Zhang M. Sea cucumber peptides inhibit the malignancy of NSCLC by regulating miR-378a-5p targeted TUSC2. Food Funct 2021; 12:12362-12371. [PMID: 34788772 DOI: 10.1039/d1fo02267a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Lung cancer is a common cancer with high mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for the majority. The clinical treatment effect of NSCLC is not ideal. The aim of this study was to investigate the inhibitory effect of sea cucumber peptide (SCP) on NSCLC and its mechanism. The results showed that SCP could effectively inhibit the proliferation, migration and invasion of A549 cells. In addition, SCP can also inhibit the formation of pleural effusion and tumor growth in lung cancer mice, reduce liver and kidney injury, increase the levels of IL-2 and IL-12, decrease the levels of IL-6 and TNF-α, and prolong the survival time of mice. The microRNA sequencing and immunohistochemistry of mouse tumors showed that the tumor suppressor gene TUSC2 targeted by miR-378a-5p was involved in the inhibition of tumor growth by SCP. This study provides an experimental basis for the further development of SCP as an anti-tumor nutritional supplement, and provides a new idea for exploring the molecular mechanism of food derived active peptides in anti-tumor applications.
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Affiliation(s)
- Jing Mao
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Zhuchi Zhang
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Yongde Chen
- Bestlife Biological Technology Co., Ltd, Hebei Province, China
| | - Tao Wu
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Viktor Fersht
- Center for Applied Medicine and Food Safety "Biomed", Lomonosov Moscow State University, Moscow, Russia
| | - Yan Jin
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Jing Meng
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China.
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Min Zhang
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China.
- China-Russia Agricultural Products Processing Joint Laboratory, Tianjin Agricultural University, Tianjin 300384, PR China
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27
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Wei X, Lv H, Yang S, Yang X. CircRNA PLOD2 enhances ovarian cancer propagation by controlling miR-378. Saudi J Biol Sci 2021; 28:6260-6265. [PMID: 34759745 PMCID: PMC8568717 DOI: 10.1016/j.sjbs.2021.06.088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/26/2021] [Accepted: 06/27/2021] [Indexed: 12/24/2022] Open
Abstract
It has been confirmed that circular RNA participates in tumorgenesis through a variety of ways, so it may be used as a molecular marker for tumor diagnosis and treatment. In this study, the expression of circ-LOPD2 in ovarian cancer tissues and cell lines was detected by qRT-PCR and Western blot. The dual luciferase report was used to verify the target of circ-LOPD2, and the silencing and overexpression of circ-CSPP1 in cell lines was used to explore its relationship with miRNA-378. The cell proliferation was detected by CCK8 method, and the expression level of miRNA-378 was detected by qRT-PCR. The results showed that circ-LOPD2 was highly expressed in ovarian cancer (OC) tissues, circ-LOPD2 expression levels were higher in OVCAR3 and A2780, and circ-LOPD2 expression levels in CAOV3 were lower. After silencing circ-LOPD2, the growth ability of OVCAR3 and A2780 cells decreased, while overexpression of circ-LOPD2 led to the opposite result. We also found that miR-378 is a target of circ-LOPD2. Silencing circ-LOPD2 will increase the expression of miR-378, and overexpression of circ-LOPD2 will decrease the expression of miR-378. In summary, our results show that circ-LOPD2 as a miR-378 sponge promotes the proliferation of ovarian cancer cells, which may in turn promote the development of OC.
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Affiliation(s)
- Xiaoqiang Wei
- Gynecological Department, Qingdao Women and Children 's Hospital, Qingdao University Affiliated Qingdao Women and Children 's Hospital, 266011 Qingdao, P. R. China
| | - Hongmei Lv
- Gynecological Department,Qingdao Central Hospital, The Second Clinical Hospital of Qingdao University, 266042 Qingdao, P. R. China
| | - Shaowen Yang
- Gynecological Department,Qingdao Central Hospital, The Second Clinical Hospital of Qingdao University, 266042 Qingdao, P. R. China
| | - Xiufeng Yang
- Gynecological Department,Qingdao Central Hospital, The Second Clinical Hospital of Qingdao University, 266042 Qingdao, P. R. China
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28
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Wang D, Lin M, Utz B, Bosompem A, Guo Y, Daneshbod Y, Alford CE, Nettles SA, Scher J, Gagne EY, O'Neill M, Barrow L, Wojciechowska N, Keegan J, Mosse CA, Lederer JA, Kim AS. miR-378-3p Knockdown Recapitulates Many of the Features of Myelodysplastic Syndromes. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:2009-2022. [PMID: 34364880 PMCID: PMC8579243 DOI: 10.1016/j.ajpath.2021.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/26/2021] [Accepted: 07/08/2021] [Indexed: 11/19/2022]
Abstract
Myelodysplastic syndromes (MDS) are clonal neoplasms of the hematopoietic stem cell that result in aberrant differentiation of hematopoietic lineages caused by a wide range of underlying genetic, epigenetic, and other causes. Despite the myriad origins, a recognizable MDS phenotype has been associated with miRNA aberrant expression. A model of aberrant myeloid maturation that mimics MDS was generated using a stable knockdown of miR-378-3p. This model exhibited a transcriptional profile indicating aberrant maturation and function, immunophenotypic and morphologic dysplasia, and aberrant growth that characterizes MDS. Moreover, aberrant signal transduction in response to stimulation specific to the stage of myeloid maturation as indicated by CyTOF mass cytometry was similar to that found in samples from patients with MDS. The aberrant signaling, immunophenotypic changes, cellular growth, and colony formation ability seen in this myeloid model could be reversed with azacytidine, albeit without significant improvement of neutrophil function.
