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Ghasroldasht MM, Park HS, Ali FL, Beckman A, Mohammadi M, Hafner N, Al-Hendy A. Adapted Exosomes for Addressing Chemotherapy-induced Premature Ovarian Insufficiency. Stem Cell Rev Rep 2025; 21:779-796. [PMID: 39921838 DOI: 10.1007/s12015-024-10820-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2024] [Indexed: 02/10/2025]
Abstract
BACKGROUND Premature ovarian insufficiency (POI) presents a multifaceted challenge with limited treatment options. This study explored the therapeutic potential of exosome-based interventions for chemotherapy-induced POI. METHODS Adapted exosomes were engineered from umbilical cord mesenchymal stem cells (UC-MSCs) under a specific co-culture system and used for treating in vitro and in vivo models of chemotherapy-induced premature ovarian insufficiency. RESULTS In vitro models revealed the significant impact of adapted exosomes, which promoted granulosa cell proliferation, decrease apoptosis, and enhanced ovarian functional markers. The findings in an in vivo chemotherapy-induced POI mouse model indicated the restoration of ovarian morphology, follicle numbers, and fertility in both the naïve and adapted exosome-treated groups. Notably, the adapted exosome group demonstrated a heightened pregnancy rate, increased numbers of primary follicles, and a significant reduction in ovarian apoptosis. MiRNA profiling revealed distinctive cargo in the adapted exosomes, among which miR-20b-5p played a pivotal role in regulating apoptosis and inflammation; this finding is especially important given that apoptosis is one of the primary complications of chemotherapy-induced POI. Furthermore, cells treated with adapted exosomes demonstrated significant overexpression of miR-20b-5p, resulting in decreased PTEN expression and the activation of the PI3K-AKT pathway-a crucial mechanism in mitigating chemotherapy-induced POI. CONCLUSIONS This study introduces an exosome-based therapeutic approach, emphasizing the importance of exosome cargo composition in treating disorders. Further investigation into the identified miRNA profile in adapted exosomes is necessary to clarify the underlying mechanisms, potentially leading to the development of a new treatment for clinical premature ovarian insufficiency.
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Affiliation(s)
| | - Hang-Soo Park
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
| | - Farzana Liakath Ali
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
| | - Analea Beckman
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
| | - Mahya Mohammadi
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
| | - Nina Hafner
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA.
- Department of Medical Sciences, Khalifa University, Abu Dhabi, United Arab Emirates.
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2
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Sperb N, Maksakova IA, Escano L, Abraham L, MacPhee L, Cabantog A, Kim D, Yu M, Krowiorz K, Im J, Grasedieck S, Pochert N, Ruess C, Rösler R, Flibotte S, Maetzig T, Calzia E, Palmqvist L, Wiese S, Fogelstrand L, Gold MR, Rouhi A, Kuchenbauer F. The proto-oncogenic miR-106a-363 cluster enhances adverse risk acute myeloid leukemia through mitochondrial activation. Leukemia 2025:10.1038/s41375-025-02558-x. [PMID: 40097604 DOI: 10.1038/s41375-025-02558-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/10/2025] [Accepted: 02/28/2025] [Indexed: 03/19/2025]
Abstract
We investigated the clinical and functional role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML). LAML miRNA-Seq TCGA analyses revealed that high expression of miR-106a-363 cluster members was associated with inferior survival, and miR-106a-5p and miR-20b-5p levels were significantly elevated in patients with adverse risk AML. Overexpression of the miR-106a-363 cluster and its individual members in a murine AML model significantly accelerated leukemogenesis. Proteomics analysis of leukemic bone marrow cells from these models emphasized the deregulation of proteins involved in intracellular transport, protein complex organization and mitochondrial function, driven predominantly by miR-106a-5p. These molecular alterations suggested mitochondrial activation as a potential mechanism for the observed increase in leukemogenicity. High-resolution respirometry and STED microscopy confirmed that miR-106a-5p enhances mitochondrial respiratory activity and increases mitochondrial volume. These findings demonstrate that the miR-106a-363 cluster, and particularly miR-106a-5p, contribute to AML progression through modulation of mitochondrial function and deregulation of mitochondria-coordinated pathways.
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Affiliation(s)
- Nadine Sperb
- Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany
| | - Irina A Maksakova
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Leo Escano
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Libin Abraham
- Department. of Microbiology and Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Liam MacPhee
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Ariene Cabantog
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Dexter Kim
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Mansen Yu
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Kathrin Krowiorz
- Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany
| | - Junbum Im
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
| | - Sarah Grasedieck
- Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany
| | - Nicole Pochert
- Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany
- Department for Gynecology and Obstetrics, University Hospital Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany
| | - Christoph Ruess
- Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany
| | - Reinhild Rösler
- Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, 89081, Germany
| | - Stephane Flibotte
- Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Tobias Maetzig
- Institute of Experimental Hematology, Hannover Medical School, Hannover, 30625, Germany
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Enrico Calzia
- Institute for Anesthesiological pathophysiology and procedure development, Ulm University Hospital, Helmholtzstrasse 8/1, 89081, Ulm, Germany
| | - Lars Palmqvist
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 41345, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, 41345, Sweden
| | - Sebastian Wiese
- Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, 89081, Germany
| | - Linda Fogelstrand
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 41345, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, 41345, Sweden
| | - Michael R Gold
- Department. of Microbiology and Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Arefeh Rouhi
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
- Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada
| | - Florian Kuchenbauer
- Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
- Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada.
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Liang Y, Shi C, Wang Y, Fan B, Song W, Shen R. MiR-363-3p induces tamoxifen resistance in breast cancer cells through PTEN modulation. Sci Rep 2024; 14:32135. [PMID: 39738797 PMCID: PMC11685982 DOI: 10.1038/s41598-024-83938-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025] Open
Abstract
Nowadays, the investigation for overcoming tamoxifen (TAM) resistance is confronting a considerable challenge. Therefore, immediate attention is required to elucidate the mechanism underlying TAM resistance in breast cancer. This research primarily aimed to define how miRNA-363-3p facilitates resistance to TAM in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and TAM-resistant MCF-7 cells (MCF-7-TAM). An increase in miRNA-363-3p levels was observed in MCF-7-TAM cells. In MCF-7 cells, miRNA-363-3p directly targeted and negatively regulated phosphatase and tensin homolog (PTEN). Reduction of miRNA-363-3p retarded cell growth and accelerated cell apoptosis, thereby enhancing the sensitivity of TAM. Moreover, analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed significant enrichment of target genes within the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Ultimately, miR-363-3p decreased the responsiveness of breast cancer cells to TAM by targeting and suppressing PTEN through a mechanism associated with the PI3K-Akt pathway. Therefore, these results suggest that miR-363-3p-dependent PTEN expression contributes to the mechanisms underlying breast cancer endocrine resistance.
