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Zhou X, Guo L, Dai Y, Zhou K, Zuo J, Liu B, Song L, Wang W, Wang L, Song L. Cgi-miR-96P2m regulates haemocyte proliferation in the immune response of oyster Crassostrea gigas. FISH & SHELLFISH IMMUNOLOGY 2025; 164:110437. [PMID: 40404029 DOI: 10.1016/j.fsi.2025.110437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 05/15/2025] [Accepted: 05/20/2025] [Indexed: 05/24/2025]
Abstract
Endogenous microRNAs have been reported to play critical roles in modulating immune response by regulating RNA silencing through cleavage or translational repression of target mRNAs. This study investigates the involvement of Cgi-miR-96P2m identified from oysters Crassostrea gigas in regulating haemocyte proliferation under Vibrio splendidus stimulation. Cgi-miR-96P2m shares a similar sequence with vertebrate miR-96 family members, while maintains an identical seed region similar to mollusk ones, highlighting its evolutionary conservation. The expression levels of Cgi-miR-96P2m in haemocytes significantly downregulated at 48 h after V. splendidus stimulation. The percentage of EdU + cells in haemocytes was significantly higher in the Cgi-miR-96P2m inhibitor + Vs group compared to the inhibitor NC + Vs group, while significantly lower in the Cgi-miR-96P2m mimics + Vs group compared to the mimics NC + Vs group. Binding sites of Cgi-miR-96P2m were predicted at 2383-2401 bp in the coding sequence region of CgVEGFR, and its binding activity with CgVEGFR mRNA was further proved by the dual-luciferase reporter assay. KEGG enrichment analysis revealed that target genes of Cgi-miR-96P2m are enriched in the MAPK signaling pathway and apoptosis process. Inhibition of Cgi-miR-96P2m resulted in upregulated expression of CgP38, cell cycle-related genes (CgCDK2, CgCDC45) and transcription factors (CgGATA, CgRunx), as well as apoptosis-associated genes such as CgBCL-2. These findings suggest that the Cgi-miR-96P2m negatively regulates haemocyte proliferation by targeting CgVEGFR and influencing the expression of cell cycle and apoptosis-related genes in the immune response of oysters.
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Affiliation(s)
- Xiaoxu Zhou
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lixin Guo
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Yuefeng Dai
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Keli Zhou
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Jiajun Zuo
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Buxin Liu
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lingyuan Song
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Weilin Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, 266237, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, 266237, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
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Miłek O, Schwarz K, Miletić A, Reisinger J, Kovar A, Behm C, Andrukhov O. Regulation and functional importance of human periodontal ligament mesenchymal stromal cells with various rates of CD146+ cells. Front Cell Dev Biol 2025; 13:1532898. [PMID: 40123853 PMCID: PMC11925893 DOI: 10.3389/fcell.2025.1532898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
Introduction Mesenchymal stromal cells (MSCs) with high expression of CD146 have superior properties for tissue regeneration. However, high variability in the rate of CD146+ cells among donors is observed. In this study, the possible reasons behind this variability in human periodontal ligament MSCs (hPDL-MSCs) were explored. Methods hPDL-MSCs were isolated from 22 different donors, and rates of CD146+ cells were analyzed by flow cytometry. Furthermore, populations with various rates of CD146+ cells were isolated with magnetic separation. The dependency of cell proliferation, viability, cell cycle, and osteogenic differentiation on the rates of CD146+ cells was investigated. Besides, the effects of various factors, like cell density, confluence, and inflammatory environment on the CD146+ rate and expression were analyzed. Results The rate of CD146+ cells exhibited high variability between donors, with the percentage of CD146+ cells ranging from 3% to 67%. Higher percentage of CD146+ cells was associated with higher proliferation, presumably due to the higher percentage of cells in the S-phase, and higher osteogenic differentiation potential. Prolonged cell confluence and higher cell seeding density led to the decline in the rate of CD146+ cells. The surface rate of CD146 in hPDL-MSCs was stimulated by the treatment with interleukin-1β and tumor necrosis factor-α, and inhibited by the treatment with interferon-γ. Conclusion These results suggest that hPDL-MSCs with high rate of CD146+ cells are a promising subpopulation for enhancing the effectiveness of MSC-based regenerative therapies, however the rate of CD146 is affected by various factors, which must be considered for cell propagation and their potential application in vivo.
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Affiliation(s)
| | | | | | | | | | | | - Oleh Andrukhov
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
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Sharma P, Naqvi RA, Borase H, Kapoor D, Valverde A, Capistrano K, Yadavalli T, Naqvi AR, Shukla D. Global MicroRNA Profiling of HSV-1 Infected Cornea Identifies miR-329 as a Novel Regulator of Virus Infection. Invest Ophthalmol Vis Sci 2025; 66:61. [PMID: 39992671 PMCID: PMC11878248 DOI: 10.1167/iovs.66.2.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/02/2025] [Indexed: 02/26/2025] Open
Abstract
Purpose Although the mechanisms underlying herpes simplex virus type-1 (HSV-1) ocular infection have been extensively studied, the role of host microRNAs (miRNAs) in the pathobiology of herpetic keratitis (HK) is not well understood. The aim of this study was to identify endogenous miRNA regulators involved in the progression of HSV-1 ocular infection. Methods C57BL/6 mice were infected with HSV-1 strain McKrae following epithelial debridement, and corneal miRNA profiles were analyzed at various time points using miRNA sequencing (miRNA-seq). The miRNA expression was measured at 2, 4, 6, and 10 days post-infection. Ingenuity Pathway Analysis (IPA) was used to identify immune pathways potentially targeted by differentially expressed miRNAs. The role of selected miRNAs in viral entry and replication was assessed by overexpression in murine embryonic fibroblasts (MEFs) and human corneal epithelial cells (HCEs). Results A total of 32 miRNAs at 2 days post-infection, 21 miRNAs at 4 days post-infection, 140 miRNAs at 6 days post-infection, and 27 miRNAs at 10 days post-infection showed significant changes in expression. IPA revealed that differentially expressed miRNAs targeted several immune pathways, including TLR and interferon signaling. Notably, mmu-miR-184-3p and mmu-let-7d-5p were upregulated, whereas mmu-miR-329-3p was down-regulated during infection. Functional assays demonstrated that overexpression of miR-329, but not miR-184-3p or miR-let-7d-5p, increased HSV-1 viral entry and replication in a dose-dependent manner. In contrast, miR-329 inhibition reversed these effects, suggesting its role as a pro-viral miRNA. Increased plaque formation and viral gB expression further confirmed miR-329's pro-viral role. Conclusions Our findings suggest that miR-329 functions as a pro-viral miRNA by disrupting TLR9 signaling, thus facilitating HSV-1 replication. Inhibition of miR-329 enhances TLR9-mediated antiviral responses, highlighting the potential of targeting host miRNAs as a novel therapeutic strategy for managing viral keratitis.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/biosynthesis
- Animals
- Herpesvirus 1, Human/physiology
- Herpesvirus 1, Human/genetics
- Keratitis, Herpetic/genetics
- Keratitis, Herpetic/virology
- Keratitis, Herpetic/metabolism
- Mice, Inbred C57BL
- Mice
- Humans
- Virus Replication
- Gene Expression Profiling
- Epithelium, Corneal/virology
- Epithelium, Corneal/metabolism
- Disease Models, Animal
- Gene Expression Regulation/physiology
- Cornea/virology
- Cornea/metabolism
- Cells, Cultured
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Affiliation(s)
- Pankaj Sharma
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Hemant Borase
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Divya Kapoor
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
- Department of Microbiology and Immunology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Araceli Valverde
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Kristelle Capistrano
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Tejabhiram Yadavalli
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Afsar R. Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Deepak Shukla
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
- Department of Microbiology and Immunology, University of Illinois - Chicago, Chicago, Illinois, United States
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Hilage P, Damle MN, Sharma RK, Joshi MG. Melanoma Cell Adhesion Molecule (CD 146) in Endometrial Physiology and Disorder. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:131-148. [PMID: 39400880 DOI: 10.1007/5584_2024_826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
The human endometrium, the innermost lining of the uterus, is the anatomic prerequisite for pregnancy. It is the only dynamic tissue that undergoes more than 400 cycles of regeneration throughout the reproductive life of women. Key to this function are endometrial stem cells as well as cell adhesion molecules. Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a membrane glycoprotein of the mucin family and a key cell adhesion protein, highly expressed by endometrial cells. CD146 is a significant molecule pivotal in endometrial physiology, assisting tissue regeneration and angiogenesis. Endometrium also acts as a culprit in causing several endometrial dysfunctions, such as endometriosis, endometrial hyperplasia, and endometrial carcinoma, due to interrupted molecular and functional mechanisms. Though most of the endometrial dysfunctions arise as a result of endocrine disturbance, it has a major pathological role associated with angiogenesis. It has already been proven that CD146 is a potential marker for the diagnosis of angiogenic dysfunctions and malignancy, including endometrial cancer. However, its mechanistic role in causing the pathology is a mystery. This chapter explores the role of CD146 in normal and pathological endometrial conditions and the therapeutic implications of CD146.
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Affiliation(s)
- Priyanka Hilage
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Mrunal N Damle
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Rakesh Kumar Sharma
- Department of Obstetrics and Gynecology, D.Y. Patil Medical College, Kolhapur, Maharashtra, India.
| | - Meghnad G Joshi
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
- Stem Plus Biotech Pvt. Ltd, Sangli, Maharashtra, India
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Chen JM, He J, Qiu JM, Yang GG, Wang D, Shen Z. Netrin-1-CD146 and netrin-1-S100A9 are associated with early stage of lymph node metastasis in colorectal cancer. BMC Gastroenterol 2024; 24:308. [PMID: 39261771 PMCID: PMC11389491 DOI: 10.1186/s12876-024-03401-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 09/03/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. METHODS The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. RESULTS The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). CONCLUSIONS The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients.
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Affiliation(s)
- Jin-Ming Chen
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China.
| | - Jun He
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Jian-Ming Qiu
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Guan-Gen Yang
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Dong Wang
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Zhong Shen
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China.
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Sun J, Ge Y, Chao T, Bai R, Wang C. The Role of miRNA in the Regulation of Angiogenesis in Ischemic Heart Disease. Curr Probl Cardiol 2023; 48:101637. [PMID: 36773949 DOI: 10.1016/j.cpcardiol.2023.101637] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
Despite continued improvements in primary prevention and treatment, ischemic heart disease (IHD) is the most common cause of mortality in both developing and developed countries. Promoting angiogenesis and reconstructing vascular network in ischemic myocardium are critical process of postischemic tissue repair. Effective strategies to promote survival and avoid apoptosis of endothelial cells in the ischemic myocardium can help to achieve long-term cardiac angiogenesis. Therefore, it is of great importance to investigate the molecular pathophysiology of angiogenesis in-depth and to find the key targets that promote angiogenesis. Recently years, many studies have found that microRNAs play important regulatory roles in almost all process of angiogenesis, including vascular sprouting, proliferation, survival and migration of vascular endothelial cells, recruitment of vascular progenitor cells, and control of angiopoietin expression. This review presents detailed information about the regulatory role of miRNAs in the angiogenesis of IHD in recent years, and provides new therapeutic ideas for the treatment of IHD.