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Affiliation(s)
- Dahai Wang
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Miao Lin
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Begum Utz
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Amma Bosompem
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yan Guo
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yahya Daneshbod
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Catherine E Alford
- Department of Pathology, Tennessee Valley Healthcare System, Veterans Affairs, Nashville, Tennessee
| | - Sabin A Nettles
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jonathan Scher
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Emma Y Gagne
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Maria O'Neill
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Lia Barrow
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Natalia Wojciechowska
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Joshua Keegan
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Claudio A Mosse
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Tennessee Valley Healthcare System, Veterans Affairs, Nashville, Tennessee
| | - James A Lederer
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Annette S Kim
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
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29
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Abdelaleem OO, Fouad NA, Shaker OG, Ahmed TI, Abdelghaffar NK, Eid HM, Mohamed AA, Elebiary AM, Mohamed MM, Mahmoud RH. Serum miR-224, miR-760, miR-483-5p, miR-378 and miR-375 as potential novel biomarkers in rheumatoid arthritis. Int J Clin Pract 2021; 75:e14651. [PMID: 34310809 DOI: 10.1111/ijcp.14651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/21/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which affects various tissues and organs mainly joints. Serum microRNAs are considered a new class of non-coding RNA which plays a vital role in pathogenesis of RA. METHODS The current study was conducted on 80 RA patients and 80 healthy participants. Serum expression levels of miR-224, miR-760, miR-483-5p, miR-378 and miR-375 were evaluated via real-time quantitative polymerase chain reaction (PCR). RESULTS Significant upregulation of miR-224, miR-760, miR-483-5p, miR-378 and miR-375 was reported in the present study with respect to the control group (P = .031, P = .017, P = .026, P = .036 and P = .05, respectively). Furthermore, significant positive correlation between the abovementioned microRNAs with DAS28 score (P < .001, each) was demonstrated. CONCLUSION Early detection of RA could be achieved through evaluation of serum expression of miR-224, miR-760, miR-483-5p, miR-378 and miR-375 which also may be used as targets for treatment of patients with RA.
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Affiliation(s)
- Omayma O Abdelaleem
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Nermeen A Fouad
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Olfat G Shaker
- Department of Biochemistry and molecular biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Tarek I Ahmed
- Department of Internal medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Noha K Abdelghaffar
- Department of clinical pathology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Hanaa M Eid
- Department of Medical microbiology and immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Abdelrahmaan A Mohamed
- Department of Medical microbiology and immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Ahmed Magdy Elebiary
- Department of Medical physiology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Mohamed M Mohamed
- Department of Internal medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rania H Mahmoud
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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30
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Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells. Int J Mol Sci 2021; 22:ijms221910890. [PMID: 34639228 PMCID: PMC8509224 DOI: 10.3390/ijms221910890] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into endothelial cells (ECs) and pericyte-like cells and to secrete angiogenesis-promoting growth factors and extracellular vesicles (EVs) makes them an ideal option in cell therapy and in regenerative medicine in conditions including tissue ischemia. In recent angiogenesis research, ASCs have often been co-cultured with an endothelial cell (EC) type in order to form mature vessel-like networks in specific culture conditions. In this review, we introduce co-culture systems and co-transplantation studies between ASCs and ECs. In co-cultures, the cells communicate via direct cell-cell contact or via paracrine signaling. Most often, ASCs are found in the perivascular niche lining the vessels, where they stabilize the vascular structures and express common pericyte surface proteins. In co-cultures, ASCs modulate endothelial cells and induce angiogenesis by promoting tube formation, partly via secretion of EVs. In vivo co-transplantation of ASCs and ECs showed improved formation of functional vessels over a single cell type transplantation. Adipose tissue as a cell source for both mesenchymal stem cells and ECs for co-transplantation serves as a prominent option for therapeutic angiogenesis and blood perfusion in vivo.
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31
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Liu H, Zhang Q, Song Y, Hao Y, Cui Y, Zhang X, Zhang X, Qin Y, Zhu G, Wang F, Dang J, Ma S, Zhang Y, Guo W, Li S, Guan F, Fan T. Long non-coding RNA SLC2A1-AS1 induced by GLI3 promotes aerobic glycolysis and progression in esophageal squamous cell carcinoma by sponging miR-378a-3p to enhance Glut1 expression. J Exp Clin Cancer Res 2021; 40:287. [PMID: 34517880 PMCID: PMC8436487 DOI: 10.1186/s13046-021-02081-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/20/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Emerging evidence demonstrates that lncRNAs play pivotal roles in tumor energy metabolism; however, the detailed mechanisms of lncRNAs in the regulation of tumor glycolysis remain largely unknown. METHODS The expression of SLC2A1-AS1 was investigated by TCGA, GEO dataset and qRT-PCR. The binding of GLI3 to SLC2A1-AS1 promoter was detected by Luciferase Reporter Assay System and Ago2-RIP assay. FISH was performed to determine the localization of SLC2A1-AS1 in ESCC cells. Double Luciferase Report assay was used to investigate the interaction of miR-378a-3p with SLC2A1-AS1 and Glut1. Gain-of-function and Loss-of-function assay were performed to dissect the function of SLC2A1-AS1/miR-378a-3p/Glut1 axis in ESCC progression in vitro and in vivo. RESULTS We identified a novel lncRNA SLC2A1-AS1 in ESCC. SLC2A1-AS1 was frequently overexpressed in ESCC tissues and cells, and its overexpression was associated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Importantly, GLI3 and SLC2A1-AS1 formed a regulatory feedback loop in ESCC cells. SLC2A1-AS1 promoted cell growth in vitro and in vivo, migration and invasion, and suppressed apoptosis, leading to EMT progression and increased glycolysis in ESCC cells. SLC2A1-AS1 functioned as ceRNA for sponging miR-378a-3p, resulting in Glut1 overexpression in ESCC cells. MiR-378a-3p inhibited cell proliferation and invasion as well as induced apoptosis, resulting in reduced glycolysis, which was partly reversed by SLC2A1-AS1 or Glut1 overexpression in ESCC cells. CONCLUSION SLC2A1-AS1 plays important roles in ESCC development and progression by regulating glycolysis, and SLC2A1-AS1/miR-378a-3p/Glut1 regulatory axis may be a novel therapeutic target in terms of metabolic remodeling of ESCC patients.
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Affiliation(s)
- Hongtao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
| | - Qing Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.,Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yinsen Song
- Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yibin Hao
- Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yunxia Cui
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Xin Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Xueying Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Yue Qin
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Guangzhao Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Feng Wang
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China.,International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Jinghan Dang
- Department of Clinical Medicine, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Yanting Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Wenna Guo
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Shenglei Li
- Department of Pathology, the First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, Henan, China.
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
| | - Tianli Fan
- Department of Pharmacology, School of Basic Medicine, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China.