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Affiliation(s)
- Yaning Liang
- Department of Minimally Invasive Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Cuiyu Shi
- Department of Minimally Invasive Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Yu Wang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Bingjie Fan
- Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Wei Song
- Department of Minimally Invasive Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Rong Shen
- Department of Minimally Invasive Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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4
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Wang Y, Bai SK, Zhang T, Liao CG. MicroRNA-363-3p inhibits colorectal cancer progression by targeting interferon-induced transmembrane protein 1. World J Gastrointest Oncol 2023; 15:1556-1566. [PMID: 37746648 PMCID: PMC10514722 DOI: 10.4251/wjgo.v15.i9.1556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/21/2023] [Accepted: 08/18/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND The molecular mechanisms of colorectal cancer development and progression are far from being elucidated. AIM To investigate the role of microRNA-363-3p (miR-363-3p) in the progression of colorectal cancer. METHODS Real-time polymerase chain reaction was performed to detect miRNA expression in human colorectal cancer tissues and paired normal colorectal tissues. PITA 6 was utilized to predict the targets of miR-363-3p. Dual-luciferase reporter system was used to validate the target of miR-363-3p. Plate colony formation assay and wound-healing assay were performed to evaluate cancer cells' clonogenic survival ability and migration ability, respectively. Cell proliferation was examined by cell counting kit-8 assay. Immunohistochemical staining was used to determine the expression level of interferon-induced transmembrane protein 1 (IFITM1) in colorectal cancer tissues and adjacent tissues. The TCGA and GTEx databases were used to compare the expression levels of IFITM1 mRNA in colorectal cancer tissues and normal colorectal tissues and analyze the correlation between the expression levels of IFITM1 mRNA and overall survival and disease-free survival of patients. A colorectal cancer cell line with a deficiency of IFITM1 was constructed, and the regulation effect of IFITM1 on the clonogenic growth of colorectal cancer cells was clarified. RESULTS MiR-363-3p was decreased in colorectal cancer tissues compared to normal colorectal tissues. IFITM1 was characterized as a direct target of miR-363-3p. Overexpression of miR-363-3p led to decreased clonogenic survival, proliferation, and migration of colorectal cancer cells, which could be reversed by forced IFITM1 expression. CONCLUSION MiR-363-3p can constrain clonogenic survival, proliferation, and migration of colorectal cancer cells via targeting IFITM1.
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Affiliation(s)
- Yun Wang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an 710038, Shaanxi Province, China
| | - Shao-Kai Bai
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an 710038, Shaanxi Province, China
| | - Tao Zhang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an 710038, Shaanxi Province, China
| | - Cheng-Gong Liao
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an 710038, Shaanxi Province, China
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Fan M, Song W, Hao Z, Zhang J, Li Y, Fu J. Construction of lncRNA-miRNA-mRNA regulatory network in severe asthmatic bronchial epithelial cells: A bioinformatics study. Medicine (Baltimore) 2023; 102:e34749. [PMID: 37657025 PMCID: PMC10476739 DOI: 10.1097/md.0000000000034749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/24/2023] [Indexed: 09/03/2023] Open
Abstract
Asthma is a chronic respiratory disease caused by environment-host interactions. Bronchial epithelial cells (BECs) are the first line of defense against environmental toxins. However, the mechanisms underlying the role of BECs in severe asthma (SA) are not yet fully understood. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been shown to play important roles in the regulation of gene expression in the pathogenesis of SA. In this study, bioinformatics was used for the first time to reveal the lncRNA-miRNA-mRNA regulatory network of BECs in SA. Five mRNA datasets of bronchial brushing samples from patients with SA and healthy controls (HC) were downloaded from the Gene Expression Omnibus (GEO) database. A combination of the Venn diagram and robust rank aggregation (RRA) method was used to identify core differentially expressed genes (DEGs). Protein-protein interaction (PPI) analysis of core DEGs was performed to screen hub genes. The miRDB, miRWalk, and ENCORI databases were used to predict the miRNA-mRNA relationships, and the ENCORI and starBase v2.0 databases were used to predict the upstream lncRNAs of the miRNA-mRNA relationships. Four core DEGs were identified: carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), interleukin-1 receptor type 2 (IL1R2), trefoil factor 3 (TFF3), and vascular endothelial growth factor A (VEGFA). These 4 core DEGs indicated that SA was not significantly associated with sex. Enrichment analysis showed that the MAPK, Rap1, Ras, PI3K-Akt and Calcium signaling pathways may serve as the principal pathways of BECs in SA. A lncRNA-miRNA-mRNA regulatory network of the severe asthmatic bronchial epithelium was constructed. The top 10 competing endogenous RNAs (ceRNAs) were FGD5 antisense RNA 1 (FGD5-AS1), metastasis associated lung adenocarcinoma transcript 1 (MALAT1), X inactive specific transcript (XIST), HLA complex group 18 (HCG18), small nucleolar RNA host gene 16 (SNHG16), has-miR-20b-5p, has-miR-106a-5p, hsa-miR-106b-5p, has-miR-519d-3p and Fms related receptor tyrosine kinase 1 (FLT1). Our study revealed a potential mechanism for the lncRNA-miRNA-mRNA regulatory network in BECs in SA.
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Affiliation(s)
- Mengzhen Fan
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenjie Song
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Key Laboratory of Modern Chinese Medicine Theory Innovation and Transformation, Tianjin, China
| | - Zheng Hao
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Key Laboratory of Modern Chinese Medicine Theory Innovation and Transformation, Tianjin, China
- Medical History Documentation Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jing Zhang
- Department of General Surgery, Henan University of Science and Technology Affiliated First Hospital, Luoyang, China
| | - Yang Li
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jinjie Fu
- School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Daneshpour M, Ghadimi-Daresajini A. Overview of miR-106a Regulatory Roles: from Cancer to Aging. Bioengineering (Basel) 2023; 10:892. [PMID: 37627777 PMCID: PMC10451182 DOI: 10.3390/bioengineering10080892] [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: 06/30/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
MicroRNAs (miRNAs) comprise a class of non-coding RNA with extensive regulatory functions within cells. MiR-106a is recognized for its super-regulatory roles in vital processes. Hence, the analysis of its expression in association with diseases has attracted considerable attention for molecular diagnosis and drug development. Numerous studies have investigated miR-106 target genes and shown that this miRNA regulates the expression of some critical cell cycle and apoptosis factors, suggesting miR-106a as an ideal diagnostic and prognostic biomarker with therapeutic potential. Furthermore, the reported correlation between miR-106a expression level and cancer drug resistance has demonstrated the complexity of its functions within different tissues. In this study, we have conducted a comprehensive review on the expression levels of miR-106a in various cancers and other diseases, emphasizing its target genes. The promising findings surrounding miR-106a suggest its potential as a valuable biomolecule. However, further validation assessments and overcoming existing limitations are crucial steps before its clinical implementation can be realized.