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Affiliation(s)
- Jinghui Sun
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yaru Ge
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tiantian Chao
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ruina Bai
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Chenglong Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Nanni M, Rütsche D, Bächler C, Pontiggia L, Klar AS, Moehrlen U, Biedermann T. CD146 expression profile in human skin and pre-vascularized dermo-epidermal skin substitutes in vivo. J Biol Eng 2023; 17:9. [PMID: 36721239 PMCID: PMC9890844 DOI: 10.1186/s13036-023-00327-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/20/2023] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND CD146 is a cell adhesion molecule whose expression profile in human skin has not yet been elucidated. Here, we characterize CD146 expression pattern in human skin, in particular in blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), which constitute human dermal microvascular endothelial cells (HDMECs), as well as in perivascular cells. RESULTS We demonstrated that CD146 is a specific marker of BECs, but not of LECs. Moreover, we found CD146 expression also in human pericytes surrounding blood capillaries in human skin. In addition, we demonstrated that CD146 expression is up-regulated by the TNFα-IL-1β/NF-kB axis in both BECs and pericytes. Finally, we engineered 3D collagen hydrogels composed of HDMECs, CD146+ pericytes, and fibroblasts which developed, in vitro and in vivo, a complete microvasculature network composed of blood and lymphatic capillaries with pericytes investing blood capillaries. CONCLUSIONS Overall, our results proved that CD146 is a specific marker of BECs and pericytes, but not LECs in human skin. Further, the combination of CD146+ pericytes with HDMECs in skin substitutes allowed to bioengineer a comprehensive 3D in vitro and in vivo model of the human dermal microvasculature.
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Affiliation(s)
- Monica Nanni
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland ,grid.5801.c0000 0001 2156 2780Department of Mechanical and Process Engineering, Institute for Mechanical Systems, ETH Zurich, Leonhardstrasse 21, 8092 Zurich, Switzerland
| | - Dominic Rütsche
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland ,grid.5801.c0000 0001 2156 2780Department of Mechanical and Process Engineering, Institute for Mechanical Systems, ETH Zurich, Leonhardstrasse 21, 8092 Zurich, Switzerland
| | - Curdin Bächler
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Luca Pontiggia
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Agnes S. Klar
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Ueli Moehrlen
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Department of Surgery, University Children’s Hospital Zurich, Zurich, Switzerland ,grid.7400.30000 0004 1937 0650University of Zurich, Zurich, Switzerland
| | - Thomas Biedermann
- grid.412341.10000 0001 0726 4330Tissue Biology Research Unit, Department of Surgery, University Children’s Hospital Zurich, Wagistrasse 12, 8952 Zurich, Switzerland ,grid.412341.10000 0001 0726 4330Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland ,grid.7400.30000 0004 1937 0650University of Zurich, Zurich, Switzerland
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Lu M, Lee Y, Lillehoj HS. Evolution of developmental and comparative immunology in poultry: The regulators and the regulated. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 138:104525. [PMID: 36058383 DOI: 10.1016/j.dci.2022.104525] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/25/2022] [Accepted: 08/28/2022] [Indexed: 06/15/2023]
Abstract
Avian has a unique immune system that evolved in response to environmental pressures in all aspects of innate and adaptive immune responses, including localized and circulating lymphocytes, diversity of immunoglobulin repertoire, and various cytokines and chemokines. All of these attributes make birds an indispensable vertebrate model for studying the fundamental immunological concepts and comparative immunology. However, research on the immune system in birds lags far behind that of humans, mice, and other agricultural animal species, and limited immune tools have hindered the adequate application of birds as disease models for mammalian systems. An in-depth understanding of the avian immune system relies on the detailed studies of various regulated and regulatory mediators, such as cell surface antigens, cytokines, and chemokines. Here, we review current knowledge centered on the roles of avian cell surface antigens, cytokines, chemokines, and beyond. Moreover, we provide an update on recent progress in this rapidly developing field of study with respect to the availability of immune reagents that will facilitate the study of regulatory and regulated components of poultry immunity. The new information on avian immunity and available immune tools will benefit avian researchers and evolutionary biologists in conducting fundamental and applied research.
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Affiliation(s)
- Mingmin Lu
- Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, U.S. Department of Agriculture-Agricultural Research Service, Beltsville, MD, 20705, USA.
| | - Youngsub Lee
- Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, U.S. Department of Agriculture-Agricultural Research Service, Beltsville, MD, 20705, USA.
| | - Hyun S Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, U.S. Department of Agriculture-Agricultural Research Service, Beltsville, MD, 20705, USA.
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Zhang ZY, Zhai C, Yang XY, Li HB, Wu LL, Li L. Knockdown of CD146 promotes endothelial-to-mesenchymal transition via Wnt/β-catenin pathway. PLoS One 2022; 17:e0273542. [PMID: 36001597 PMCID: PMC9401105 DOI: 10.1371/journal.pone.0273542] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022] Open
Abstract
Purpose Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) proteins and leads to the maladaptive changes in myocardium. Endothelial cells (ECs) undergoing mesenchymal transition contributes to the occurrence and development of cardiac fibrosis. CD146 is an adhesion molecule highly expressed in ECs. The present study was performed to explore the role of CD146 in modulating endothelial to mesenchymal transition (EndMT). Methods C57BL/6 mice were subjected to subcutaneous implantation of osmotic minipump infused with angiotensin II (Ang Ⅱ). Adenovirus carrying CD146 short hairpin RNA (shRNA) or CD146 encoding sequence were infected into cultured human umbilical vein endothelial cells (HUVECs) followed by stimulation with Ang II or transforming growth factor-β1 (TGF-β1). Differentially expressed genes were revealed by RNA-sequencing (RNA-Seq) analysis. Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blot and immunofluorescence staining, respectively. Results CD146 was predominantly expressed by ECs in normal mouse hearts. CD146 was upregulated in ECs but not fibroblasts and myocytes in hearts of Ang II-infused mice and in HUVECs stimulated with Ang Ⅱ. RNA-Seq analysis revealed the differentially expressed genes related to EndMT and Wnt/β-catenin signaling pathway. CD146 knockdown and overexpression facilitated and attenuated, respectively, EndMT induced by Ang II or TGF-β1. CD146 knockdown upregulated Wnt pathway-related genes including Wnt4, LEF1, HNF4A, FOXA1, SOX6, and CCND3, and increased the protein level and nuclear translocation of β-catenin. Conclusions Knockdown of CD146 exerts promotional effects on EndMT via activating Wnt/β-catenin pathway and the upregulation of CD146 might play a protective role against EndMT and cardiac fibrosis.
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Affiliation(s)
- Zhao-Yu Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Chao Zhai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Xue-Yuan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Hai-Bing Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Li-Ling Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Li Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- * E-mail:
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10
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Lin J, Cui K, Xu Y, Tang X, Shi Y, Lu X, Yang B, He Q, Yu S, Liang X. Inhibition of CD146 attenuates retinal neovascularization via vascular endothelial growth factor receptor 2 signalling pathway in proliferative diabetic retinopathy. Acta Ophthalmol 2022; 100:e899-e911. [PMID: 34477295 DOI: 10.1111/aos.15007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 06/24/2021] [Accepted: 08/04/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE To investigate the expression of CD146 and its role in proliferative diabetic retinopathy (PDR). METHODS Enzyme linked immunosorbent assay was performed to analyse the expression and relationship of sCD146, vascular endothelial growth factor (VEGF), sVEGFR1 and sVEGFR2 in vitreous specimens from PDR and idiopathic epiretinal membranes (IERM) or idiopathic macular hole patients. The location of CD146 in ERMs was detected by immunofluorescence. The oxygen-induced retinopathy (OIR) mice model was established and the adeno-associated virus expressing a shRNA of CD146 (AAV1-shCD146-GFP) was administered via intravitreal injection. The effect of AAV1-shCD146-GFP was explored by immunofluorescence, Western blot and quantitative real-time PCR. RESULTS The levels of sCD146 in vitreous specimens from PDR patients and CD146 in retinas from OIR mice were significantly increased. Immunofluorescence showed that CD146 was co-located with CD31, VEGF, VEGFR1 and VEGFR2, respectively. Intravitreal injection of AAV1-shCD146-GFP could dramatically reduce the formation of neovascularization and non-perfusion area by inhibiting VEGFR2 phosphorylation. CONCLUSION Our results indicated that CD146 was involved in the development of retinal neovascularization via VEGFR2 pathway. Anti-CD146 may be an innovative or adjuvant therapy, which provides a new direction for the treatment of PDR and other ocular neovascular diseases.
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Affiliation(s)
- Jianqiang Lin
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Kaixuan Cui
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Yue Xu
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Xiaoyu Tang
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Yuxun Shi
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Xi Lu
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Boyu Yang
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Qingjing He
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Shanshan Yu
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
| | - Xiaoling Liang
- State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China
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11
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Gao W, Zhang J, Wu R, Yuan J, Ge J. Integrated Analysis of Angiogenesis Related lncRNA-miRNA-mRNA in Patients With Coronary Chronic Total Occlusion Disease. Front Genet 2022; 13:855549. [PMID: 35547243 PMCID: PMC9081538 DOI: 10.3389/fgene.2022.855549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/06/2022] [Indexed: 11/27/2022] Open
Abstract
Background: Coronary chronic total occlusion (CTO) disease is common and its specific characteristic is collateral formation. The Integrated analysis of angiogenesis related lncRNA-miRNA-mRNA network remains unclear and might provide target for future studies. Methods: A total of five coronary artery disease (control group) and five CTO (CTO group) patients were selected for deep RNA and miRNA sequencing. The expression profiles of lncRNAs, mRNAs circRNA and miRNAs were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were then performed. The expression of a 14q32 miRNA gene cluster, including miRNA-494, miRNA-495 and miRNA-329, were selected to be determined in another larger patient cohort. Analysis of the lncRNA-miRNA495-mRNA network was constructed to find potential targets for future studies. Results: A total of 871 lncRNAs, 1,080 mRNAs, 138 circRNAs and 56 miRNAs were determined as differentially expressed (DE) in CTO patients compared with control patients. GO and KEGG analyses revealed that the top terms included MAPK signaling pathway, HIF-1 signaling pathway, EGFR tyrosine kinase inhibitor resistance, embryonic organ development, wound healing, MAPK signaling pathway and JAK-STAT signaling pathway, which are related to angiogenesis. The expression of miRNA-494, miRNA-495 and miRNA-329 were all significantly down-regulated in CTO patients and they were confirmed to be down-regulated in another cohort of 68 patients. Then we divided the CTO patients into two groups according to CC grade (poor CC group, CC = 0 or one; good CC group, CC = 2). MiRNA-494, miRNA-495 and miRNA-329 were found to be down-regulated in good CC group compared with poor CC group. Analysis of the lncRNA-miRNA495-mRNA network showed 3 DE lncRNA sponges (NONHSAG008675, NONHSAG020957 and NONHSAG010989), 4 DE lncRNA targets (NONHSAT079547.2, NONHSAT081776.2, NONHSAT148555.1 and NONHSAT150928.1) and 2 DE mRNA targets (RAD54L2 and ZC3H4) of miRNA495. Conclusion: This study revealed that the lncRNA-miRNA-mRNA network might play a critical role in angiogenesis in CTO patients.