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32
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Aspriţoiu VM, Stoica I, Bleotu C, Diaconu CC. Epigenetic Regulation of Angiogenesis in Development and Tumors Progression: Potential Implications for Cancer Treatment. Front Cell Dev Biol 2021; 9:689962. [PMID: 34552922 PMCID: PMC8451900 DOI: 10.3389/fcell.2021.689962] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis is a multi-stage process of new blood vessel development from pre-existing vessels toward an angiogenic stimulus. The process is essential for tissue maintenance and homeostasis during embryonic development and adult life as well as tumor growth. Under normal conditions, angiogenesis is involved in physiological processes, such as wound healing, cyclic regeneration of the endometrium, placental development and repairing certain cardiac damage, in pathological conditions, it is frequently associated with cancer development and metastasis. The control mechanisms of angiogenesis in carcinogenesis are tightly regulated at the genetic and epigenetic level. While genetic alterations are the critical part of gene silencing in cancer cells, epigenetic dysregulation can lead to repression of tumor suppressor genes or oncogene activation, becoming an important event in early development and the late stages of tumor development, as well. The global alteration of the epigenetic spectrum, which includes DNA methylation, histone modification, chromatin remodeling, microRNAs, and other chromatin components, is considered one of the hallmarks of cancer, and the efforts are concentrated on the discovery of molecular epigenetic markers that identify cancerous precursor lesions or early stage cancer. This review aims to highlight recent findings on the genetic and epigenetic changes that can occur in physiological and pathological angiogenesis and analyze current knowledge on how deregulation of epigenetic modifiers contributes to tumorigenesis and tumor maintenance. Also, we will evaluate the clinical relevance of epigenetic markers of angiogenesis and the potential use of "epi-drugs" in modulating the responsiveness of cancer cells to anticancer therapy through chemotherapy, radiotherapy, immunotherapy and hormone therapy as anti-angiogenic strategies in cancer.
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Affiliation(s)
| | - Ileana Stoica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Coralia Bleotu
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Romanian Academy, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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MicroRNA-378a-3p is overexpressed in psoriasis and modulates cell cycle arrest in keratinocytes via targeting BMP2 gene. Sci Rep 2021; 11:14186. [PMID: 34244572 PMCID: PMC8270917 DOI: 10.1038/s41598-021-93616-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 06/28/2021] [Indexed: 02/08/2023] Open
Abstract
Psoriasis is a chronic autoimmune skin disease driven by dysregulations at the cellular, genomic and genetic levels. MicroRNAs are key mediators of gene expression regulation. However, how microRNAs control the pathogenesis of psoriasis is still unclear. Here, we reported a significant up-regulation of miR-378a-3p (miR-378a) in skin biopsies from active psoriatic lesions while it was down-regulated after treatment with methotrexate or narrow-band ultraviolet B phototherapy. Using the keratinocyte in vitro model, we showed that miR-378a disturbed the cell cycle progression, causing cell cycle arrest at G1 phase. Transcriptomic analysis of keratinocytes with miR-378a overexpression and depletion revealed several important biological mechanisms related to inflammation and tight junction. Target mRNA transcript assessed by luciferase assay identified bone morphogenetic protein 2 as a novel target gene of miR-378a. These findings offer a mechanistic model where miR-378a contributes to the pathogenesis of psoriasis.
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Madel MB, Elefteriou F. Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis. Cancers (Basel) 2021; 13:cancers13122887. [PMID: 34207620 PMCID: PMC8228198 DOI: 10.3390/cancers13122887] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Bone represents the most common site of metastasis for breast cancer and the establishment and growth of metastatic cancer cells within the skeleton significantly reduces the quality of life of patients and their survival. The interplay between sympathetic nerves and bone cells, and its influence on the process of breast cancer bone metastasis is increasingly being recognized. Several mechanisms, all dependent on β-adrenergic receptor signaling in stromal bone cells, were shown to promote the establishment of disseminated cancer cells into the skeleton. This review provides a summary of these mechanisms in support of the therapeutic potential of β-blockers for the early management of breast cancer metastasis. Abstract The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases.
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Affiliation(s)
| | - Florent Elefteriou
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX 77030, USA;
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence:
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Nan K, Zhang Y, Zhang X, Li D, Zhao Y, Jing Z, Liu K, Shang D, Geng Z, Fan L. Exosomes from miRNA-378-modified adipose-derived stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by enhancing angiogenesis and osteogenesis via targeting miR-378 negatively regulated suppressor of fused (Sufu). Stem Cell Res Ther 2021; 12:331. [PMID: 34099038 PMCID: PMC8186190 DOI: 10.1186/s13287-021-02390-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/13/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Local ischemia and defective osteogenesis are implicated in the progression of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies have revealed that exosomes released from adipose-derived stem cells (ASCs) play important roles in ONFH therapy. The present study aimed to investigate whether exosomes derived from miR-378-overexpressing ASCs (miR-378-ASCs-Exos) could promote angiogenesis and osteogenesis in GC-induced ONFH. METHODS In vitro, we investigated the osteogenic potential of miR-378-ASCs-Exos on bone marrow stromal cells (BMSCs) by alkaline phosphatase staining and western blotting. The angiogenic effects of miR-378-ASCs-Exos on human umbilical vein endothelial cells (HUVECs) were examined by evaluating their proliferation, migration, and tube-forming analyses. We identified the underlying mechanisms of miR-378 in osteogenic and angiogenic regulation. In addition, an ONFH rat model was established to explore the effects of miR-378-ASCs-Exos through histological and immunohistochemical staining and micro-CT in vivo. RESULTS Administration of miR-378-ASCs-Exos improved the osteogenic and angiogenic potentials of BMSCs and HUVECs. miR-378 negatively regulated the suppressor of fused (Sufu) and activated Sonic Hedgehog (Shh) signaling pathway, and recombinant Sufu protein reduced the effects triggered by miR-378-ASCs-Exos. In vivo experiments indicated that miR-378-ASCs-Exos markedly accelerated bone regeneration and angiogenesis, which inhibited the progression of ONFH. CONCLUSION Our study indicated that miR-378-ASCs-Exos enhances osteogenesis and angiogenesis by targeting Sufu to upregulate the Shh signaling pathway, thereby attenuating GC-induced ONFH development.