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Affiliation(s)
- Maryam Daneshpour
- Biotechnology Department, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Ali Ghadimi-Daresajini
- Department of Medical Biotechnology, School of Allied Medicine, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran;
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Qin H, Song Z, Zhao C, Li S, Ali A, Zheng W. miR-363-3p/PTEN is involved in the regulation of lipid metabolism by genistein in HepG2 cells via ERβ. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 115:154839. [PMID: 37121060 DOI: 10.1016/j.phymed.2023.154839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/16/2023] [Accepted: 04/25/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND Genistein (GEN) is one of the most well-known phytoestrogens identified in various legumes. Although increasing evidence shows GEN has a potential use in phytotherapy to regulate lipid metabolism, its therapeutic mechanisms have not yet been completely elucidated, especially epigenetic alterations of miRNAs to alleviate lipid accumulation in the liver remains unknown. PURPOSE To clarify how GEN modulates the miRNA profile in HepG2 cells and investigate molecular mechanisms of the modulated miRNA on regulating hepatic lipid metabolism. METHODS The miRNA microarray was performed to compare the miRNAs expression patterns, followed by determining principal miRNA and its target gene associated with hepatic lipid metabolism modulated by GEN. miR-363-3p mimics (mi) and phosphatase and tensin homolog (PTEN)-siRNA were transfected into HepG2 cells and GEN was further treated with the cells for 24 h RESULTS: GEN induced downregulation of miR-363-3p and upregulation of PTEN, which was a target mRNA of miR-363-3p. The miR-363-3p mi led to an upregulation of sterol-regulatory element-binding protein-1c (SREBP-1c) and its downstream lipid synthesis-related factors in HepG2 cells. In addition, the inhibition of PTEN led to an increase of lipogenesis, which was associated with the AKT/mTOR signal regulation. However, GEN treatment could abrogate the lipogenic effects of miR-363-3p mi or PTEN siRNA. The modulation was associated with estrogen receptor β (ERβ). CONCLUSION We discerned a new mechanism that GEN regulated hepatic lipid metabolism by inhibiting miR-363-3p, which could be mediated via ERβ and by targeting PTEN in HepG2 cells. Additionally, GEN reduced hepatic lipid accumulation by regulating PTEN-AKT/mTOR signal. It implicated a protective role of GEN by elucidating its epigenetic modification of the miRNA modulated by ERβ on improving hepatic lipid metabolism and provided novel evidence of the mechanism on targeting miR-363-3p/PTEN in treating hepatic lipid disorders.
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Affiliation(s)
- Hong Qin
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Ziyu Song
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Chunyu Zhao
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Sha Li
- Changsha Center for Disease Control and Prevention, 509 Wanjiali North Road, Changsha, Hunan, 410005, China
| | - Anwar Ali
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Wenya Zheng
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China.
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8
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MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia. Int J Mol Sci 2023; 24:ijms24065436. [PMID: 36982511 PMCID: PMC10049736 DOI: 10.3390/ijms24065436] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/03/2023] [Accepted: 02/04/2023] [Indexed: 03/14/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common kind of pediatric cancer. Although the cure rates in ALL have significantly increased in developed countries, still 15–20% of patients relapse, with even higher rates in developing countries. The role of non-coding RNA genes as microRNAs (miRNAs) has gained interest from researchers in regard to improving our knowledge of the molecular mechanisms underlying ALL development, as well as identifying biomarkers with clinical relevance. Despite the wide heterogeneity reveled in miRNA studies in ALL, consistent findings give us confidence that miRNAs could be useful to discriminate between leukemia linages, immunophenotypes, molecular groups, high-risk-for-relapse groups, and poor/good responders to chemotherapy. For instance, miR-125b has been associated with prognosis and chemoresistance in ALL, miR-21 has an oncogenic role in lymphoid malignancies, and the miR-181 family can act either as a oncomiR or tumor suppressor in several hematological malignancies. However, few of these studies have explored the molecular interplay between miRNAs and their targeted genes. This review aims to state the different ways in which miRNAs could be involved in ALL and their clinical implications.
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9
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Liu W, Sun X, Huang J, Zhang J, Liang Z, Zhu J, Chen T, Zeng Y, Peng M, Li X, Zeng L, Lei W, Cheng J. Development and validation of a genomic nomogram based on a ceRNA network for comprehensive analysis of obstructive sleep apnea. Front Genet 2023; 14:1084552. [PMID: 36968605 PMCID: PMC10036397 DOI: 10.3389/fgene.2023.1084552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/13/2023] [Indexed: 03/12/2023] Open
Abstract
Objectives: Some ceRNA associated with lncRNA have been considered as possible diagnostic and therapeutic biomarkers for obstructive sleep apnea (OSA). We intend to identify the potential hub genes for the development of OSA, which will provide a foundation for the study of the molecular mechanism underlying OSA and for the diagnosis and treatment of OSA.Methods: We collected plasma samples from OSA patients and healthy controls for the detection of ceRNA using a chip. Based on the differential expression of lncRNA, we identified the target genes of miRNA that bind to lncRNAs. We then constructed lncRNA-related ceRNA networks, performed functional enrichment analysis and protein-protein interaction analysis, and performed internal and external validation of the expression levels of stable hub genes. Then, we conducted LASSO regression analysis on the stable hub genes, selected relatively significant genes to construct a simple and easy-to-use nomogram, validated the nomogram, and constructed the core ceRNA sub-network of key genes.Results: We successfully identified 282 DElncRNAs and 380 DEmRNAs through differential analysis, and we constructed an OSA-related ceRNA network consisting of 292 miRNA-lncRNAs and 41 miRNA-mRNAs. Through PPI and hub gene selection, we obtained 7 additional robust hub genes, CCND2, WT1, E2F2, IRF1, BAZ2A, LAMC1, and DAB2. Using LASSO regression analysis, we created a nomogram with four predictors (CCND2, WT1, E2F2, and IRF1), and its area under the curve (AUC) is 1. Finally, we constructed a core ceRNA sub-network composed of 74 miRNA-lncRNA and 7 miRNA-mRNA nodes.Conclusion: Our study provides a new foundation for elucidating the molecular mechanism of lncRNA in OSA and for diagnosing and treating OSA.