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Affiliation(s)
- Wei Gao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianhui Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Runda Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Yuan
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
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12
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Lv Z, Feng HY, Tao W, Li HZ, Zhang X. CD146 as a Prognostic-Related Biomarker in ccRCC Correlating With Immune Infiltrates. Front Oncol 2021; 11:744107. [PMID: 34956870 PMCID: PMC8692769 DOI: 10.3389/fonc.2021.744107] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022] Open
Abstract
Backgrounds CD146 is highly expressed in various malignant tumors and associated with the poor prognosis. However, the role of CD146 in clear cell renal cell carcinoma (ccRCC) is still unknown. This study aimed to identify the role of CD146 in ccRCC by integrated bioinformatics analysis. Methods CD146 mRNA expression and methylation data in ccRCC was examined using the TIMER, UALCAN, and MethSurv databases. CD146 expression in paraffin-embedded tissues (140 cancer samples and 140 paracancer tissues) from our cohort were examined by immunohistochemistry assay. The LinkedOmics database was used to study the signaling pathways related to CD146 expression. TIMER and TISIDB were used to analyze the correlations among CD146, CD146-coexpressed genes, tumor-infiltrating immune cells, and immunomodulators. The relationship between CD146 and drug response in renal cancer cell lines was analyzed by the CTRP and CCLE databases. Results The mRNA and protein levels of CD146 were elevated in ccRCC tissues than that in paracancer tissues. The DNA methylation of CD146 in ccRCC tissues were lower than that in normal tissues. Importantly, high CD146 expression was associated with poor prognosis in patients with ccRCC. Furthermore, multivariate Cox regression analysis showed that CD146 was an independent prognostic factor in ccRCC. GO and KEGG pathway analyses indicated the co-expressed genes of CD146 were mainly related to a variety of immune-related pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, and leukocyte transendothelial migration. Our data demonstrated that the expression and methylation status of CD146 were strongly correlated with immune infiltration levels, immunomodulators, and chemokines. Further, the sensitivity and resistance of renal cancer cell lines to some drugs were related to CD146 expression. Conclusions Our study highlights the clinical significance of CD146 in ccRCC and provides novel insights into the immune function of CD146 in the tumor microenvironment.
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Affiliation(s)
- Zheng Lv
- School of Medicine, Nankai University, Tianjin, China.,Department of Urology, The Third Medical Center, Chinese People Liberation Army (PLA) General Hospital, Beijing, China
| | - Hua-Yi Feng
- Department of Urology, The Third Medical Center, Chinese People Liberation Army (PLA) General Hospital, Beijing, China.,Medical School of Chinese People Liberation Army (PLA), Beijing, China
| | - Wang Tao
- Department of Urology, The Third Medical Center, Chinese People Liberation Army (PLA) General Hospital, Beijing, China.,Medical School of Chinese People Liberation Army (PLA), Beijing, China
| | - Hong-Zhao Li
- Department of Urology, The Third Medical Center, Chinese People Liberation Army (PLA) General Hospital, Beijing, China
| | - Xu Zhang
- School of Medicine, Nankai University, Tianjin, China.,Department of Urology, The Third Medical Center, Chinese People Liberation Army (PLA) General Hospital, Beijing, China
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13
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Kübler M, Beck S, Peffenköver LL, Götz P, Ishikawa-Ankerhold H, Preissner KT, Fischer S, Lasch M, Deindl E. The Absence of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) Promotes Pro-Angiogenic Microenvironmental Conditions and Angiogenesis in Muscle Tissue Ischemia. Int J Mol Sci 2021; 22:ijms22179484. [PMID: 34502391 PMCID: PMC8431021 DOI: 10.3390/ijms22179484] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular Cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released from cells upon hypoxia and cold-stress. The overall absence of extra- and intracellular CIRP is associated with increased angiogenesis, most likely induced through influencing leukocyte accumulation. The aim of the present study was to specifically characterize the role of eCIRP in ischemia-induced angiogenesis together with the associated leukocyte recruitment. For analyzing eCIRPs impact, we induced muscle ischemia via femoral artery ligation (FAL) in mice in the presence or absence of an anti-CIRP antibody and isolated the gastrocnemius muscle for immunohistological analyses. Upon eCIRP-depletion, mice showed increased capillary/muscle fiber ratio and numbers of proliferating endothelial cells (CD31+/CD45−/BrdU+). This was accompanied by a reduction of total leukocyte count (CD45+), neutrophils (MPO+), neutrophil extracellular traps (NETs) (MPO+CitH3+), apoptotic area (ascertained via TUNEL assay), and pro-inflammatory M1-like polarized macrophages (CD68+/MRC1−) in ischemic muscle tissue. Conversely, the number of regenerative M2-like polarized macrophages (CD68+/MRC1+) was elevated. Altogether, we observed that eCIRP depletion similarly affected angiogenesis and leukocyte recruitment as described for the overall absence of CIRP. Thus, we propose that eCIRP is mainly responsible for modulating angiogenesis via promoting pro-angiogenic microenvironmental conditions in muscle ischemia.
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Affiliation(s)
- Matthias Kübler
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Sebastian Beck
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Lisa Lilian Peffenköver
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Hellen Ishikawa-Ankerhold
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Department of Internal Medicine I, Faculty of Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Klaus T. Preissner
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Silvia Fischer
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Manuel Lasch
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Correspondence: ; Tel.: +49-(0)-89-2180-76504
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14
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Abu El-Asrar AM, Nawaz MI, Ahmad A, Siddiquei MM, Allegaert E, Gikandi PW, De Hertogh G, Opdenakker G. CD146/Soluble CD146 Pathway Is a Novel Biomarker of Angiogenesis and Inflammation in Proliferative Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2021; 62:32. [PMID: 34293080 PMCID: PMC8300056 DOI: 10.1167/iovs.62.9.32] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Purpose Inflammation, angiogenesis and fibrosis are pathological hallmarks of proliferative diabetic retinopathy (PDR). The CD146/sCD146 pathway displays proinflammatory and proangiogenic properties. We investigated the role of this pathway in the pathophysiology of PDR. Methods Vitreous samples from 41 PDR and 27 nondiabetic patients, epiretinal fibrovascular membranes from 18 PDR patients, rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy analysis. Blood-retinal barrier breakdown was assessed with fluorescein isothiocyanate-conjugated dextran. Results sCD146 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic patients. In epiretinal membranes, immunohistochemical analysis revealed CD146 expression in leukocytes, vascular endothelial cells and myofibroblasts. Significant positive correlations were detected between numbers of blood vessels expressing CD31, reflecting angiogenic activity of PDR, and numbers of blood vessels and stromal cells expressing CD146. Western blot analysis showed significant increase of CD146 in diabetic rat retinas. sCD146 induced upregulation of phospho-ERK1/2, NF-κB, VEGF and MMP-9 in Müller cells. The hypoxia mimetic agent cobalt chloride, VEGF and TNF-α induced upregulation of sCD146 in HRMECs. The MMP inhibitor ONO-4817 attenuated TNF-α-induced upregulation of sCD146 in HRMECs. Intravitreal administration of sCD146 in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, intercellular adhesion molecule-1 and VEGF in the retina. sCD146 induced migration of HRMECs. Conclusions These results suggest that the CD146/sCD146 pathway is involved in the initiation and progression of PDR.
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Affiliation(s)
- Ahmed M Abu El-Asrar
- Department of Ophthalmology, College of Medicine and Medical City, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine and Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Ajmal Ahmad
- Department of Ophthalmology, College of Medicine and Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad Mairaj Siddiquei
- Department of Ophthalmology, College of Medicine and Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Eef Allegaert
- Laboratory of Histochemistry and Cytochemistry, University of Leuven (KU Leuven), Leuven, Belgium.,University Hospitals, UZ Gasthuisberg, Leuven, Belgium
| | - Priscilla W Gikandi
- Department of Ophthalmology, College of Medicine and Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Gert De Hertogh
- Laboratory of Histochemistry and Cytochemistry, University of Leuven (KU Leuven), Leuven, Belgium.,University Hospitals, UZ Gasthuisberg, Leuven, Belgium
| | - Ghislain Opdenakker
- University Hospitals, UZ Gasthuisberg, Leuven, Belgium.,Department of Microbiology and Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven (KU Leuven), Leuven, Belgium
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15
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Becker K, Klein H, Simon E, Viollet C, Haslinger C, Leparc G, Schultheis C, Chong V, Kuehn MH, Fernandez-Albert F, Bakker RA. In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy. Sci Rep 2021; 11:10494. [PMID: 34006945 PMCID: PMC8131353 DOI: 10.1038/s41598-021-88698-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/15/2021] [Indexed: 02/03/2023] Open
Abstract
Diabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP-PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.
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Affiliation(s)
- Kolja Becker
- Global Computational Biology & Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Holger Klein
- Global Computational Biology & Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Eric Simon
- Global Computational Biology & Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Coralie Viollet
- Global Computational Biology & Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Christian Haslinger
- Global Computational Biology & Digital Sciences, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria
| | - German Leparc
- Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Christian Schultheis
- Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Victor Chong
- Therapeutic Area CNS Retinopathies Emerging Areas, BI International GmbH, Ingelheim, Germany
| | - Markus H Kuehn
- Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
- Department of Veterans Affairs, Center for the Prevention and Treatment of Visual Loss, Iowa City, IA, 52246, USA
| | - Francesc Fernandez-Albert
- Global Computational Biology & Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
| | - Remko A Bakker
- Global Department Cardio-Metabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
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16
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Absence of Cold-Inducible RNA-Binding Protein (CIRP) Promotes Angiogenesis and Regeneration of Ischemic Tissue by Inducing M2-Like Macrophage Polarization. Biomedicines 2021; 9:biomedicines9040395. [PMID: 33916904 PMCID: PMC8067566 DOI: 10.3390/biomedicines9040395] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 12/19/2022] Open
Abstract
Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated and is the topic of the present study. We investigated the role of CIRP employing CIRP deficient mice along with a hindlimb model of ischemia-induced angiogenesis. 1 and 7 days after femoral artery ligation or sham operation, gastrocnemius muscles of CIRP-deficient and wildtype mice were isolated and processed for (immuno-) histological analyses. CIRP deficient mice showed decreased ischemic tissue damage as evidenced by Hematoxylin and Eosin staining, whereas angiogenesis was enhanced as demonstrated by increased capillary/muscle fiber ratio and number of proliferating endothelial (CD31+/BrdU+) cells on day 7 after surgery. Moreover, CIRP deficiency resulted in a reduction of total leukocyte count (CD45+), neutrophils (myeloperoxidase, MPO+), neutrophil extracellular traps (NETs) (MPO+/CitH3+), and inflammatory M1-like polarized macrophages (CD68+/MRC1-), whereas the number of tissue regenerating M2-like polarized macrophages (CD68+/MRC1-) was increased in ischemic tissue samples. In summary, we show that the absence of CIRP ameliorates angiogenesis and regeneration of ischemic muscle tissue, most likely by influencing macrophage polarization in direction to regenerative M2-like macrophages.