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Affiliation(s)
- Kai Nan
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Yuankai Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Xin Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Dong Li
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Yan Zhao
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Zhaopu Jing
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Kang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Donglong Shang
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Zilong Geng
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
| | - Lihong Fan
- Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi Province People’s Republic of China
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Yu Q, Zheng B, Ji X, Li P, Guo Z. miR-378c suppresses Wilms tumor development via negatively regulating CAMKK2. Acta Biochim Biophys Sin (Shanghai) 2021; 53:739-747. [PMID: 33956079 DOI: 10.1093/abbs/gmab047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Indexed: 01/03/2023] Open
Abstract
Wilms tumor is a rare kidney malignancy primarily developed in children. Treatment for Wilms tumor includes surgery, radiotherapy, and chemotherapy. Recent studies have demonstrated that microRNAs (miRNAs) play important roles in regulating Wilms tumor development. In this study, we aimed to elucidate the expression and function of miR-378c in Wilms tumor. Quantitative real-time PCR (qRT-PCR) results showed that miR-378c was downregulated in Wilms tumor tissues and cell lines. Functionally, further CCK-8, would healing, and transwell assays revealed that overexpression of miR-378c impaired Wilms tumor cell growth and metastasis in vitro. In addition, xenograft assay showed that miR-378c overexpression inhibited Wilms tumor development in vivo. Mechanistically, luciferase reporter assay confirmed that miR-378c directly targets CAMKK2 in Wilms tumor. qRT-PCR and western blot assays demonstrated that CAMKK2 was highly expressed in Wilms tumor tissues and cell lines. Rescue experiments were performed to further evaluate the functional relationship between miR-378c and CAMKK2. Overexpression of miR-378c suppressed Wilms tumor cell metastasis via negatively regulating CAMKK2 expression. Consistently, inhibition of miR-378c enhanced Wilms tumor cell malignancy behavior via augmenting CAMKK2 expression, which could be abrogated by CAMKK2 knockdown. In summary, our findings suggest that miR-378c inhibits the development and metastasis of Wilms tumor via negatively regulating CAMKK2 expression, which could be utilized to develop new therapy strategy.
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Affiliation(s)
- Qiang Yu
- Department of Paediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Baijun Zheng
- Department of Paediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Xiang Ji
- Department of Paediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Peng Li
- Department of Paediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Zhengtuan Guo
- Department of Paediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
- Department of Paediatric Surgery, Xi’an International Medical Center Hospital, Xi’an 710100, China
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Peng Y, Qin Y, Zhang X, Deng S, Yuan Y, Feng X, Chen W, Hu F, Gao Y, He J, Cheng Y, Wei Y, Fan X, Ashktorab H, Smoot D, Li S, Meltzer SJ, Zhuang S, Tang N, Jin Z. MiRNA-20b/SUFU/Wnt axis accelerates gastric cancer cell proliferation, migration and EMT. Heliyon 2021; 7:e06695. [PMID: 33912703 PMCID: PMC8065298 DOI: 10.1016/j.heliyon.2021.e06695] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 08/17/2020] [Accepted: 04/01/2021] [Indexed: 12/25/2022] Open
Abstract
Previous research has found that miRNA-20b is highly expressed in gastric cancer (GC), however, its function and underlying mechanism are not clear. Wnt signaling pathway, implicated in tumorigeneisis, is activated in more than 30% of GC. We would like to characterize the biological behavior of miRNA-20b in terms of modulating Wnt/β-catenin signaling and EMT. We showed that miRNA-20b inhibitors suppressed Topflash/Fopflash dependent luciferase activity and the β-catenin nuclear translocation, resulting in inhibition of Wnt pathway activity and EMT. SUFU, negatively regulating Wnt and Hedgehog signaling pathway, was proved to be targeted by miRNA-20b. Moreover, additional knockdown of SUFU alleviated the inhibitory effect on Wnt pathway activity, EMT, cell proliferation/migration and colony formation caused by miRNA-20b inhibition. In summary, miRNA-20b is an oncogenic miRNA and promoted cell proliferation, migration and EMT in GC partially by activating Wnt pathway via targeting SUFU.
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Affiliation(s)
- Yin Peng
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen, Guangdong, 518055, China,Corresponding author.
| | - Ying Qin
- Department of Gastrointestinal Surgery, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518000, China
| | - Xiaojing Zhang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen, Guangdong, 518055, China,Department of Pathology, Guangdong Province Key Laboratory of Molecular Oncologic Pathology, China
| | - Shiqi Deng
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Yuan Yuan
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Xianling Feng
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Wangchun Chen
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Fan Hu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Yuli Gao
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Jieqiong He
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Yulan Cheng
- Department of Medicine/GI Division, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Yanjie Wei
- Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Shenzhen, Guangdong, 518000, China
| | - Xinmin Fan
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
| | - Hassan Ashktorab
- Department of Medicine and Cancer Center, Howard University, College of Medicine, Washington, DC 20060, USA
| | - Duane Smoot
- Department of Medicine, Meharry Medical Center, Nashville, TN 37208, USA
| | - Song Li
- Shenzhen Science & Technology Development Exchange Center, Shenzhen Science and Technology Building, Shenzhen, Guangdong, 518055, China
| | - Stephen J. Meltzer
- Department of Medicine/GI Division, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Shutong Zhuang
- Department of Gastrointestinal Surgery, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518000, China
| | - Na Tang
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Zhe Jin
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China,Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Health Science Center, Shenzhen University, Shenzhen, Guangdong, 518055, China,Corresponding author.