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Affiliation(s)
- Wang Liu
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xishi Sun
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiewen Huang
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jinjian Zhang
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhengshi Liang
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jinru Zhu
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tao Chen
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yu Zeng
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Min Peng
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiongbin Li
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Lijuan Zeng
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Wei Lei
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- *Correspondence: Junfen Cheng, ; Wei Lei,
| | - Junfen Cheng
- The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- *Correspondence: Junfen Cheng, ; Wei Lei,
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10
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Yuan P, Sun T, Han Z, Chen Y, Meng Q. Uncovering the genetic links of diabetic erectile dysfunction and chronic prostatitis/chronic pelvic pain syndrome. Front Physiol 2023; 14:1096677. [PMID: 36846330 PMCID: PMC9946966 DOI: 10.3389/fphys.2023.1096677] [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: 11/18/2022] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
Background: Clinical associations between erectile dysfunction and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been noticed, but the common pathogenic mechanisms between them remain elusive. The aim of the study was to mine shared genetic alterations between ED and chronic prostatitis/chronic pelvic pain syndrome. Method: Transcriptome data of ED and chronic prostatitis/chronic pelvic pain syndrome-related genes (CPRGs) were retrieved from relevant databases and differentially expressed analysis was used to obtain significant CPRGs. Then function enrichment and interaction analyses were performed to show shared transcriptional signature, including gene ontology and pathway enrichment, the construction of protein-protein interaction (PPI) network, cluster analysis, and co-expression analysis. Hub CPRGs and key cross-link were selected by validating these genes in clinical samples, chronic prostatitis/chronic pelvic pain syndrome and ED-related datasets. Then the miRNA-OSRGs co-regulatory network was predicted and validated. Subpopulation distribution and disease association of hub CPRGs were further identified. Result: Differentially expressed analysis revealed 363 significant CPRGs between ED and chronic prostatitis/chronic pelvic pain syndrome, functioning in inflammatory reaction, oxidative stress, apoptosis, smooth muscle cell proliferation, and extracellular matrix organization. A PPI network containing 245 nodes and 504 interactions was constructed. Module analysis depicted that multicellular organismal process and immune metabolic process were enriched. 17 genes were screened in PPI via topological algorithms, and reactive oxygen species as well as interleukin-1 metabolism were regarded as the bridging interactive mechanism. After screening and validation, a hub-CPRG signature consisting of COL1A1, MAPK6, LPL, NFE2L2 and NQO1 were identified and associated miRNA were verified. These miRNAs played an important role in immune and inflammatory response likewise. Finally, NQO1 was identified as a key genetic link between ED and chronic prostatitis/chronic pelvic pain syndrome. It was predominately enriched in corpus cavernosum endothelial cell, and correlated with other male urogenital and immune system diseases tightly. Conclusion: We identified the genetic profiles as well as corresponding regulatory network underlying interaction between ED and chronic prostatitis/chronic pelvic pain syndrome via multi-omics analysis. These findings expanded a new understanding for the molecular mechanism of ED with chronic prostatitis/chronic pelvic pain syndrome.
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Affiliation(s)
- Penghui Yuan
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,*Correspondence: Penghui Yuan, ; Yinwei Chen, ; Qingjun Meng,
| | - Taotao Sun
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhengyang Han
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yinwei Chen
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Penghui Yuan, ; Yinwei Chen, ; Qingjun Meng,
| | - Qingjun Meng
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,*Correspondence: Penghui Yuan, ; Yinwei Chen, ; Qingjun Meng,
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11
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Khalilian S, Abedinlou H, Hussen BM, Imani SZH, Ghafouri-Fard S. The emerging role of miR-20b in human cancer and other disorders: Pathophysiology and therapeutic implications. Front Oncol 2022; 12:985457. [PMID: 36582800 PMCID: PMC9792503 DOI: 10.3389/fonc.2022.985457] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 11/16/2022] [Indexed: 12/15/2022] Open
Abstract
miR-20b is a microRNA with diverse and somehow contradictory roles in the pathogenesis of human disorders, especially cancers. It has been known to be a tumor suppressor in colon cancer, renal cell carcinoma, prostate cancer, osteosarcoma and papillary thyroid cancer. In lung cancer and breast cancers, both tumor suppressor and oncogenic effects have been identified for this miRNA. Finally, in T cell leukemia, hepatocellular carcinoma, esophageal squamous cell carcinoma and cervical and gastric cancers, miR-20b is regarded as an oncogenic miRNA. In several types of cancer, dysregulation of miR-20b has been recognized as a predictive marker for patients' survival. Dysregulation of miR-20b has also been recognized in Alzheimer's disease, diabetic retinopathy, myocardial ischemia/infarction, chronic hepatitis B and multiple sclerosis. In the current review, we have summarized the miR-20b targets and related cellular processes. We have also provided a review of participation of this miRNA in different human disorders.
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Affiliation(s)
- Sheyda Khalilian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Abedinlou
- Department of Medical Biotechnology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Bashdar Mahmud Hussen
- Department of Biomedical Sciences, Cihan University, Erbil, Kurdistan Region, Iraq,Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Iraq
| | - Seyedeh Zahra Hosseini Imani
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran,*Correspondence: Soudeh Ghafouri-Fard,
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12
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Drobna‐Śledzińska M, Maćkowska‐Maślak N, Jaksik R, Kosmalska M, Szarzyńska B, Lejman M, Sędek Ł, Szczepański T, Taghon T, Van Vlierberghe P, Witt M, Dawidowska M. Multiomics to investigate the mechanisms contributing to repression of PTPRC and SOCS2 in pediatric T-ALL: Focus on miR-363-3p and promoter methylation. Genes Chromosomes Cancer 2022; 61:720-733. [PMID: 35778917 PMCID: PMC9796420 DOI: 10.1002/gcc.23085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 01/01/2023] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous and aggressive malignancy arising from T-cell precursors. MiRNAs are implicated in negative regulation of gene expression and when aberrantly expressed contribute to various cancer types, including T-ALL. Previously we demonstrated the oncogenic potential of miR-363-3p overexpression in a subgroup of T-ALL patients. Here, using combined proteomic and transcriptomic approaches, we show that miR-363-3p enhances cell growth of T-ALL in vitro via inhibition of PTPRC and SOCS2, which are implicated in repression of the JAK-STAT pathway. We propose that overexpression of miR-363-3p is a novel mechanism potentially contributing to overactivation of JAK-STAT pathway. Additionally, by combining the transcriptomic and methylation data of T-ALL patients, we show that promoter methylation may also contribute to downregulation of SOCS2 expression and thus potentially to JAK-STAT activation. In conclusion, we highlight aberrant miRNA expression and aberrant promoter methylation as mechanisms, alternative to mutations of JAK-STAT-related genes, which might lead to the upregulation of JAK-dependent signaling in T-ALL.