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17
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Yoon JY, de Kock L, Stewart CJR, McCluggage WG, Foulkes WD, Clarke BA, Rouzbahman M. Endometrial Stem/Progenitor cell (ES/PC) Marker Expression Profile in Adenosarcoma and Endometrial Stromal Sarcoma. Cancer Treat Res Commun 2021; 27:100363. [PMID: 33838572 DOI: 10.1016/j.ctarc.2021.100363] [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: 10/15/2020] [Revised: 02/28/2021] [Accepted: 03/23/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND The uterus is one of the most dynamic organs in the human body, and this dynamic homeostasis is supported by endometrial stem/progenitor cells (ES/PCs), which are heterogeneous in their phenotype and degree of differentiation. ES/PCs are generally localized in the endometrial stroma, the site of origin for adenosarcoma and endometrial stromal sarcoma (ESS). Subsets of ESSs and adenosarcomas harbor SUZ12 or DICER1 gene alterations, two genes with roles in embryonic stem cell biology. However, the possible contribution of ES/PCs to tumorigenesis is unexplored. METHOD We examined the expression of eleven ES/PC markers, along with three proteins expressed in the mature endometrial stroma (ER, PR and CD10) in 60 uterine tumors (24 low-, 11 high-grade ESS, 25 adenosarcomas). Protein expression profiles were assessed by unsupervised hierarchical clustering. miRNA expression profiles were examined in a subset of adenosarcoma with/without DICER1 mutations, using the NanoString platform. RESULTS ES/PC markers were variably expressed, and the tumors exhibited limited immunophenotypic resemblance to different ES/PCs. Within the ESSs, the ES/PC marker clustering pattern was prognostic for both overall and disease-free survival. Comparing adenosarcomas and ESSs, most high-grade ESSs clustered with one another, while low-grade ESSs and adenosarcomas tended to cluster with one another. Among the adenosarcomas, the miRNA expression profiles were varied with respect to the DICER1 mutation status, with pathway analysis pointing to dysregulated signal transduction and stem cell biology. CONCLUSIONS ESSs and adenosarcomas exhibit varying immunophenotypic resemblance to ES/PCs. These expression profiles have prognostic implications and may be genetically driven.
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Affiliation(s)
- Ju-Yoon Yoon
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, St. Michael's Hospital, Toronto, ON, Canada.
| | - Leanne de Kock
- Department of Human Genetics, McGill University, Montréal, Québec, Canada; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, Québec, Canada; Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
| | - Colin J R Stewart
- School for Women's and Infants' Health, University of Western Australia, Perth, WA, Australia
| | - W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - William D Foulkes
- Department of Human Genetics, McGill University, Montréal, Québec, Canada; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, Québec, Canada; Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
| | - Blaise A Clarke
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Toronto General Hospital, Toronto, ON, Canada
| | - Marjan Rouzbahman
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Toronto General Hospital, Toronto, ON, Canada
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18
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Kitami K, Yoshihara M, Koya Y, Sugiyama M, Iyoshi S, Uno K, Mogi K, Tano S, Fujimoto H, Nawa A, Kikkawa F, Kajiyama H. Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer. Int J Mol Sci 2020; 21:E9776. [PMID: 33371469 PMCID: PMC7767511 DOI: 10.3390/ijms21249776] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 11/16/2022] Open
Abstract
Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa.
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Affiliation(s)
- Kazuhisa Kitami
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
| | - Masato Yoshihara
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
| | - Yoshihiro Koya
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (M.S.); (A.N.)
| | - Mai Sugiyama
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (M.S.); (A.N.)
| | - Shohei Iyoshi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
- Spemann Graduate School of Biology and Medicine, University of Freiburg, Albertstr. 19A, 79104 Freiburg, Germany
| | - Kaname Uno
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
- Faculty of Medicine, Lund University, Sölvegatan 19, 22184 Lund, Sweden
| | - Kazumasa Mogi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
| | - Sho Tano
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
| | - Hiroki Fujimoto
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
| | - Akihiro Nawa
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (M.S.); (A.N.)
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; (K.K.); (S.I.); (K.U.); (K.M.); (S.T.); (H.F.); (F.K.); (H.K.)
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19
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Song G, Li L, Yang Y. MicroRNA-329-3p alleviates high glucose-induced endothelial cell injury via inhibition of the TLR4/TRAF6/NF-κB signaling pathway. Exp Ther Med 2020; 21:29. [PMID: 33262815 PMCID: PMC7690244 DOI: 10.3892/etm.2020.9461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 08/22/2019] [Indexed: 12/25/2022] Open
Abstract
The aim of the current study was to determine the expression of microRNA (miRNA/miR)-329-3p in patients with type 2 diabetes mellitus (T2DM) and to investigate the effect of miR-329-3p on vascular endothelial cell function under high-glucose conditions. A total of 33 healthy individuals and 31 patients with T2DM were enrolled in the present study. Peripheral blood was collected from all participants. Human umbilical vein endothelial cells (HUVECs) were transfected with a miR-329-3p mimic or miR-329-3p inhibitor. Following treatment with 25 mmol/l glucose, a Cell Counting Kit-8 assay and flow cytometry analysis were used to assess cell viability and apoptosis levels, respectively. A dual luciferase reporter assay, western blot analysis and reverse transcription-quantitative PCR were used to assess molecular mechanism of miR-329-3p in HUVECs. The results revealed that plasma miR-329-3p expression was decreased patients with T2DM compared with healthy controls, and in HUVECs treated with high glucose concentrations. In addition, miR-329-3p reduced high glucose-induced damage to HUVEC cells. miR-329-3p directly bound to toll like receptor (TLR)-4 and regulated its expression at the transcriptional and post-transcriptional levels. miR-329-3p was also demonstrated to be involved in the regulation of the TLR4/tumor necrosis factor receptor associated factor 6 (TRAF6)/nuclear factor (NF)-κB signaling pathway and the nuclear translocation of NF-κB under a high glucose environment. In conclusion, the results indicated that miR-329-3p may protect endothelial cells from high glucose-induced apoptosis via inhibition of the TLR4/TRAF6/NF-κB signaling pathway. The present study also demonstrated that miR-329-3p expression in the plasma of patients with T2DM was reduced, suggesting that upregulation of miR-329-3p may alleviate high glucose-induced endothelial cell injury via inhibition of the TLR4/TRAF6/NF-κB signaling pathway.
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Affiliation(s)
- Guangzhao Song
- Department of Endocrinology, The First People's Hospital of Jinan, Jinan, Shandong 250011, P.R. China
| | - Liyan Li
- Department of Endocrinology, The First People's Hospital of Jinan, Jinan, Shandong 250011, P.R. China
| | - Ying Yang
- Department of Medicine, Licheng District Maternal and Child Healthcare and Family Planning Service Center, Jinan, Shandong 250100, P.R. China
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20
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Abstract
Vascularization is a major hurdle in complex tissue and organ engineering. Tissues greater than 200 μm in diameter cannot rely on simple diffusion to obtain nutrients and remove waste. Therefore, an integrated vascular network is required for clinical translation of engineered tissues. Microvessels have been described as <150 μm in diameter, but clinically they are defined as <1 mm. With new advances in super microsurgery, vessels less than 1 mm can be anastomosed to the recipient circulation. However, this technical advancement still relies on the creation of a stable engineered microcirculation that is amenable to surgical manipulation and is readily perfusable. Microvascular engineering lays on the crossroads of microfabrication, microfluidics, and tissue engineering strategies that utilize various cellular constituents. Early research focused on vascularization by co-culture and cellular interactions, with the addition of angiogenic growth factors to promote vascular growth. Since then, multiple strategies have been utilized taking advantage of innovations in additive manufacturing, biomaterials, and cell biology. However, the anatomy and dynamics of native blood vessels has not been consistently replicated. Inconsistent results can be partially attributed to cell sourcing which remains an enigma for microvascular engineering. Variations of endothelial cells, endothelial progenitor cells, and stem cells have all been used for microvascular network fabrication along with various mural cells. As each source offers advantages and disadvantages, there continues to be a lack of consensus. Furthermore, discord may be attributed to incomplete understanding about cell isolation and characterization without considering the microvascular architecture of the desired tissue/organ.
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21
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Cai S, Yang Q, Cao Y, Li Y, Liu J, Wang J, Zhang X, Liu L, Li X, Zhang Y. PF4 antagonizes retinal neovascularization via inhibiting PRAS40 phosphorylation in a mouse model of oxygen-induced retinopathy. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165604. [PMID: 31740404 DOI: 10.1016/j.bbadis.2019.165604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/19/2019] [Accepted: 11/01/2019] [Indexed: 12/22/2022]
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22
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Leroyer AS, Blin MG, Bachelier R, Bardin N, Blot-Chabaud M, Dignat-George F. CD146 (Cluster of Differentiation 146). Arterioscler Thromb Vasc Biol 2020; 39:1026-1033. [PMID: 31070478 DOI: 10.1161/atvbaha.119.312653] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CD146 (cluster of differentiation 146) is an adhesion molecule that is expressed by different cells constituting vessels, particularly endothelial cells. The last 30 years of research in this field have shown that CD146 plays a key role in the control of several vessel functions. Three forms of CD146 have been described, including 2 transmembrane isoforms and a soluble protein that is detectable in the plasma. These CD146 forms mediate pleiotropic functions through homophilic and heterophilic interactions with proteins present on surrounding partners. Several studies used neutralizing antibodies, siRNA, or genetically modified mice to demonstrate the involvement of CD146 in the regulation of angiogenesis, vascular permeability, and leukocyte transmigration. In this review, we will focus on the current knowledge of the roles of CD146 in vascular homeostasis and diseases associated with endothelial dysfunction.
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Affiliation(s)
- Aurélie S Leroyer
- From the Aix-Marseille University, Center for CardioVascular and Nutrition Research, INSERM 1263, INRA 1260, France (A.S.L., M.G.B., R.B., N.B., M.B.-C., F.D.-G.)
| | - Muriel G Blin
- From the Aix-Marseille University, Center for CardioVascular and Nutrition Research, INSERM 1263, INRA 1260, France (A.S.L., M.G.B., R.B., N.B., M.B.-C., F.D.-G.)
| | - Richard Bachelier
- From the Aix-Marseille University, Center for CardioVascular and Nutrition Research, INSERM 1263, INRA 1260, France (A.S.L., M.G.B., R.B., N.B., M.B.-C., F.D.-G.)
| | - Nathalie Bardin
- From the Aix-Marseille University, Center for CardioVascular and Nutrition Research, INSERM 1263, INRA 1260, France (A.S.L., M.G.B., R.B., N.B., M.B.-C., F.D.-G.).,Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, France (N.B., F.D.-G.)
| | - Marcel Blot-Chabaud
- From the Aix-Marseille University, Center for CardioVascular and Nutrition Research, INSERM 1263, INRA 1260, France (A.S.L., M.G.B., R.B., N.B., M.B.-C., F.D.-G.)
| | - Françoise Dignat-George
- From the Aix-Marseille University, Center for CardioVascular and Nutrition Research, INSERM 1263, INRA 1260, France (A.S.L., M.G.B., R.B., N.B., M.B.-C., F.D.-G.).,Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, France (N.B., F.D.-G.)
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23
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Nuthikattu S, Milenkovic D, Rutledge J, Villablanca A. The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice. Sci Rep 2019; 9:19058. [PMID: 31836762 PMCID: PMC6911042 DOI: 10.1038/s41598-019-55533-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 11/22/2019] [Indexed: 01/05/2023] Open
Abstract
Hyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.
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Affiliation(s)
- Saivageethi Nuthikattu
- Division of Cardiovascular Medicine, University of California, Davis, Davis, California, USA
| | - Dragan Milenkovic
- Division of Cardiovascular Medicine, University of California, Davis, Davis, California, USA.,Université Clermont Auvergne, INRA, UNH, CRNH Auvergne, F-63000, Clermont-Ferrand, France
| | - John Rutledge
- Division of Cardiovascular Medicine, University of California, Davis, Davis, California, USA
| | - Amparo Villablanca
- Division of Cardiovascular Medicine, University of California, Davis, Davis, California, USA.