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LncRNA VPS9D1-AS1 promotes cell proliferation in acute lymphoblastic leukemia through modulating GPX1 expression by miR-491-5p and miR-214-3p evasion. Biosci Rep 2021; 40:226132. [PMID: 32808668 PMCID: PMC7536331 DOI: 10.1042/bsr20193461] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 08/13/2020] [Accepted: 08/17/2020] [Indexed: 12/16/2022] Open
Abstract
Alterations in messenger RNAs (mRNAs) of protein-coding genes can influence the malignant behaviors of acute lymphoblastic leukemia (ALL) cells. According to the prediction from The Cancer Genome Atlas (TCGA) database, we discovered that glutathione peroxidase 1 (GPX1) was up-regulated in acute myeloid leukemia (LAML) tissues, which pushed us to explore the feasible role and its related modulatory mechanism of GPX1 in ALL. In this research, we first proved the high expression of GPX1 in ALL cells compared with normal cells. Functional assays further revealed that the proliferation was obstructed and the apoptosis was facilitated in ALL cells with silenced GPX1. Then, both miR-491-5p and miR-214-3p that were down-regulated in ALL cells were affirmed to target GPX1. Subsequently, VPS9D1 antisense RNA 1 (VPS9D1-AS1) was recognized as the upstream regulator of miR-491-5p-miR-214-3p/GPX1 axis in a competing endogenous RNA (ceRNA) model. Importantly, we proved that VPS9D1-AS1 served as a tumor promoter in ALL through elevating GPX1. In conclusion, VPS9D1-AS1 contributed to ALL cell proliferation through miR-491-5p-miR-214-3p/GPX1 axis, hinting an optional choice for the treatment of ALL.
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Budakoti M, Panwar AS, Molpa D, Singh RK, Büsselberg D, Mishra AP, Coutinho HDM, Nigam M. Micro-RNA: The darkhorse of cancer. Cell Signal 2021; 83:109995. [PMID: 33785398 DOI: 10.1016/j.cellsig.2021.109995] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 12/21/2022]
Abstract
The discovery of micro RNAs (miRNA) in cancer has opened up new vistas for researchers in recent years. Micro RNAs area set of small, endogenous, highly conserved, non-coding RNAs that control the expression of about 30% genes at post-transcriptional levels. Typically, microRNAs impede the translation and stability of messenger RNAs (mRNA), control genes associated with cellular processes namely inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Compelling findings revealed that miRNA mutations or disruption correspond to diverse human cancers and suggest that miRNAs can function as tumor suppressors or oncogenes. Here we summarize the literature on these master regulators in clinical settings from last three decades as both abrupt cancer therapeutics and as an approach to sensitize tumors to chemotherapy. This review highlights (I) the prevailing perception of miRNA genomics, biogenesis, as well as function; (II) the significant advancements in regulatory mechanisms in the expression of carcinogenic genes; and (III) explains, how miRNA is utilized as a diagnostic and prognostic biomarker for the disease stage indicating survival as well as therapeutic targets in cancer.
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Affiliation(s)
- Mridul Budakoti
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Abhay Shikhar Panwar
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Diksha Molpa
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Rahul Kunwar Singh
- Department of Microbiology, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Abhay Prakash Mishra
- Department of Pharmaceutical Chemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
| | | | - Manisha Nigam
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
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Zhu L, Liu Z. Serum from patients with hypertension promotes endothelial dysfunction to induce trophoblast invasion through the miR‑27b‑3p/ATPase plasma membrane Ca 2+ transporting 1 axis. Mol Med Rep 2021; 23:319. [PMID: 33760199 PMCID: PMC7974411 DOI: 10.3892/mmr.2021.11958] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 08/08/2020] [Indexed: 01/11/2023] Open
Abstract
Pregnancy‑induced hypertension is often accompanied by preeclampsia. The present study investigated whether microRNA (miR)‑27b‑3p affected the occurrence of preeclampsia by regulating the function of endothelial cells. Expressions levels of miR‑27b‑3p and ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) were determined using reverse‑transcription quantitative PCR. miR‑27b‑3p targeting ATP2B1 was predicted using bioinformatics and further confirmed by dual‑luciferase reporter assays. Cell Counting Kit‑8, Transwell and Matrigel tube formation assays were performed to detect the effects of miR‑27b‑3p on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), respectively. Moreover, HTR8/SVneos cells were co‑cultured with HUVECs to detect the invasion of trophoblast cells, and the expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)‑2 and MMP‑9 of HUVECs and HTR8/SVneos were detected by western blotting. Expression levels of miR‑27b‑3p were upregulated in the serum of patients with hypertension and preeclampsia, which could target and regulate the expression of ATP2B1. The expression levels of miR‑27b‑3p were increased and those of ATP2B1 were reduced in HUVECs from hypertensive serums. Moreover, miR‑27b‑3p mimics reduced the expression level of ATP2B1, and miR‑27b‑3p inhibitor reversed the effect of hypertensive serum on ATP2B1 expression. Furthermore, patients with hypertension showed increased endothelial dysfunction, reduced trophoblastic invasion and the expressions of VEGF, MMP‑2 and MMP‑9, and miR‑27b‑3p mimics and silencing of ATP2B1 produced similar results to HUVECs. The miR‑27b‑3p inhibitor reversed the effect of hypertensive serum, and silencing of ATP2B1 inhibited the improvement of miR‑27b‑3p inhibitor to HUVECs and HTR‑8/SVneo cells in proliferation, migration and tube formation. The current findings suggested that miR‑27b‑3p promoted proliferation, migration and tube formation of HUVECs and enhanced invasion of trophoblast cells, via regulation of ATP2B1. Thus, miR‑27b‑3p could be considered as a molecular risk factor in the pathogenesis and development of preeclampsia.