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Affiliation(s)
| | | | - Roman Jaksik
- Department of Systems Biology and EngineeringSilesian University of TechnologyGliwicePoland
| | - Maria Kosmalska
- Institute of Human Genetics Polish Academy of SciencesPoznańPoland
| | - Bronisława Szarzyńska
- Institute of Human Genetics Polish Academy of SciencesPoznańPoland,Polish Stem Cells BankWarsawPoland
| | - Monika Lejman
- Laboratory of Genetic DiagnosticsMedical University of LublinLublinPoland
| | - Łukasz Sędek
- Department of Microbiology and ImmunologyZabrze, Medical University of Silesia in KatowiceZabrzePoland
| | - Tomasz Szczepański
- Department of Pediatric Hematology and OncologyMedical University of Silesia in KatowiceZabrzePoland
| | - Tom Taghon
- Department of Diagnostic SciencesGhent UniversityGhentBelgium,Cancer Research Institute GhentGhentBelgium
| | - Pieter Van Vlierberghe
- Cancer Research Institute GhentGhentBelgium,Department of Biomolecular MedicineGhent UniversityGhentBelgium
| | - Michał Witt
- Institute of Human Genetics Polish Academy of SciencesPoznańPoland
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13
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Wang J, Liu Y, Gao Y, Liang J, Wang B, Xia Q, Xie Y, Shan F, Xia Q. Comprehensive bioinformatics analysis and molecular validation of lncRNAs-mediated ceRNAs network in schizophrenia. Life Sci 2022; 312:121205. [PMID: 36410410 DOI: 10.1016/j.lfs.2022.121205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/31/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022]
Abstract
AIMS The present study aimed to investigate how Schizophrenia (SCZ)-specific long non-coding RNAs (lncRNAs) served as competing endogenous RNAs (ceRNAs) to modulate the biological functions and pathways involved in the pathogenesis of SCZ. MAIN METHODS Microarray dataset (GSE54913) was obtained from Gene Expression Omnibus (GEO) database. Differently expressed (DE) lncRNAs and mRNAs were identified by "limma" package. The binding miRNAs of lncRNAs and target mRNAs of shared miRNAs were predicted by miRcode, miRDB, miRTarbase and targetscan databases. Following the ceRNAs theory, interaction network was established and visualized with the cytoscape. Functional enrichment analysis uncovered the concentrated functions and signaling pathways that may be associated with SCZ progression. Protein-protein interaction (PPI) analysis was utilized to determine hub genes. Quantitative real-time PCR (qRT-PCR) and receiver operating characteristic curve (ROC) were performed to evaluate the expression and diagnostic value of ceRNAs members, respectively. KEY FINDINGS DElncRNAs and DEmRNAs were initially screened from GSE54913 to construct the SCZ-related ceRNAs network with 42 nodes and 53 edges. Functional enrichment analysis revealed that ceRNAs members appeared to be highly correlated with transcription factor activation, cell replication and tumor-related pathways. Once validated, a significant ceRNAs subnetwork was proposed as being implicated in the pathogenesis of SCZ. ROC analysis indicated that SCZ-related ceRNAs members may be sensitive diagnostic biomarkers for SCZ. SIGNIFICANCE The significant SCZ-related ceRNAs subnetworks (lncRNA-C2orf48A/hsa-miR-20b-5p,-17-5p/KIF23, FOXJ2) may represent promising predictive and diagnostic biomarkers and provide novel insights into the mechanism by which lncRNAs act as microRNA sponges and contribute to the pathogenesis of SCZ.
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Affiliation(s)
- Jiequan Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Yaru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China
| | - Yejun Gao
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jun Liang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Baoshi Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China
| | - Yawen Xie
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
| | - Feng Shan
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Qingrong Xia
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China.
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14
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Bai L, Gong J, Guo Y, Li Y, Huang H, Liu X. Construction of a ceRNA network in polycystic ovary syndrome (PCOS) driven by exosomal lncRNA. Front Genet 2022; 13:979924. [PMID: 36406137 PMCID: PMC9672461 DOI: 10.3389/fgene.2022.979924] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/17/2022] [Indexed: 01/26/2025] Open
Abstract
Polycystic ovary syndrome (PCOS), a common and frustrating syndrome in women of reproductive age, is characterized by symptoms including hyperandrogenemia, ovulation dysfunction, and polycystic ovaries. The role of competitive endogenous RNA (ceRNA) networks is receiving increasing attention and has been reported in multiple complicated diseases, such as various carcinomas, endometriosis, and tubal factor infertility. However, the association of ceRNA networks with the pathogenesis of PCOS remains unclear. This study aimed to construct a ceRNA network orchestrated by exosomal lnRNA and circRNA in PCOS. We screened RNA data of 34 samples from the Gene Expression Omnibus (GEO) database for differentially expressed lncRNAs (DELs), miRNAs (DEMs), mRNAs (DEGs), and circRNA associated with the progression of PCOS (PCOS, n = 17 vs. normal, n = 17). A protein-protein interaction (PPI) network, gene set enrichment analysis (GSEA), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. Importantly, the function of the ceRNA network was explored using GO and KEGG enrichment analyses. We identified 46 DELs (25 upregulated and 21 downregulated), 31 DEMs (20 upregulated and 11 downregulated), 165 DEGs (52 upregulated and 113 downregulated), and 1 differentially expressed circRNA. The PPI network had 79 nodes and 112 edges. The GSEA results showed that these genes were mainly related to oxidative phosphorylation; TNF signaling pathways; and valine, leucine, and isoleucine degradation. GO and KEGG analyses revealed that the DEGs were significantly enriched in lipid metabolism, peroxisome proliferator-activated receptor (PPAR) signaling pathways, and fatty acid metabolism. Additionally, we constructed a novel PCOS-associated lncRNA-miRNA-mRNA ceRNA triple network and a circRNA-related network. Thereafter, we described the potential roles played by follicular fluid exosomes in PCOS. Our present study describes the molecular pathogenesis of PCOS in human ovarian granulosa cells at the post-transcriptional level, which provides new insights for the clinical diagnosis and treatment of PCOS and further scientific research.