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24
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Goossens EAC, de Vries MR, Simons KH, Putter H, Quax PHA, Nossent AY. miRMap: Profiling 14q32 microRNA Expression and DNA Methylation Throughout the Human Vasculature. Front Cardiovasc Med 2019; 6:113. [PMID: 31440517 PMCID: PMC6694280 DOI: 10.3389/fcvm.2019.00113] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/26/2019] [Indexed: 12/13/2022] Open
Abstract
Aims: MicroRNAs are regulators of (patho)physiological functions with tissue-specific expression patterns. However, little is known about inter-vascular differences in microRNA expression between blood vessel types or vascular beds. Differences in microRNA expression could influence cardiovascular pathophysiology at specific sites in the vasculature. Therefore, we aimed to map expression profiles of vasoactive 14q32 microRNAs throughout the human vasculature, as well as expression of vasoactive target genes of the 14q32 microRNAs. Furthermore, we aimed to map the DNA methylation status of the 14q32 locus, which has been linked to cardiovascular disease. Methods and Results: We collected 109 samples from different blood vessels, dissected during general surgery. Expression of a representative set of 17 14q32 microRNAs was measured in each sample. All 17 microRNAs showed a unique expression pattern throughout the vasculature. 14q32 microRNA expression was highest in lower limb vessels and lowest in head and neck vessels. All 17 microRNAs were expressed more abundantly in arteries than in veins. Throughout the human vasculature, we observed trends toward an inverse correlation between expression levels of the 14q32 microRNAs and their vasoactive target genes. DNA methylation of the 3 Differentially Methylated Regions (DMRs) along the 14q32 locus did not associate with primary or mature microRNA expression. However, hyper-methylation in venous coronary artery bypass grafts compared to arterial bypass grafts was observed in the Intergenic-DMR and MEG3-DMR. In patients with end-stage peripheral arterial disease we found differential DNA methylation throughout all DMRs in their lower limb veins. These findings were confirmed in a mouse model for vein-graft disease in which we found regulated 14q32 DNA methylation during the active phase of vascular remodeling. In ischemic tissues of a murine hind limb ischemia model we observed an increase in DNA methylation associated with increased ischemia over time. Conclusions: We show that 14q32 microRNAs are abundantly expressed in the human vasculature and that expression differs significantly between different blood vessels. 14q32 DNA methylation also varies throughout the vasculature and is associated with vascular health, independently of microRNA levels. These findings could have important implications for future research and for future site-specific targeting of epigenetics-based therapeutics.
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Affiliation(s)
- Eveline A C Goossens
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Einthoven Laboratory for Experimental Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Margreet R de Vries
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Einthoven Laboratory for Experimental Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Karin H Simons
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Einthoven Laboratory for Experimental Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Hein Putter
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
| | - Paul H A Quax
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Einthoven Laboratory for Experimental Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - A Yaël Nossent
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
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25
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MicroRNA-Based Diagnosis and Treatment of Metastatic Human Osteosarcoma. Cancers (Basel) 2019; 11:cancers11040553. [PMID: 31003401 PMCID: PMC6521107 DOI: 10.3390/cancers11040553] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/15/2019] [Accepted: 04/16/2019] [Indexed: 12/24/2022] Open
Abstract
Osteosarcoma is a malignant tumor of the bones that commonly occurs in young individuals. The 5-year survival rate of osteosarcoma patients is 60-70%. Metastasis to the lungs leads to death in 30-40% of osteosarcoma patients. Therefore, the development of effective strategies for early detection and treatment of this disease are important to improve the survival of osteosarcoma patients. However, metastatic markers for osteosarcoma and molecules that might be targeted for the treatment of metastatic osteosarcoma have not been identified yet. Therefore, the mechanism of metastasis to the lungs needs to be explored from a novel viewpoint. Recently, the aberrant expression of microRNAs (miRNAs) has been reported to be involved in the carcinogenesis and cancer progression of many cancers. Furthermore, miRNAs in the blood have been reported to show an aberrant expression unique to several cancers. Therefore, miRNAs are gaining attention as potential diagnostic markers for cancers. On the other hand, normalizing the dysregulated expression of miRNAs in cancer cells has been shown to alter the phenotype of cancer cells, and thus treatment strategies targeting miRNAs are also being considered. This review summarizes the abnormality of miRNA expression associated with the metastasis of osteosarcoma and describes the present situation and issues regarding the early diagnosis and development of treatment strategies for metastatic osteosarcoma based on the current understanding of this disease.
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26
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Liu YY, Bin Y, Wang X, Peng H. Increased serum levels of soluble CD146 and vascular endothelial growth factor receptor 2 in patients with exudative age-related macular degeneration. Int J Ophthalmol 2019; 12:457-463. [PMID: 30918816 DOI: 10.18240/ijo.2019.03.17] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/12/2018] [Indexed: 12/24/2022] Open
Abstract
AIM To investigate serum levels of soluble CD146 (sCD146) and vascular endothelial growth factor receptor 2 (VEGFR2) in patients with age-related macular degeneration (AMD). METHODS Eighty-eight patients with exudative AMD and 45 sex- and age-matched healthy controls were enrolled in this study conducted in China. Serum samples was obtained from the patients with exudative AMD and from the controls. Serum sCD146 and VEGFR2 protein levels were measured using an enzyme-linked immunosorbent assay. RESULTS We found that serum sCD146 and VEGFR2 protein levels were significantly higher in the patients with exudative AMD group than in the controls (t=3.859, P<0.001 and t=3.829, P<0.001, respectively). Serum sCD146 levels were significantly higher in patients with classic choroidal neovascularization (CNV) than in those with occult CNV (t=9.899, P<0.001). There was a significant difference in the trend for exudative AMD in the highest versus lowest quartile of circulating sCD146 levels (χ 2=10.29, P=0.001). The receiver operating characteristic curve analysis showed that the area under the curve was 0.696 for sCD146 (95%CI: 0.601-0.791) with an optimum diagnostic cut-off value of 157.16 ng/mL, a sensitivity of 55.7%, and a specificity of 82.2%. CONCLUSION The serum sCD146 level increases and may be a biomarker for exudative AMD.
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Affiliation(s)
- Yan-Yao Liu
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing 400016, China
| | - Yue Bin
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing 400016, China
| | - Xing Wang
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing 400016, China
| | - Hui Peng
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.,Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing 400016, China
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27
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Ying Z, Minghui T, Feng B, Ke W. Tanshinone II A improves distribution and anti-tumor efficacy of pegylated liposomal doxorubicin via normalizing the structure and function of tumor vasculature in hepa1-6 hepatoma mice model. J TRADIT CHIN MED 2018. [DOI: 10.1016/s0254-6272(18)30980-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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28
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Wu L, Pei F, Men X, Wang K, Ma D. miR-329 inhibits papillary thyroid cancer progression via direct targeting WNT1. Oncol Lett 2018; 16:3561-3568. [PMID: 30127962 PMCID: PMC6096240 DOI: 10.3892/ol.2018.9102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 06/29/2018] [Indexed: 12/22/2022] Open
Abstract
Dysregulated microRNA-329 (miR-329) serves an important role in the progression of certain types of tumor. However, the exact function and mechanisms of miR-329 in papillary thyroid cancer (PTC) remain unknown. The present study investigated the function and mechanisms of miR-329 in regulating PTC cell progression. The results revealed that the expression of miR-329 was significantly downregulated in PTC tissues and cell lines compared with adjacent normal tissues and a human immortalized follicular cell line. miR-329 mimics notably decreased PTC cell proliferation, colony formation and WNT1 expression in vitro, as well as suppressing PTC tumor growth in vivo. In addition, luciferase assays determined that miR-329 was able to directly bind with the 3'untranslated region of WNT1. Furthermore, short interfering RNA-WNT1-induced downregulation of WNT1, which demonstrated similar effects to miR-329 overexpression. WNT1 overexpression rescued the tumor suppressive effects of miR-329 in PTC cells. The present study provided new insights into the role of miR-329 in PTC progression and suggests the potential application of miR-329 as a therapy for PTC.
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Affiliation(s)
- Liang Wu
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
| | - Fulai Pei
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
| | - Xiaojuan Men
- Department of Breast Surgery, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Kai Wang
- Department of Breast Surgery, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Deliang Ma
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
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29
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Liu Y, Zhang Y, Yang Q. Retracted
: Downregulated expression of microRNA‐329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson's disease. J Cell Physiol 2018; 233:8617-8629. [DOI: 10.1002/jcp.26608] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 03/22/2018] [Indexed: 01/03/2023]
Affiliation(s)
- Yuan‐Yuan Liu
- Department of Neurologythe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouP.R. China
| | - Yi‐Nan Zhang
- Department of Neurologythe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouP.R. China
| | - Qing‐Shan Yang
- Department of Radiation Oncologythe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouLiaoning ProvinceP.R. China
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30
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Yukawa H, Suzuki K, Aoki K, Arimoto T, Yasui T, Kaji N, Ishikawa T, Ochiya T, Baba Y. Imaging of angiogenesis of human umbilical vein endothelial cells by uptake of exosomes secreted from hepatocellular carcinoma cells. Sci Rep 2018; 8:6765. [PMID: 29713019 PMCID: PMC5928189 DOI: 10.1038/s41598-018-24563-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 04/06/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a typical hyper-vascular tumor, so the understanding the mechanisms of angiogenesis in HCC is very important for its treatment. However, the influence of the exosomes secreted from HCC cells (HCC-exosomes) on angiogenesis remains poorly understood. We herein examined the effects of the exosomes secreted from HepG2 cells (HepG2-exosomes) on the lumen formation of human umbilical vein endothelial cells (HUVECs) by the imaging of angiogenesis. The degree of lumen formation of HUVECs was dependent on the number of HepG2-exosomes. The HepG2-exosomes expressed NKG2D, an activating receptor for immune cells, and HSP70, a stress-induced heat shock protein associated with angiogenesis through the vascular endothelial growth factor (VEGF) receptor. In addition, the HepG2-exosomes contained several microRNAs (miRNAs) reported to exist in the serum of HCC patients. These results suggest that the HCC-exosomes play an important role in angiogenesis. Further studies on the function of HCC-exosomes may provide a new target for HCC treatment.
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Affiliation(s)
- Hiroshi Yukawa
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan. .,ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.
| | - Kaoru Suzuki
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan
| | - Keita Aoki
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan
| | - Tomoko Arimoto
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan
| | - Takao Yasui
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.,ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.,JST, PRESTO, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan
| | - Noritada Kaji
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.,ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.,JST, PRESTO, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan
| | - Tetsuya Ishikawa
- Department of Medical Technology, Nagoya University Graduate School of Medicine, Daikominami, Higashi-ku, Nagoya, 461-8673, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yoshinobu Baba
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan. .,ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan. .,Institute of Innovation for Future Society, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan. .,Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2217-14, Hayashi-cho, Takamatsu, 761-0395, Japan. .,College of Pharmacy, Kaohsiung Medical University, 100, Shin-Chuan 1 st Rd., Kaohsiung, 807, Taiwan R.O.C..