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Affiliation(s)
- Libo Zhu
- Department of Obstetrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Zhuqing Liu
- Department of Obstetrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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Zhou H, Li X, Wu RX, He XT, An Y, Xu XY, Sun HH, Wu LA, Chen FM. Periodontitis-compromised dental pulp stem cells secrete extracellular vesicles carrying miRNA-378a promote local angiogenesis by targeting Sufu to activate the Hedgehog/Gli1 signalling. Cell Prolif 2021; 54:e13026. [PMID: 33759282 PMCID: PMC8088471 DOI: 10.1111/cpr.13026] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Objectives Previously, our investigations demonstrated robust pro‐angiogenic potentials of extracellular vesicles secreted by periodontitis‐compromised dental pulp stem cells (P‐EVs) when compared to those from healthy DPSCs (H‐EVs), but the underlying mechanism remains unknown. Materials and methods Here, circulating microRNAs (miRNAs) specifically found in P‐EVs (compared with H‐EVs) were identified by Agilent miRNA microarray analysis, and the roles of the candidate miRNA in P‐EV‐enhanced cell angiogenesis were confirmed by cell transfection and RNA interference methods. Next, the direct binding affinity between the candidate miRNA and its target gene was evaluated by luciferase reporter assay. CCK‐8, transwell/scratch wound healing and tube formation assays were established to investigate the proliferation, migration, and tube formation abilities of endothelial cells (ECs). Western blot was employed to measure the protein levels of Hedgehog/Gli1 signalling pathway components and angiogenesis‐related factors. Results The angiogenesis‐related miRNA miR‐378a was found to be enriched in P‐EVs, and its role in P‐EV‐enhanced cell angiogenesis was confirmed, wherein Sufu was identified as a downstream target gene of miR‐378a. Functionally, silencing of Sufu stimulated EC proliferation, migration and tube formation by activating Hedgehog/Gli1 signalling. Further, we found that incubation with P‐EVs enabled the transmission of P‐EV‐contained miR‐378a to ECs. Subsequently, the expressions of Sufu, Gli1 and vascular endothelial growth factor in ECs were significantly influenced by P‐EV‐mediated miR‐378a transmission. Conclusions These data suggest that P‐EVs carrying miR‐378a promote EC angiogenesis by downregulating Sufu to activate the Hedgehog/Gli1 signalling pathway. Our findings reveal a crucial role for EV‐derived miR‐378a in cell angiogenesis and hence offer a new target for modifying stem cells and their secreted EVs to enhance vessel regenerative potential.
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Affiliation(s)
- Huan Zhou
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China.,Shaanxi Key Laboratory of Free Radical Biology and Medicine, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environments, Fourth Military Medical University, Xi'an, China
| | - Xuan Li
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Rui-Xin Wu
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Xiao-Tao He
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Ying An
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Xin-Yue Xu
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China.,Shaanxi Key Laboratory of Free Radical Biology and Medicine, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environments, Fourth Military Medical University, Xi'an, China
| | - Hai-Hua Sun
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Li-An Wu
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Fa-Ming Chen
- Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
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Shen J, Chang C, Ma J, Feng Q. Potential of Circulating Proangiogenic MicroRNAs for Predicting Major Adverse Cardiac and Cerebrovascular Events in Unprotected Left Main Coronary Artery Disease Patients Who Underwent Coronary Artery Bypass Grafting. Cardiology 2021; 146:400-408. [PMID: 33730720 DOI: 10.1159/000509275] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 06/06/2020] [Indexed: 11/19/2022]
Abstract
OBJECTIVE This study aimed to explore the association of 14 proangiogenic microRNAs (miRNAs) with major adverse cardiac and cerebrovascular events (MACCE) occurrence in unprotected left main coronary artery disease (ULMCAD) patients who underwent coronary artery bypass grafting (CABG). METHODS A total of 196 ULMCAD patients who underwent first ever CABG were recruited. The peripheral blood samples were collected prior to CABG, and then plasma samples were separated to detect expressions of 14 proangiogenic miRNAs by the reverse transcription quantitative PCR. Patients were regularly followed up to MACCE occurrence or 36 months after CABG. RESULTS MACCE occurrence at 1 year, 2 years, and 3 years was 7.1, 11.2, and 14.3%, respectively, and accumulating MACCE occurrence time was 32.7 (95% confidence interval: 31.5-33.9) months. Both Kaplan-Meier curves and univariate Cox's regression analyses displayed that miR-let-7f, miR-19a, miR-126, miR-130a, and miR-378 high expressions were associated with lower accumulating MACCE occurrence. Furthermore, forward stepwise multivariate Cox's regression disclosed that miR-let-7f high expression and miR-378 high expression independently predicted decreased accumulating MACCE occurrence, whereas BMI (>25.0 kg/m2), diabetes, previous stroke, and higher disease extent were independent predictive factors for elevated accumulating MACCE occurrence. CONCLUSION Measurement of circulating proangiogenic miRNAs especially miR-let-7f, miR-19a, miR-126, miR-130a, and miR-378 helps predict MACCE risk in ULMCAD patients who underwent CABG.
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Affiliation(s)
- Jian Shen
- Department of Cardiothoracic Surgery, Affiliated Changzhi People's Hospital of Shanxi Medical University, Changzhi, China
| | - Chun Chang
- Department of Cardiothoracic Surgery, Affiliated Changzhi People's Hospital of Shanxi Medical University, Changzhi, China
| | - Jie Ma
- Department of Cardiothoracic Surgery, Second Hospital of Shanxi Medical University, School of Medicine, Shanxi Medical University, Taiyuan, China,
| | - Qiang Feng
- Department of Cardiology, HanDan Central Hospital, HanDan, China
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Gong W, Zhu C, Liu Y, Muckenhuber A, Bronger H, Scorilas A, Kiechle M, Dorn J, Magdolen V, Dreyer T. Elevated levels of both microRNA 378 (miR-378) and kallikrein-related peptidase 4 (KLK4) mRNA are associated with an unfavorable prognosis in triple-negative breast cancer. Am J Transl Res 2021; 13:1594-1606. [PMID: 33841682 PMCID: PMC8014413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/08/2021] [Indexed: 06/12/2023]
Abstract
Triple-negative breast cancer (TNBC) patients have the worst outcome among all breast cancer subtypes. In oral squamous carcinoma cells, miR-378 was reported to target the mRNA of kallikrein-related peptidase 4 (KLK4), resulting in inhibition of cell proliferation, migration and invasion, induction of apoptosis, and reduction of tumor growth in vivo. Similarly, a miR-378/KLK4 axis has been proposed in prostate cancer. Here, we analyzed the correlation between miR-378 and KLK4 mRNA expression and determined the prognostic impact of both factors in TNBC. miR-378 and KLK4 mRNA expression levels were determined by quantitative PCR in tumor tissue of TNBC patients (n=103) and correlated with clinical parameters and patients' survival. There was no significant correlation between miR-378 and KLK4 mRNA expression. In univariate Cox regression analysis, elevated miR-378 expression was significantly associated with shortened disease-free survival (DFS, P=0.047) and overall survival (OS, P=0.031), high KLK4 mRNA levels were linked to a worse DFS (P=0.033). Combination of KLK4 mRNA and miR-378 (KLK4+miR-378, low/low versus high and/or high) allowed even better discrimination between favorable and unfavorable prognosis (DFS, P=0.008; OS, P=0.025). In multivariable analysis, miR-378 and KLK4+miR-378 expression remained independent predictive factors for DFS (P=0.014, P=0.010, respectively) and OS (P=0.016, P=0.049, respectively), while KLK4 mRNA only showed a trend towards significance for DFS (P=0.061). Our findings suggest that in TNBC there is no significant impact of miR-378 on KLK4 expression. Both factors, miR-378 and, to a lesser extent, KLK4 mRNA represent unfavorable prognostic markers in TNBC patients.