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Affiliation(s)
- Lilian Bai
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
| | - Junxing Gong
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Yanyan Guo
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
| | - Yuchen Li
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
| | - Hefeng Huang
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xinmei Liu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
- Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
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15
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Targeting ferroptosis in ischemia/reperfusion renal injury. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1331-1341. [PMID: 35920897 DOI: 10.1007/s00210-022-02277-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 07/18/2022] [Indexed: 10/16/2022]
Abstract
Renal I/R injury is a severe medical condition contributing to acute kidney injury (AKI), leading to rapid kidney dysfunction and high mortality rates. It is generally observed during renal transplantation, shock, trauma, and urologic and cardiovascular surgery, for which there is no effective treatment. Cell death and damage are commonly linked to I/R. Cell death triggered by iron-dependent lipid peroxidation, such as ferroptosis, has been demonstrated to have a significant detrimental effect in renal IRI models, making it a new type of cell death currently being researched. Ferroptosis is a nonapoptotic type of cell death that occurs when free iron enters the cell and is a critical component of many biological processes. In ferroptosis-induced renal I/R injury, iron chelators such as Deferasirox, Deferiprone, and lipophilic antioxidants are currently suppressed lipid peroxidation Liproxstatin-1 (Lip-1), Ferrostatin-1 along with antioxidants like vitamin and quercetin. Ferroptosis has been considered a potential target for pharmaceutical intervention to alleviate renal IRI-associated cell damage. Thus, this review emphasized the role of ferroptosis and its inhibition in renal IRI. Also, Pharmacological modulation of ferroptosis mechanism in renal I/R injury has been conferred. Graphical abstract.
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16
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Ritiu SA, Rogobete AF, Sandesc D, Bedreag OH, Papurica M, Popovici SE, Toma D, Ivascu RI, Velovan R, Garofil DN, Corneci D, Bratu LM, Pahontu EM, Pistol A. The Impact of General Anesthesia on Redox Stability and Epigenetic Inflammation Pathways: Crosstalk on Perioperative Antioxidant Therapy. Cells 2022; 11:1880. [PMID: 35741011 PMCID: PMC9221536 DOI: 10.3390/cells11121880] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 02/07/2023] Open
Abstract
Worldwide, the prevalence of surgery under general anesthesia has significantly increased, both because of modern anesthetic and pain-control techniques and because of better diagnosis and the increased complexity of surgical techniques. Apart from developing new concepts in the surgical field, researchers and clinicians are now working on minimizing the impact of surgical trauma and offering minimal invasive procedures due to the recent discoveries in the field of cellular and molecular mechanisms that have revealed a systemic inflammatory and pro-oxidative impact not only in the perioperative period but also in the long term, contributing to more difficult recovery, increased morbidity and mortality, and a negative financial impact. Detailed molecular and cellular analysis has shown an overproduction of inflammatory and pro-oxidative species, responsible for augmenting the systemic inflammatory status and making postoperative recovery more difficult. Moreover, there are a series of changes in certain epigenetic structures, the most important being the microRNAs. This review describes the most important molecular and cellular mechanisms that impact the surgical patient undergoing general anesthesia, and it presents a series of antioxidant therapies that can reduce systemic inflammation.
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Affiliation(s)
- Stelian Adrian Ritiu
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
| | - Alexandru Florin Rogobete
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
- Anaesthesia and Intensive Care Research Center (CCATITM), “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Dorel Sandesc
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
- Anaesthesia and Intensive Care Research Center (CCATITM), “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Ovidiu Horea Bedreag
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
- Anaesthesia and Intensive Care Research Center (CCATITM), “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Marius Papurica
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
- Anaesthesia and Intensive Care Research Center (CCATITM), “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Sonia Elena Popovici
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
| | - Daiana Toma
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
| | - Robert Iulian Ivascu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.I.I.); (D.C.); (A.P.)
- Clinic of Anaesthesia and Intensive Care, Central Military Emergency Hospital “Dr. Carol Davila”, 010242 Bucharest, Romania
| | - Raluca Velovan
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital “Pius Brînzeu”, 300723 Timișoara, Romania; (S.A.R.); (D.S.); (O.H.B.); (M.P.); (S.E.P.); (D.T.); (R.V.)
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
| | - Dragos Nicolae Garofil
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.I.I.); (D.C.); (A.P.)
| | - Dan Corneci
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.I.I.); (D.C.); (A.P.)
- Clinic of Anaesthesia and Intensive Care, Central Military Emergency Hospital “Dr. Carol Davila”, 010242 Bucharest, Romania
| | - Lavinia Melania Bratu
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
| | - Elena Mihaela Pahontu
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Adriana Pistol
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.I.I.); (D.C.); (A.P.)
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Luo C, Li JJ, Wen F, Cao YX, Luo ZY, Long XX. CircFBXW7 inhibits the tumorigenesis of T-cell acute lymphoblastic leukemia through modulating miR-494-3p/SOX1 axis. Cell Death Dis 2022; 8:256. [PMID: 35538053 PMCID: PMC9091256 DOI: 10.1038/s41420-022-00857-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 12/20/2021] [Accepted: 01/13/2022] [Indexed: 11/09/2022]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a type of leukemia with high malignant behaviors, which seriously threatens the health of people. It has been reported that circFBXW7 is downregulated in lymphoblastic leukemia. Nevertheless, the exact role of circFBXW7 in T-ALL remains elusive. MTT assay was used to assess the cell viability. Cell apoptosis was assessed by flow cytometry. In addition, mRNA expressions were assessed by RT-qPCR, and a western blot was applied to investigate the protein levels. Meanwhile, the correlation among circFBXW7, miR-494-3p, and SOX1 was explored by RNA pull-down and dual-luciferase reporter assays. Furthermore, a xenograft mice model was conducted to verify the function of circFBXW7 in T-ALL in vivo. CircFBXW7 was significantly downregulated in T-ALL, of which overexpression inhibited the cell viability and induced the apoptosis of Jurkat cells. Moreover, miR-494-3p was identified to be a functional downstream effector to be involved in circFBXW7-mediated T-ALL cell proliferation. Besides, SOX1 was a direct target of miR-494-3p, and the impact of miR-494-3p mimics on T-ALL cell growth was inhibited in the presence of SOX1 overexpression. Furthermore, overexpression of circFBXW7 dramatically inhibited T-ALL tumor growth. In summary, circFBXW7 attenuated the tumorigenesis of T-ALL through the mediation of the miR-494-3p/SOX1 axis, which might be novel targets for T-ALL treatment.
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Affiliation(s)
- Cong Luo
- Department of Hematology, the First Affiliated Hospital, Hengyang Medical school, University of South China, Hengyang421001, Hengyang, Hunan Province, China
| | - Jun-Jun Li
- Department of Hematology, the First Affiliated Hospital, Hengyang Medical school, University of South China, Hengyang421001, Hengyang, Hunan Province, China
| | - Feng Wen
- Department of Hematology, the First Affiliated Hospital, Hengyang Medical school, University of South China, Hengyang421001, Hengyang, Hunan Province, China
| | - Yi-Xiong Cao
- Department of Hematology, the First Affiliated Hospital, Hengyang Medical school, University of South China, Hengyang421001, Hengyang, Hunan Province, China
| | - Ze-Yu Luo
- Department of Hematology, the First Affiliated Hospital, Hengyang Medical school, University of South China, Hengyang421001, Hengyang, Hunan Province, China
| | - Xing-Xing Long
- Department of Hematology, the First Affiliated Hospital, Hengyang Medical school, University of South China, Hengyang421001, Hengyang, Hunan Province, China.