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31
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Abstract
Purpose of Review Hypertension is either a cause or a consequence of the endothelial dysfunction and a major risk factor for cardiovascular disease (CVD). In vitro and in vivo studies established that microRNAs (miRNAs) are decisive for endothelial cell gene expression and function in various pathological conditions associated with CVD. This review provides an overview of the miRNA role in controlling the key connections between endothelial dysfunction and hypertension. Recent Findings Herein we summarize the present understanding of mechanisms underlying hypertension and its associated endothelial dysfunction as well as the miRNA role in endothelial cells with accent on the modulation of renin-angiotensin-aldosterone-system, nitric oxide, oxidative stress and on the control of vascular inflammation and angiogenesis in relation to endothelial dysfunction in hypertension. In particular, latest insights in the identification of endothelial-specific microRNAs and their targets are added to the understanding of miRNA significance in hypertension. Summary This comprehensive knowledge of the role of miRNAs in endothelial dysfunction and hypertension and of molecular mechanisms proposed for miRNA actions may offer novel diagnostic biomarkers and therapeutic targets for controlling hypertension-associated endothelial dysfunction and other cardiovascular complications.
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Affiliation(s)
- Miruna Nemecz
- Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology, 'Nicolae Simionescu' of Romanian Academy, 8, BP Hasdeu Street, PO Box 35-14, 050568, Bucharest, Romania
| | - Nicoleta Alexandru
- Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology, 'Nicolae Simionescu' of Romanian Academy, 8, BP Hasdeu Street, PO Box 35-14, 050568, Bucharest, Romania
| | - Gabriela Tanko
- Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology, 'Nicolae Simionescu' of Romanian Academy, 8, BP Hasdeu Street, PO Box 35-14, 050568, Bucharest, Romania.
| | - Adriana Georgescu
- Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology, 'Nicolae Simionescu' of Romanian Academy, 8, BP Hasdeu Street, PO Box 35-14, 050568, Bucharest, Romania.
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32
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Askou AL, Alsing S, Holmgaard A, Bek T, Corydon TJ. Dissecting microRNA dysregulation in age-related macular degeneration: new targets for eye gene therapy. Acta Ophthalmol 2018; 96:9-23. [PMID: 28271607 DOI: 10.1111/aos.13407] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 01/02/2017] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are key regulators of gene expression in humans. Overexpression or depletion of individual miRNAs is associated with human disease. Current knowledge suggests that the retina is influenced by miRNAs and that dysregulation of miRNAs as well as alterations in components of the miRNA biogenesis machinery are involved in retinal diseases, including age-related macular degeneration (AMD). Furthermore, recent studies have indicated that the vitreous has a specific panel of circulating miRNAs and that this panel varies according to the specific pathological stress experienced by the retinal cells. MicroRNA (miRNA) profiling indicates subtype-specific miRNA profiles for late-stage AMD highlighting the importance of proper miRNA regulation in AMD. This review will describe the function of important miRNAs involved in inflammation, oxidative stress and pathological neovascularization, the key molecular mechanisms leading to AMD, and focus on dysregulated miRNAs as potential therapeutic targets in AMD.
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Affiliation(s)
| | - Sidsel Alsing
- Department of Biomedicine; Aarhus University; Aarhus C Denmark
| | | | - Toke Bek
- Department of Ophthalmology; Aarhus University Hospital; Aarhus C Denmark
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33
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Liu D, Du L, Chen D, Ye Z, Duan H, Tu T, Feng J, Yang Y, Chen Q, Yan X. Reduced CD146 expression promotes tumorigenesis and cancer stemness in colorectal cancer through activating Wnt/β-catenin signaling. Oncotarget 2018; 7:40704-40718. [PMID: 27302922 PMCID: PMC5130037 DOI: 10.18632/oncotarget.9930] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 04/18/2016] [Indexed: 01/05/2023] Open
Abstract
Cancer stemness drives tumor progression and drug resistance, representing a challenge to cancer eradication. Compelling evidence indicates that cancer cells can reenter the stem cell state due to the reprogramming of self-renewal machinery. Here, we show that CD146 knockdown induces stem cell properties in colorectal cancer (CRC) cells through activating canonical Wnt signaling. shRNA-mediated CD146 knockdown in CRC cells facilitates tumor initiation in serial xenotransplantation experiments. Moreover, upon CD146 knockdown, CRC cells show elevated expression of specific cancer stem cell (CSC) markers, increased sphere and clone formation as well as drug resistance in vitro. Mechanistically, our findings provide evidence that CD146 expression negatively correlates with canonical Wnt/β-catenin activity in CRC cell lines and primary CRC specimens. Knockdown of CD146 results in inhibition of NF-κB/p65-initiated GSK-3β expression, subsequently promoting nuclear translocation and activation of β-catenin, and as a consequence restoring stem cell phenotypes in differentiated CRC cells. Together, our data strongly suggest that CD146 functions as a suppressor of tumorigenesis and cancer stemness in CRC through inactivating the canonical Wnt/β-catenin cascade. Our findings provide important insights into stem cell plasticity and the multifunctional role of CD146 in CRC progression.
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Affiliation(s)
- Dan Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lei Du
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Dong Chen
- Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Zhongde Ye
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hongxia Duan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Tao Tu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jing Feng
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yili Yang
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Quan Chen
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Cai L, Chen Q, Fang S, Lian M, Cai M. MicroRNA-329 inhibits cell proliferation and tumor growth while facilitates apoptosis via negative regulation of KDM1A in gastric cancer. J Cell Biochem 2017; 119:3338-3351. [PMID: 29130516 DOI: 10.1002/jcb.26497] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 11/09/2017] [Indexed: 01/05/2023]
Abstract
Altered expression of microRNA (miRNA) is strongly implicated in gastric cancer (GC). Here, we demonstrated a decreased expression of miRNA-329 in GC. Then we explored the regulatory mechanisms responsible for its effect on GC cells. GC tissues and their adjacent non-tumor tissues were collected. Complete follow-up was updated. A series of inhibitors, mimics, and siRNA against KDM1A were introduced to validate regulatory mechanisms for miR-497 and KDM1A in BGC-823 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay were employed for evaluating the expressions of miRNA-329, KDM1A, H3K4me1, and H3K4me2. Cell proliferation, cycle progression, and apoptosis were assessed by means of an MTT assay and flow cytometry. Cell colony formation was assessed. uman gastric cancer xenotransplanted into nude mice was studied. As opposed to adjacent tissues and gastritis tissues, miRNA-329 was highly expressed and KDM1A was low expressed in GC tissues. The patients with high miRNA-329 expression or low KDM1A expression had longer survival periods. The miRNA-329 mimics and siRNA against KDM1A decreased KDM1A expression and increased H3K4me1 and H3K4me2 expressions. Forced expression of miRNA-329 in gastric cancer cells significantly promotes their capacity of apoptosis but reduces proliferation, migration, and invasion. KDM1A is a direct downstream target for miRNA-329. In a nude mouse subcutaneous tumor system, in vivo tumor growth of BGC-823 was significantly inhibited after treatment of miRNA-329 mimics or siRNA against KDM1A. We conclude that miRNA-329 functions as a tumor suppressor in GC, which could be achieved via transcriptional suppression of KDM1A.
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Affiliation(s)
- Lisheng Cai
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, P.R.China
| | - Qiuxian Chen
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, P.R.China
| | - Shunyong Fang
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, P.R.China
| | - Mingqiao Lian
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, P.R.China
| | - Mingzhi Cai
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, P.R.China
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35
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Sun CC, Li SJ, Zhang F, Pan JY, Wang L, Yang CL, Xi YY, Li DJ. Hsa-miR-329 exerts tumor suppressor function through down-regulation of MET in non-small cell lung cancer. Oncotarget 2017; 7:21510-26. [PMID: 26909600 PMCID: PMC5008302 DOI: 10.18632/oncotarget.7517] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 02/05/2016] [Indexed: 12/31/2022] Open
Abstract
MicroRNAs (miRNAs) act as key regulators of multiple cancers. Hsa-miR-329 (miR-329) functions as a tumor suppressor in some malignancies. However, its role on lung cancer remains poorly understood. In this study, we investigated the role of miR-329 on the development of lung cancer. The results indicated that miR-329 was decreased in primary lung cancer tissues compared with matched adjacent normal lung tissues and very low levels were found in a non-small cell lung cancer (NSCLC) cell lines. Ectopic expression of miR-329 in lung cancer cell lines substantially repressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibiting cyclin D1, cyclin D2 and up-regulatiing p57(Kip2) and p21(WAF1/CIP1). In addition, miR-329 promoted NSCLC cell apoptosis, as indicated by up-regulation of key apoptosis gene cleaved caspase-3, and down-regulation of anti-apoptosis gene Bcl2. Moreover, miR-329 inhibited cellular migration and invasiveness through inhibiting matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene MET was revealed to be a putative target of miR-329, which was inversely correlated with miR-329 expression. Furthermore, down-regulation of MET by siRNA performed similar effects to over-expression of miR-329. Collectively, our results demonstrated that miR-329 played a pivotal role in lung cancer through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic MET.
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Affiliation(s)
- Cheng-Cao Sun
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - Shu-Jun Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China.,Wuhan Hospital for The Prevention and Treatment of Occupational Diseases, Wuhan, P. R. China
| | - Feng Zhang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - Jing-Yu Pan
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - Liang Wang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - Cui-Li Yang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - Yong-Yong Xi
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - De Jia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
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36
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MicroRNA as a Therapeutic Target in Cardiac Remodeling. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1278436. [PMID: 29094041 PMCID: PMC5637866 DOI: 10.1155/2017/1278436] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/23/2017] [Accepted: 08/09/2017] [Indexed: 12/20/2022]
Abstract
MicroRNAs (miRNAs) are small RNA molecules that contain 18–25 nucleotides. The alterations in their expression level play crucial role in the development of many disorders including heart diseases. Myocardial remodeling is the final pathological consequence of a variety of myocardial diseases. miRNAs have central role in regulating pathogenesis of myocardial remodeling by modulating cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response through multiple mechanisms. The balancing and tight regulation of different miRNAs is a key to drive the cellular events towards functional recovery and any fall in this leads to detrimental effect on cardiac function following various insults. In this review, we discuss the impact of alterations of miRNAs expression on cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response. We have also described the targets (receptors, signaling molecules, transcription factors, etc.) of miRNAs on which they act to promote or attenuate cardiac remodeling processes in different type cells of cardiac tissues.
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37
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Abstract
PURPOSE OF REVIEW Osteogenesis is a complex process involving the specification of multiple progenitor cells and their maturation and differentiation into matrix-secreting osteoblasts. Osteogenesis occurs not only during embryogenesis but also during growth, after an injury, and in normal homeostatic maintenance. While much is known about osteogenesis-associated regulatory genes, the role of microRNAs (miRNAs), which are epigenetic regulators of protein expression, is just beginning to be explored. While miRNAs do not abrogate all protein expression, their purpose is to finely tune it, allowing for a timely and temporary protein down-regulation. RECENT FINDINGS The last decade has unveiled a multitude of miRNAs that regulate key proteins within the osteogenic lineage, thus qualifying them as "ostemiRs." These miRNAs may endogenously target an activator or inhibitor of differentiation, and depending on the target, may either lead to the prolongation of a progenitor maintenance state or to early differentiation. Interestingly, cellular identity seems intimately coupled to the expression of miRNAs, which participate in the suppression of previous and subsequent differentiation steps. In such cases where key osteogenic proteins were identified as direct targets of miRNAs in non-bone cell types, or through bioinformatic prediction, future research illuminating the activity of these miRNAs during osteogenesis will be extremely valuable. Many bone-related diseases involve the dysregulation of transcription factors or other proteins found within osteoblasts and their progenitors, and the dysregulation of miRNAs, which target such factors, may play a pivotal role in disease etiology, or even as a possible therapy.