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Affiliation(s)
- Weiwei Gong
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
- Department of Hematology-Oncology, Guangzhou Women and Children’s Medical CenterGuangzhou, People’s Republic of China
| | - Caixia Zhu
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen UniversityGuangzhou, People’s Republic of China
| | - Yueyang Liu
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
- Department of Gynecology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical SciencesGuangzhou, People’s Republic of China
| | | | - Holger Bronger
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, University of AthensGreece
| | - Marion Kiechle
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
| | - Julia Dorn
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
| | - Viktor Magdolen
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
| | - Tobias Dreyer
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of MunichGermany
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Martinez B, Peplow PV. MicroRNAs as diagnostic and prognostic biomarkers of age-related macular degeneration: advances and limitations. Neural Regen Res 2021; 16:440-447. [PMID: 32985463 PMCID: PMC7996036 DOI: 10.4103/1673-5374.293131] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/11/2020] [Accepted: 04/02/2020] [Indexed: 01/10/2023] Open
Abstract
A main cause of vision loss in the elderly is age-related macular degeneration (AMD). Among the cellular, biochemical, and molecular changes linked to this disease, inflammation and angiogenesis appear as being crucial in AMD pathogenesis and progression. There are two forms of the disease: dry AMD, accounting for 80-90% of cases, and wet AMD. The disease usually begins as dry AMD associated with retinal pigment epithelium and photoreceptor degeneration, whereas wet AMD is associated with choroidal neovascularization resulting in severe vision impairment. The new vessels are largely malformed, leading to blood and fluid leakage within the disrupted tissue, which provokes inflammation and scar formation and results in retinal damage and detachment. MicroRNAs are dysregulated in AMD and may facilitate the early detection of the disease and monitoring disease progression. Two recent reviews of microRNAs in AMD had indicated weaknesses or limitations in four earlier investigations. Studies in the last three years have shown considerable progress in overcoming some of these concerns and identifying specific microRNAs as biomarkers for AMD. Further large-scale studies are warranted using appropriate statistical methods to take into account gender and age disparity in the study populations and confounding factors such as smoking status.
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Affiliation(s)
- Bridget Martinez
- Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM, USA
- Department of Medicine, St. George's University School of Medicine, Grenada
| | - Philip V. Peplow
- Department of Anatomy, University of Otago, Dunedin, New Zealand
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Chanjiao Y, Chunyan C, Xiaoxin Q, Youjian H. MicroRNA-378a-3p contributes to ovarian cancer progression through downregulating PDIA4. Immun Inflamm Dis 2021; 9:108-119. [PMID: 33159506 PMCID: PMC7860521 DOI: 10.1002/iid3.350] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/18/2020] [Accepted: 09/02/2020] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE MicroRNAs, as essential players in tumorigenesis, have been demonstrated to have a revolutionary effect on human cancer research. Ovarian cancer is the primary reason of death among gynecologic malignancies. In view of this, it is significant to identify prognostic and predictive markers for treatment of ovarian cancer. The aim of this study was to probe into the effects of miR-378a-3p and protein disulfide-isomerase A4 (PDIA4) on the biological functions of ovarian cancer cells. METHODS miR-378a-3p expression and PDIA4 messenger RNA expression in human ovarian cancer cells, normal human ovarian epithelial cells, and serum of both ovarian cancer patients and healthy people were detected by reverse transcription-quantitative polymerase chain reaction, and the PDIA4 protein expression was tested by Western blot analysis. Ovarian cancer OVCAR3 and SKOV3 cells were transfected or cotransfected with miR-378a-3p mimic or pcDNA3.1-PDIA4 or their negative control plasmids to explore their roles in biological functions in ovarian cancer cells. Luciferase activity and RIPA assays were implemented to validate the interaction between miR-378a-3p and PDIA4. Western blot analysis was utilized to detect phosphatidylinositol-3 kinase/serine/threonine kinase (PI3K/AKT) signaling pathway-related protein expression and their phosphate expression levels. RESULTS miR-378a-3p was elevated and PDIA4 was decreased in ovarian cancer cells and serum. In addition, miR-378a-3p mimic induced ovarian cancer cell growth, while miR-378a-3p inhibitor and pcDNA3.1-PDIA4 presented an inverse trend. pcDNA3.1-PDIA4 partially eliminated the capabilities of miR-378a-3p mimic on ovarian cancer progression. Meanwhile, miR-378a-3p was found to negatively regulate PDIA4, and miR-378a-3p mimic increased the phosphorylation levels of AKT and PI3K, while pcDNA3.1-PDIA4 exhibited an opposite tendency. Furthermore, pcDNA3.1-PDIA4 largely eliminated the functions of miR-378a-3p mimic on phosphorylation levels of AKT and PI3K. CONCLUSION This study provides evidences that miR-378a-3p activates PI3K/AKT signaling pathway by modulating PDIA4 expression, thereby playing a role in promoting the growth of ovarian cancer cells. This study provides novel directions for targeted therapy of ovarian cancer.