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Vanhooren J, Van Camp L, Depreter B, de Jong M, Uyttebroeck A, Van Damme A, Dedeken L, Dresse MF, van der Werff Ten Bosch J, Hofmans M, Philippé J, De Moerloose B, Lammens T. Deciphering the Non-Coding RNA Landscape of Pediatric Acute Myeloid Leukemia. Cancers (Basel) 2022; 14:2098. [PMID: 35565228 PMCID: PMC9100904 DOI: 10.3390/cancers14092098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 02/01/2023] Open
Abstract
Pediatric acute myeloid leukemia (pedAML) is a heterogeneous blood cancer that affects children. Although survival rates have significantly improved over the past few decades, 20-30% of children will succumb due to treatment-related toxicity or relapse. The molecular characterization of the leukemic stem cell, shown to be responsible for relapse, is needed to improve treatment options and survival. Recently, it has become clear that non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a role in the development of human diseases, including pediatric cancer. Nevertheless, non-coding RNA expression data in pedAML are scarce. Here, we explored lncRNA (n = 30,168) and miRNA (n = 627) expression in pedAML subpopulations (leukemic stem cells (LSCs) and leukemic blasts (L-blasts)) and their normal counterparts (hematopoietic stem cells and control myeloblasts). The potential regulatory activity of differentially expressed lncRNAs in LSCs (unique or shared with the L-blast comparison) on miRNAs was assessed. Moreover, pre-ranked gene set enrichment analyses of (anti-) correlated protein-coding genes were performed to predict the functional relevance of the differentially upregulated lncRNAs in LSCs (unique or shared with the L-blast comparison). In conclusion, this study provides a catalog of non-coding RNAs with a potential role in the pathogenesis of pedAML, paving the way for further translational research studies.
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Affiliation(s)
- Jolien Vanhooren
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
| | - Laurens Van Camp
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
| | - Barbara Depreter
- Department of Laboratory Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel, 1050 Brussels, Belgium
| | - Martijn de Jong
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
| | - Anne Uyttebroeck
- Department of Pediatrics, University Hospital Gasthuisberg, 3000 Leuven, Belgium
| | - An Van Damme
- Department of Pediatric Hematology Oncology, University Hospital Saint-Luc, 1200 Brussels, Belgium
| | - Laurence Dedeken
- Department of Pediatric Hematology Oncology, Queen Fabiola Children's University Hospital, 1020 Brussels, Belgium
| | - Marie-Françoise Dresse
- Department of Pediatric Hematology Oncology, University Hospital Liège, 4000 Liège, Belgium
| | | | - Mattias Hofmans
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Jan Philippé
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Barbara De Moerloose
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
| | - Tim Lammens
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
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Drobna-Śledzińska M, Maćkowska-Maślak N, Jaksik R, Dąbek P, Witt M, Dawidowska M. CRISPRi for specific inhibition of miRNA clusters and miRNAs with high sequence homology. Sci Rep 2022; 12:6297. [PMID: 35428787 PMCID: PMC9012752 DOI: 10.1038/s41598-022-10336-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 03/23/2022] [Indexed: 11/08/2022] Open
Abstract
miRNAs form a class of noncoding RNAs, involved in post-transcriptional regulation of gene expression, broadly studied for their involvement in physiological and pathological context. Inhibition of mature miRNA transcripts, commonly used in miRNA loss-of-function experiments, may not be specific in case of miRNAs with high sequence homology, e.g. miRNAs from the same seed family. Phenotypic effects of miRNA repression might be biased by the repression of highly similar miRNAs. Another challenge is simultaneous inhibition of multiple miRNAs encoded within policistronic clusters, potentially co-regulating common biological processes. To elucidate roles of miRNA clusters and miRNAs with high sequence homology, it is of key importance to selectively repress only the miRNAs of interest. Targeting miRNAs on genomic level with CRISPR/dCas9-based methods is an attractive alternative to blocking mature miRNAs. Yet, so far no clear guidelines on the design of CRISPR inhibition (CRISPRi) experiments, specifically for miRNA repression, have been proposed. To address this need, here we propose a strategy for effective inhibition of miRNAs and miRNA clusters using CRISPRi. We provide clues on how to approach the challenges in using CRISPR/dCas in miRNA studies, which include prediction of miRNA transcription start sites (TSSs) and the design of single guide RNAs (sgRNAs). The strategy implements three TSS prediction online tools, dedicated specifically for miRNAs: miRStart, FANTOM 5 miRNA atlas, DIANA-miRGen, and CRISPOR tool for sgRNAs design; it includes testing and selection of optimal sgRNAs. We demonstrate that compared to siRNA/shRNA-based miRNA silencing, CRISPRi improves the repression specificity for miRNAs with highly similar sequence and contribute to higher uniformity of the effects of silencing the whole miRNA clusters. This strategy may be adapted for CRISPR-mediated activation (CRISPRa) of miRNA expression.
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Affiliation(s)
- Monika Drobna-Śledzińska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznań, Poland.
| | - Natalia Maćkowska-Maślak
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznań, Poland
| | - Roman Jaksik
- Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland
| | - Paulina Dąbek
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznań, Poland
| | - Michał Witt
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznań, Poland
| | - Małgorzata Dawidowska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznań, Poland.
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20
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MiR-652-5p elevated glycolysis level by targeting TIGAR in T-cell acute lymphoblastic leukemia. Cell Death Dis 2022; 13:148. [PMID: 35165280 PMCID: PMC8844069 DOI: 10.1038/s41419-022-04600-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 01/17/2022] [Accepted: 01/28/2022] [Indexed: 12/12/2022]
Abstract
The effect of glycolysis remains largely elusive in acute T lymphoblastic leukemia (T-ALL). Increasing evidence has indicated that the dysregulation of miRNAs is involved in glycolysis, by targeting the genes coding glycolysis rate-limiting enzymes. In our previous studies, we found that overexpression of the ARRB1-derived miR-223 sponge repressed T-ALL progress and reduced the expression of miR-652-5p. However, little is known about miR-652-5p on T-ALL. Here, we showed that impaired miR-652-5p expression inhibited growth, promoted apoptosis of T-ALL cells in vitro and prolonged overall survival (OS) in vivo. Based on the GO enrichment of miR-652-5p target genes, we uncovered that impaired miR-652-5p decreased glycolysis, including reduced the lactate, pyruvate, ATP level and the total extracellular acidification rate (ECAR), elevated oxygen consumption rate (OCR) in T-ALL cell lines. Mechanically, miR-652-5p targeted the 3ʹUTR of Tigar mRNA and inhibited its expression. Furthermore, the alteration of glycosis level was attributed to Tigar overexpression, consistent with the effect of impaired miR-652-5p. Additionally, Tigar suppressed the expression of PFKFB3, a glycolysis rate-limiting enzyme, in vivo and in vitro. Taken together, our results demonstrate that impaired miR-652-5p/Tigar axis could repress glycolysis, thus to slow growth of T-ALL cells, which support miR-652-5p as a novel potential drug target for T-ALL therapeutics.