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Affiliation(s)
- Steven R Sera
- Department of Cell Biology and Neuroscience and Stem Cell Center, College of Natural and Agricultural Sciences, University of California Riverside, 1113 Biological Sciences Building, Riverside, CA, 92521, USA
| | - Nicole I Zur Nieden
- Department of Cell Biology and Neuroscience and Stem Cell Center, College of Natural and Agricultural Sciences, University of California Riverside, 1113 Biological Sciences Building, Riverside, CA, 92521, USA.
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38
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Zhang Y, Cai S, Jia Y, Qi C, Sun J, Zhang H, Wang F, Cao Y, Li X. Decoding Noncoding RNAs: Role of MicroRNAs and Long Noncoding RNAs in Ocular Neovascularization. Am J Cancer Res 2017; 7:3155-3167. [PMID: 28839470 PMCID: PMC5566112 DOI: 10.7150/thno.19646] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 06/15/2017] [Indexed: 12/11/2022] Open
Abstract
Ocular neovascularization is a pathological sequel of multiple eye diseases. Based on the anatomical site into which the abnormal neovessels grow, ocular neovascularization can be categorized into corneal neovascularization, choroidal neovascularization, and retinal neovascularization. Each category is intractable, and may lead to blindness if not appropriately treated. However, the current therapeutic modalities, including laser photocoagulation, vitrectomy surgery, and anti-VEGF drugs, raise concerns due to limited efficacy, damage on retinal parenchyma and vasculature, and the patients' unresponsiveness to the treatments. Therefore, the in-depth study on pathogenesis of and the search for novel therapeutic targets to the ocular neovascularization are needed. During the last 10 years or so, a large number of literatures have emerged indicating a critical role of noncoding RNAs, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), in the pathogenesis and regulation of the ocular neovascularization. This review summarizes the current understanding of the biosynthesis and functions of the miRNAs and lncRNAs, the regulation of the miRNAs and lncRNAs in neovascular eye diseases, as well as the roles of these noncoding RNAs in the disease models of ocular neovascularization, in the hope that it could provide clues for the pathogenesis of and molecular targets to the ocular neovascularization.
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39
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Li W, Liang J, Zhang Z, Lou H, Zhao L, Xu Y, Ou R. MicroRNA-329-3p targets MAPK1 to suppress cell proliferation, migration and invasion in cervical cancer. Oncol Rep 2017; 37:2743-2750. [PMID: 28393232 DOI: 10.3892/or.2017.5555] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/03/2016] [Indexed: 11/06/2022] Open
Abstract
Cervical cancer is the second most common gynecological cancer worldwide and remains as one of the leading causes of cancer-related death among women. Despite great progress in the treatment of cervical cancer, the 5-year overall survival rate for patients with this disease remains unsatisfactory. Over the past decade, an increasing number of studies indicate a central role for microRNAs in the initiation and progression of cervical cancer. microRNA‑329-3p (miR-329-3p) has been studied in many types of human cancer; however, the expression level, biological role and the underlying mechanism of miR-329-3p in cervical cancer has not yet been investigated. In the present study, we found that the expression levels of miR-329-3p were reduced in both cervical cancer tissues and cell lines. Low miR-329-3p expression was negatively correlated with histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis of cervical cancer patients. In addition, upregulation of miR‑329-3p suppressed cell proliferation, migration and invasion of cervical cancer. Furthermore, MAPK1 was identified as a direct target gene of miR-329-3p. MAPK1 was significantly upregulated in cervical cancer tissues and was inversely correlated with miR-329-3p expression in the cervical cancer tissues. Silencing of MAPK1 by RNA interference mimicked the effects of miR-329-3p overexpression on cell proliferation, migration and invasion in cervical cancer. Moreover, rescue experiments showed that restoration of the expression of MAPK1 reversed the effects of miR‑329-3p overexpression in cervical cancer cells. Taken together, these findings suggest that miR-329-3p has a critical tumor-suppressive roles by directly targeting MAPK1 in cervical cancer, and it may be investigated as a novel therapeutic target for the treatment of patients with this disease.
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Affiliation(s)
- Wenfeng Li
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jingjing Liang
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhechao Zhang
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Hongyan Lou
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Liang Zhao
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yunsheng Xu
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Rongying Ou
- Laboratory for Advanced Interdisciplinary Research, Center for Personalized Medicine/Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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40
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Luo Y, Duan H, Qian Y, Feng L, Wu Z, Wang F, Feng J, Yang D, Qin Z, Yan X. Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res 2017; 27:352-372. [PMID: 28084332 PMCID: PMC5339843 DOI: 10.1038/cr.2017.8] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 10/18/2016] [Accepted: 11/28/2016] [Indexed: 12/24/2022] Open
Abstract
The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low-density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE-/- mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment.
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Affiliation(s)
- Yongting Luo
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hongxia Duan
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yining Qian
- Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing 100029, China
| | - Liqun Feng
- Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing 100029, China
| | - Zhenzhen Wu
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Fei Wang
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jing Feng
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Dongling Yang
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhihai Qin
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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41
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Yan YY, Wang ZH, Zhao L, Song DD, Qi C, Liu LL, Wang JN. MicroRNA-210 Plays a Critical Role in the Angiogenic Effect of Isoprenaline on Human Umbilical Vein Endothelial Cells via Regulation of Noncoding RNAs. Chin Med J (Engl) 2017; 129:2676-2682. [PMID: 27823999 PMCID: PMC5126158 DOI: 10.4103/0366-6999.193452] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: β-adrenoceptors play a crucial regulatory role in blood vessel endothelial cells. Isoprenaline (ISO, a β-adrenergic agonist) has been reported to promote angiogenesis through upregulation of vascular endothelial growth factor (VEGF) expression; however, the underlying mechanism remains to be investigated. It is widely accepted that certain noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), can regulate endothelial cell behavior, including their involvement in angiogenesis. Therefore, we aimed to investigate whether noncoding RNAs participate in ISO-mediated angiogenesis using human umbilical vein endothelial cells (HUVECs). Methods: We evaluated VEGF-A messenger RNA (mRNA) and protein levels in ISO-treated HUVECs by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To establish whether noncoding RNAs are associated with ISO-mediated angiogenesis, we measured expression of the miRNAs miR-210, miR-21, and miR-1, as well as that of the lncRNAs growth arrest-specific transcript 5 (GAS5), maternally expressed 3 (MEG3), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in HUVECs exposed to ISO. Furthermore, to ascertain its importance in ISO-mediated angiogenesis, we constructed the HUVECs with overexpressing miR-210 and detected the subsequent expression of VEGF-A and noncoding RNAs. All statistical analyses were performed using SPSS 16.0 software. Intergroup comparisons were carried out by one-way analysis of variance. Results: VEGF-A mRNA levels were elevated in the ISO group (1.57 ± 0.09) compared to those in the control group (P < 0.01). Moreover, concentrations of VEGF-A in culture supernatants significantly differed between the control (113.00 ± 19.21 pg/ml) and ISO groups (287.00 ± 20.27 pg/ml; P < 0.01). Expression of miR-1, miR-21, and miR-210 was higher (3.89 ± 0.44, 2.87 ± 087, and 3.33 ± 1.31, respectively) in ISO-treated cells than that in controls (P < 0.01), whereas that of GAS5 and MEG3 (0.22 ± 0.10 and 0.58 ± 0.16, respectively) was lower as a result of ISO administration (P < 0.05). There was no significant difference in the expression of MALAT1 between the groups. Interestingly, miR-210 overexpression heightened the levels of VEGF-A and miR-21 (5.87 ± 1.24 and 2.74 ± 1.15, respectively; P < 0.01) and reduced those of GAS5 and MEG3 (0.19 ± 0.01 and 0.09 ± 0.05, respectively; P < 0.01). Conclusions: ISO-mediated angiogenesis was associated with altered expression of miR-210, miR-21, and the lncRNAs GAS5 and MEG3. The effects of miR-210 on the expression of VEGF-A and noncoding RNAs were similar to those of ISO, indicating that it might play an important role in ISO-mediated angiogenesis.
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Affiliation(s)
- You-You Yan
- Department of Cardiology, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Zhi-Hui Wang
- Department of Cardiology, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Lei Zhao
- Department of Cardiology, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Dan-Dan Song
- Department of Clinical Laboratory, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Chao Qi
- Department of Cardiology, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Lu-Lu Liu
- Department of Cardiology, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Jun-Nan Wang
- Department of Cardiology, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China
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Kar S, Bali KK, Baisantry A, Geffers R, Samii A, Bertalanffy H. Genome-Wide Sequencing Reveals MicroRNAs Downregulated in Cerebral Cavernous Malformations. J Mol Neurosci 2017; 61:178-188. [PMID: 28181149 DOI: 10.1007/s12031-017-0880-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 01/05/2017] [Indexed: 12/29/2022]
Abstract
Cerebral cavernous malformations (CCM) are vascular lesions associated with loss-of-function mutations in one of the three genes encoding KRIT1 (CCM1), CCM2, and PDCD10. Recent understanding of the molecular mechanisms that lead to CCM development is limited. The role of microRNAs (miRNAs) has been demonstrated in vascular pathologies resulting in loss of tight junction proteins, increased vascular permeability and endothelial cell dysfunction. Since the relevance of miRNAs in CCM pathophysiology has not been elucidated, the primary aim of the study was to identify the miRNA-mRNA expression network associated with CCM. Using small RNA sequencing, we identified a total of 764 matured miRNAs expressed in CCM patients compared to the healthy brains. The expression of the selected miRNAs was validated by qRT-PCR, and the results were found to be consistent with the sequencing data. Upon application of additional statistical stringency, five miRNAs (let-7b-5p, miR-361-5p, miR-370-3p, miR-181a-2-3p, and miR-95-3p) were prioritized to be top CCM-relevant miRNAs. Further in silico analyses revealed that the prioritized miRNAs have a direct functional relation with mRNAs, such as MIB1, HIF1A, PDCD10, TJP1, OCLN, HES1, MAPK1, VEGFA, EGFL7, NF1, and ENG, which are previously characterized as key regulators of CCM pathology. To date, this is the first study to investigate the role of miRNAs in CCM pathology. By employing cutting edge molecular and in silico analyses on clinical samples, the current study reports global miRNA expression changes in CCM patients and provides a rich source of data set to understand detailed molecular machinery involved in CCM pathophysiology.