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Affiliation(s)
- Yao Chanjiao
- No. 3 Department of Obstetrics and GynecologyHunan Provincial People's HospitalChangshaChina
| | - Chen Chunyan
- No. 3 Department of Obstetrics and GynecologyHunan Provincial People's HospitalChangshaChina
| | - Qiu Xiaoxin
- No. 3 Department of Obstetrics and GynecologyHunan Provincial People's HospitalChangshaChina
| | - Han Youjian
- Department of cardiologyHunan Provincial People's HospitalChangshaChina
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Krist B, Podkalicka P, Mucha O, Mendel M, Sępioł A, Rusiecka OM, Józefczuk E, Bukowska-Strakova K, Grochot-Przęczek A, Tomczyk M, Klóska D, Giacca M, Maga P, Niżankowski R, Józkowicz A, Łoboda A, Dulak J, Florczyk-Soluch U. miR-378a influences vascularization in skeletal muscles. Cardiovasc Res 2021; 116:1386-1397. [PMID: 31504257 DOI: 10.1093/cvr/cvz236] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 06/28/2019] [Accepted: 08/22/2019] [Indexed: 12/14/2022] Open
Abstract
AIMS MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumour angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischaemic injury in mice. METHODS AND RESULTS Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischaemic muscles in both normo- and hyperglycaemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibres was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischaemic skeletal muscles of miR-378+/+ mice already on Day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors-based miR-378a overexpression was enough to improve the revascularization of the ischaemic limb of wild-type mice on Day 7 after FAL, what was not reported after systemic delivery of vectors. In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischaemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS Data indicate miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischaemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation.
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Affiliation(s)
- Bart Krist
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Olga Mucha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Mateusz Mendel
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Aleksandra Sępioł
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Olga Martyna Rusiecka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Ewelina Józefczuk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Karolina Bukowska-Strakova
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.,Department of Clinical Immunology and Transplantology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Grochot-Przęczek
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Mateusz Tomczyk
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Damian Klóska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Mauro Giacca
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.,School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, UK
| | - Paweł Maga
- Department of Angiology, Faculty of Medicine, Jagiellonian University, Krakow, Poland
| | - Rafał Niżankowski
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre, London, UK
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.,Kardio-Med Silesia, Zabrze, Poland
| | - Urszula Florczyk-Soluch
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
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Wang J, Li Y, Zhou JH, Shen FR, Shi X, Chen YG. CircATRNL1 activates Smad4 signaling to inhibit angiogenesis and ovarian cancer metastasis via miR-378. Mol Oncol 2021; 15:1217-1233. [PMID: 33372356 PMCID: PMC8024733 DOI: 10.1002/1878-0261.12893] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 11/20/2020] [Accepted: 12/24/2020] [Indexed: 01/10/2023] Open
Abstract
Ovarian cancer is one of the most frequent carcinomas in females, and the occurrence rate is still rising despite many advances made. The pathogenesis of ovarian cancer remains greatly unclear. Here, we investigated the mechanisms of ovarian cancer, with the focus on circATRNL1. Human ovarian cancer tissues and cell lines were used to examine levels of circATRNL1, miR‐378, Smad4, AKT, and other proliferation‐related and migration‐related proteins. Cellular assays were used to determine cancer cell proliferation, invasion, migration, apoptosis, and angiogenesis. We validated the interactions of circATRNL1/miR‐378 and miR‐378/Smad4, and a mouse tumor xenograft model was employed to assess the effect of circATRNL1 on tumor growth and metastasis in vivo. We found that circATRNL1 was decreased while miR‐378 was increased in human ovarian cancer tissues and cells. circATRNL1 bound to miR‐378 while miR‐378 directly targeted Smad4. Overexpression of circATRNL1 or knockdown of miR‐378 suppressed angiogenesis and ovarian cancer cell proliferation, invasion, and migration via decreasing proliferation‐ and migration‐related proteins via miR‐378 or Smad4, respectively. Overexpression of circATRNL1 restrained ovarian cancer growth and abdominal metastasis in vivo. Our findings indicate that circATRNL1 acts as a miR‐378 sponge to active Smad4 signaling and suppresses angiogenesis and ovarian cancer metastasis.
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Affiliation(s)
- Juan Wang
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yan Li
- Department of Gynecology and Obstetrics, the First People's Hospital of Yancheng, China
| | - Jin-Hua Zhou
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fang-Rong Shen
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiu Shi
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - You-Guo Chen
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Soochow University, Suzhou, China
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Javed Z, Javed Iqbal M, Rasheed A, Sadia H, Raza S, Irshad A, Koch W, Kukula-Koch W, Głowniak-Lipa A, Cho WC, Sharifi-Rad J. Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer. Front Oncol 2021; 10:607607. [PMID: 33489917 PMCID: PMC7817854 DOI: 10.3389/fonc.2020.607607] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.
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Affiliation(s)
- Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Muhammad Javed Iqbal
- Department of Biotechnology, Faculty of Sciences, University of Sialkot, Sialkot, Pakistan
| | - Amna Rasheed
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Haleema Sadia
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Shahid Raza
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Asma Irshad
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Wojciech Koch
- Chair and Department of Food and Nutrition, Medical University of Lublin, Lublin, Poland
| | | | - Anna Głowniak-Lipa
- Department of Cosmetology, University of Information Technology and Management in Rzeszów, Rzeszów, Poland
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
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miR-378a-3p Participates in Metformin's Mechanism of Action on C2C12 Cells under Hyperglycemia. Int J Mol Sci 2021; 22:ijms22020541. [PMID: 33430391 PMCID: PMC7827403 DOI: 10.3390/ijms22020541] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/30/2020] [Accepted: 01/05/2021] [Indexed: 01/10/2023] Open
Abstract
Metformin is the most used biguanide drug for the treatment of type 2 diabetes mellitus. Despite being mostly known for its hepatic anti-gluconeogenic effect, it is also known to modulate microRNAs (miRNAs, miRs) associated with metabolic diseases. The latter mechanism could be relevant for better understanding metformin’s mechanisms underlying its biological effects. In the current work, we found that metformin increases miR-378a-3p expression (p < 0.002) in C2C12 myoblasts previously exposed to hyperglycemic conditions. While the inhibition of miR-378a-3p was shown to impair metformin’s effect in ATP production, PEPCK activity and the expression of Tfam. Finally, mitophagy, an autophagic process responsible for the selective degradation of mitochondria, was found to be induced by miR-378a-3p (p < 0.04). miR-378a-3p stimulated mitophagy through a process independent of sestrin-2 (SESN2), a stress-responsible protein that has been recently demonstrated to positively modulate mitophagy. Our findings provide novel insights into an alternative mechanism of action of metformin involving miR-378a-3, which can be used in the future for the development of improved therapeutic strategies against metabolic diseases.
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