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Affiliation(s)
- Souvik Kar
- International Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, 30625, Hannover, Germany.
| | - Kiran Kumar Bali
- Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Arpita Baisantry
- Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany
| | - Robert Geffers
- Genome Analytics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Amir Samii
- International Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, 30625, Hannover, Germany
| | - Helmut Bertalanffy
- International Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, 30625, Hannover, Germany
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Wang JH, Ling D, Tu L, van Wijngaarden P, Dusting GJ, Liu GS. Gene therapy for diabetic retinopathy: Are we ready to make the leap from bench to bedside? Pharmacol Ther 2017; 173:1-18. [PMID: 28132907 DOI: 10.1016/j.pharmthera.2017.01.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetic retinopathy (DR), a chronic and progressive complication of diabetes mellitus, is a sight-threatening disease characterized in the early stages by neuronal and vascular dysfunction in the retina, and later by neovascularization that further damages vision. A major contributor to the pathology is excess production of vascular endothelial growth factor (VEGF), a growth factor that induces formation of new blood vessels and increases permeability of existing vessels. Despite the recent availability of effective treatments for the disease, including laser photocoagulation and therapeutic VEGF antibodies, DR remains a significant cause of vision loss worldwide. Existing anti-VEGF agents, though generally effective, are limited by their short therapeutic half-lives, necessitating frequent intravitreal injections and the risk of attendant adverse events. Management of DR with gene therapies has been proposed for several years, and pre-clinical studies have yielded enticing findings. Gene therapy holds several advantages over conventional treatments for DR, such as a longer duration of therapeutic effect, simpler administration, the ability to intervene at an earlier stage of the disease, and potentially fewer side-effects. In this review, we summarize the current understanding of the pathophysiology of DR and provide an overview of research into DR gene therapies. We also examine current barriers to the clinical application of gene therapy for DR and evaluate future prospects for this approach.
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Affiliation(s)
- Jiang-Hui Wang
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Damien Ling
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Discipline of Ophthalmology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Leilei Tu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Peter van Wijngaarden
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Gregory J Dusting
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Guei-Sheung Liu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia; Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia.
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Lin Z, Zhang Q, Luo W. Angiogenesis inhibitors as therapeutic agents in cancer: Challenges and future directions. Eur J Pharmacol 2016; 793:76-81. [PMID: 27840192 DOI: 10.1016/j.ejphar.2016.10.039] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 10/08/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023]
Abstract
Angiogenesis has become an attractive target for cancer therapy since the US Food and Drug Administration (FDA) approved the first angiogenesis inhibitor (bevacizumab) for the treatment of metastatic colorectal cancer in 2004. In following years, a large number of angiogenesis inhibitors have been discovered and developed, ranging from monoclonal antibodies, endogenous peptides, to small organic molecules and microRNAs. Many of them are now entering the clinical trial, or achieving approval for clinical use. However, major limitations have been observed about angiogenesis inhibitors by continued clinical investigations, such as resistance, enhancing tumor hypoxia and reducing delivery of chemotherapeutic agents, which might be the main reason for poor improvement in overall survival after angiogenesis inhibitor administration in clinic. Therefore, optimal anti-angiogenic therapy strategies become critical. The present review summarizes recent researches in angiogenesis inhibitors, and proposes a perspective on future directions in this field.
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Affiliation(s)
- Zhexuan Lin
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Quanwei Zhang
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Wenhong Luo
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China.
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Xie J, Liu JH, Liu H, Liao XZ, Chen Y, Lin MG, Gu YY, Liu TL, Wang DM, Ge H, Mo SL. Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way. BMC Cancer 2016; 16:899. [PMID: 27863471 PMCID: PMC5116215 DOI: 10.1186/s12885-016-2921-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 11/02/2016] [Indexed: 12/18/2022] Open
Abstract
Background The study was designed to develop a platform to verify whether the extract of herbs combined with chemotherapy drugs play a synergistic role in anti-tumor effects, and to provide experimental evidence and theoretical reference for finding new effective sensitizers. Methods Inhibition of tanshinone IIA and adriamycin on the proliferation of A549, PC9 and HLF cells were assessed by CCK8 assays. The combination index (CI) was calculated with the Chou-Talalay method, based on the median-effect principle. Migration and invasion ability of A549 cells were determined by wound healing assay and transwell assay. Flow cytometry was used to detect the cell apoptosis and the distribution of cell cycles. TUNEL staining was used to detect the apoptotic cells. Immunofluorescence staining was used to detect the expression of Cleaved Caspase-3. Western blotting was used to detect the proteins expression of relative apoptotic signal pathways. CDOCKER module in DS 2.5 was used to detect the binding modes of the drugs and the proteins. Results Both tanshinone IIA and adriamycin could inhibit the growth of A549, PC9, and HLF cells in a dose- and time-dependent manner, while the proliferative inhibition effect of tanshinone IIA on cells was much weaker than that of adriamycin. Different from the cancer cells, HLF cells displayed a stronger sensitivity to adriamycin, and a weaker sensitivity to tanshinone IIA. When tanshinone IIA combined with adriamycin at a ratio of 20:1, they exhibited a synergistic anti-proliferation effect on A549 and PC9 cells, but not in HLF cells. Tanshinone IIA combined with adriamycin could synergistically inhibit migration, induce apoptosis and arrest cell cycle at the S and G2 phases in A549 cells. Both groups of the single drug treatment and the drug combination up-regulated the expressions of Cleaved Caspase-3 and Bax, but down-regulated the expressions of VEGF, VEGFR2, p-PI3K, p-Akt, Bcl-2, and Caspase-3 protein. Compared with the single drug treatment groups, the drug combination groups were more statistically significant. The molecular docking algorithms indicated that tanshinone IIA could be docked into the active sites of all the tested proteins with H-bond and aromatic interactions, compared with that of adriamycin. Conclusions Tanshinone IIA can be developed as a novel agent in the postoperative adjuvant therapy combined with other anti-tumor agents, and improve the sensibility of chemotherapeutics for non-small cell lung cancer with fewer side effects. In addition, this experiment can not only provide a reference for the development of more effective anti-tumor medicine ingredients, but also build a platform for evaluating the anti-tumor effects of Chinese herbal medicines in combination with chemotherapy drugs. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2921-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jun Xie
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.,School of Chinese Medicine, The University of Hong Kong, Hong Kong S.A.R., People's Republic of China
| | - Jia-Hui Liu
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Heng Liu
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Xiao-Zhong Liao
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Yuling Chen
- Kiang Wu Hospital, Macau S.A.R., People's Republic of China
| | - Mei-Gui Lin
- Liwan District Shiweitang Street Community Health Service Center, Guangzhou, 510360, People's Republic of China
| | - Yue-Yu Gu
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Tao-Li Liu
- The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, People's Republic of China
| | - Dong-Mei Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, People's Republic of China
| | - Hui Ge
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
| | - Sui-Lin Mo
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
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Li Z, Yu X, Wang Y, Shen J, Wu WKK, Liang J, Feng F. By downregulating TIAM1 expression, microRNA-329 suppresses gastric cancer invasion and growth. Oncotarget 2016; 6:17559-69. [PMID: 25654811 PMCID: PMC4627328 DOI: 10.18632/oncotarget.2755] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 11/16/2014] [Indexed: 01/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Emerging evidence has shown that abnormal microRNAs (miRNAs) expression is involved in tumorigenesis. MiR-329 was previously reported to act as a tumor suppressor or oncogene in some types of cancer. However, its function in gastric cancer (GC) is unclear. Here, we found that miR-329 was down-regulated in GC compared with adjacent controls. Enforced expression of miR-329 inhibited proliferation, migration and invasion of gastric cancer cells in vitro. We identified T lymphoma invasion and metastasis 1 (TIAM1) gene as potential target of miR-329. MiR-329 levels inversely correlated with TIAM1 expression in GC. Importantly, TIAM1 rescued the miR-329-mediated inhibition of cell invasion and proliferation. Finally, reintroduction of miR-329 significantly inhibited tumor formation of GC in the xenograft mice. Our findings suggest that miR-329 is a tumor suppressor and potential therapeutic target of GC
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Affiliation(s)
- Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Yu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Wang
- Department of Abdominal Surgery, Cancer Institute and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jianxiong Shen
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Jinqian Liang
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Feng
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Pankratz F, Bemtgen X, Zeiser R, Leonhardt F, Kreuzaler S, Hilgendorf I, Smolka C, Helbing T, Hoefer I, Esser JS, Kustermann M, Moser M, Bode C, Grundmann S. Response to Letter Regarding Article, "MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization". Circulation 2016; 132:e376. [PMID: 26644256 DOI: 10.1161/circulationaha.115.018754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Franziska Pankratz
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany, Department of Biology, Albert-Ludwigs-University, Freiburg, Germany
| | - Xavier Bemtgen
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany
| | - Franziska Leonhardt
- Department of Biology, Albert-Ludwigs-University, Freiburg, Germany, Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany
| | - Sheena Kreuzaler
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Ingo Hilgendorf
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Christian Smolka
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Thomas Helbing
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Imo Hoefer
- Experimental Cardiology Laboratory, University Medical Center, Utrecht, the Netherlands
| | - Jennifer S Esser
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Max Kustermann
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Martin Moser
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Christoph Bode
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Sebastian Grundmann
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
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Welten S, Goossens E, Quax P, Nossent A. The multifactorial nature of microRNAs in vascular remodelling. Cardiovasc Res 2016; 110:6-22. [DOI: 10.1093/cvr/cvw039] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 02/07/2016] [Indexed: 12/22/2022] Open
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Chandra V, Kim JJ, Mittal B, Rai R. MicroRNA aberrations: An emerging field for gallbladder cancer management. World J Gastroenterol 2016; 22:1787-1799. [PMID: 26855538 PMCID: PMC4724610 DOI: 10.3748/wjg.v22.i5.1787] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/12/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer (GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment options. These necessitate development of early prognostic/predictive markers and novel therapeutic interventions. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a key role in tumor biology by functioning like tumor suppressor- or onco- genes and their aberrant expression are associated with the pathogenesis of several neoplasms with overwhelming clinical implications. Since miRNA signature is tissue specific, here, we focused on current data concerning the miRNAs aberrations in GBC pathogenesis. In GBC, miRNAs with tumor suppressor activity (miR-135-5p, miR-335, miR-34a, miR-26a, miR-146b-5p, Mir-218-5p, miR-1, miR-145, mir-130a) were found downregulated, while those with oncogenic property (miR-20a, miR-182, mir-155) were upregulated. The expression profile of miRNAs was significantly associated with GBC prognosis and prediction, and forced over-expression/ inhibition of these miRNAs was shown to affect tumor growth and development. Further, differential expression of miRNAs in the blood samples of GBC patients suggest miRNAs as promising noninvasive biomarker. Thus, miRNAs represent potential candidate for GBC management, though many hurdles need to be overcome before miRNAs therapy can be clinically applied to GBC prevention and treatment.
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Gao YQ, Chen X, Wang P, Lu L, Zhao W, Chen C, Chen CP, Tao T, Sun J, Zheng YY, Du J, Li CJ, Gan ZJ, Gao X, Chen HQ, Zhu MS. Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance. Proc Natl Acad Sci U S A 2015; 112:13627-32. [PMID: 26487685 PMCID: PMC4640741 DOI: 10.1073/pnas.1511448112] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance.
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Affiliation(s)
- Yun-Qian Gao
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Xin Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Pei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Lei Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Wei Zhao
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Chen Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Cai-Ping Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Tao Tao
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Jie Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Yan-Yan Zheng
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Jie Du
- Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Beijing 100029, China
| | - Chao-Jun Li
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Zhen-Ji Gan
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Xiang Gao
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
| | - Hua-Qun Chen
- School of Life Science, Nanjing Normal University, Nanjing 210009, China
| | - Min-Sheng Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China; Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Beijing 100029, China;
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