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21
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Zhou Y, Li Q, Pan R, Wang Q, Zhu X, Yuan C, Cai F, Gao Y, Cui Y. Regulatory roles of three miRNAs on allergen mRNA expression in Tyrophagus putrescentiae. Allergy 2022; 77:469-482. [PMID: 34570913 DOI: 10.1111/all.15111] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 09/01/2021] [Accepted: 09/03/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Tyrophagus putresecentiae is an important mite species in rural and urban environments, causing sensitization and allergic disease. While evidence suggests that microRNAs (miRNAs) may regulate the expression of allergen-encoding genes, no study has directly investigated this possibility. Here, this gap was addressed by profiling miRNAs and elucidating their target allergen messenger RNAs (mRNAs) in this mite species. METHODS Small RNA and transcriptome libraries were constructed for eggs, larvae, nymphs, and adults. After deep miRNA and whole-transcriptome sequencing were performed, the miRNA and allergen-encoding mRNA regulatory networks were explored. RESULTS A total of 540 miRNAs were identified, including 155 with expression levels differing significantly across the four mite developmental stages (p < .01), 59 of which were novel. The mRNA expression for allergens was higher for Tyr p 1 in adults than in other developmental stages; Tyr p 2-5, 7, 10, 13, 33, and 34 in immature stages; and Tyr p 28, 35, and 36 in eggs and adults. A combined miRNA and transcriptome bioinformatics analysis showed that allergen Tyr p 3 was regulated by miRNA PC-5p-5698441_1, Tyr p 4 was regulated by PC-5p-7050653_1, and Tyr p 34 was regulated by PC-5p-5534223_1 and PC-5p-5698441_1. These three allergen mRNA and three miRNAs were identified using qRT-PCR, and their regulatory roles were confirmed by double-fluorescent reporter gene system and site-directed mutagenesis technology. CONCLUSIONS For the first time, allergen mRNA expression and miRNAs were profiled throughout the life cycle for an allergen-producing mite, and the results showed that miRNAs bind to target allergen mRNAs to regulate their expression.
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Affiliation(s)
- Ying Zhou
- Department of Pediatrics Laboratory The Affiliated Wuxi Children's Hospital of Nanjing Medical University Wuxi China
| | - Qingqing Li
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
| | - Ruilin Pan
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
| | - Qiong Wang
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
| | - Xuming Zhu
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
| | - Cunyin Yuan
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
| | - Fangfang Cai
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
| | - Ya‐dong Gao
- Department of Allergology Zhongnan Hospital of Wuhan University Wuhan China
| | - Yubao Cui
- Department of Clinical Laboratory The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi China
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22
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Deng W, Pan M, Zhu S, Chao R, Wang L. Emerging roles of microRNAs in acute lymphoblastic leukemia and their clinical prospects. Expert Rev Hematol 2021; 14:987-992. [PMID: 34784832 DOI: 10.1080/17474086.2021.2007763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Targeted therapy with microRNAs (miRNAs) has been a significant challenge in recent years. Studying the role and mechanism through which miRNAs regulate various cancer processes is very critical in cancer treatment, including acute lymphoblastic leukemia (ALL). AREAS COVERED This review summarizes the diverse roles of miRNAs in ALL and provides new perspectives in miRNA-based therapeutic strategies. EXPERT OPINION MiRNAs belong to a kind of endogenous non-coding small RNA with the length of 19 ~ 25 nucleotides. They inhibit the expression of target genes and participate in almost all essential physiological processes such as cell proliferation, apoptosis, differentiation, and inflammatory responses. Many miRNAs are abnormally expressed in tumor cells, suggesting that they might be related to the occurrence and development of tumor. ALL is a common hematological malignancy in children. Its clinical manifestation, morphology, immunophenotype, and genetic characteristics are highly heterogeneous. A number of miRNAs have been found to be abnormally expressed in ALL and related to the biological characteristics, clinical features, diagnosis, and treatment in ALL patients. The understanding of miRNAs could help reveal ALL pathogenesis and identify accurate molecular markers for ALL diagnosis, prognosis, and therapeutic targets.
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Affiliation(s)
- Wei Deng
- Department of Pediatric General Internal Medicine, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, Gansu, China
| | - Ming Pan
- Department of Hematology, Wuwei People's Hospital, Wuwei, Gansu, China
| | - Shengdong Zhu
- Department of Pediatric General Internal Medicine, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, Gansu, China
| | - Rong Chao
- Department of Pediatric General Internal Medicine, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, Gansu, China
| | - Li Wang
- Department of Pediatric General Internal Medicine, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, Gansu, China
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23
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Fan B, Su B, Song G, Liu X, Yan Z, Wang S, Hu F, Yang J. miR-363-3p induces EMT via the Wnt/β-catenin pathway in glioma cells by targeting CELF2. J Cell Mol Med 2021; 25:10418-10429. [PMID: 34636136 PMCID: PMC8581338 DOI: 10.1111/jcmm.16970] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/17/2021] [Accepted: 09/23/2021] [Indexed: 01/05/2023] Open
Abstract
In our previous study, we reported that CELF2 has a tumour‐suppressive function in glioma. Here, we performed additional experiments to elucidate better its role in cancer. The expression profile of CELF2 was analysed by the GEPIA database, and Kaplan–Meier curves were used to evaluate the overall survival rates. Four different online databases were used to predict miRNAs targeting CELF2, and the luciferase assay was performed to identify the binding site. The biological effects of miR‐363‐3p and CELF2 were also investigated in vitro using MTT, Transwell, and flow cytometry assays. Western blotting, qPCR, and TOP/FOP flash dual‐luciferase assays were performed to investigate the impact of miR‐363‐3p and CELF2 on epithelial‐to‐mesenchymal transition (EMT) and the Wnt/β‐catenin pathway. The effect of miR‐363‐3p was also tested in vivo using a xenograft mouse model. We observed an abnormal expression pattern of CELF2 in glioma cells, and higher CELF2 expression correlated with better prognosis. We identified miR‐363‐3p as an upstream regulator of CELF2 and confirmed its direct binding to the 3′‐untranslated region of CELF2. Cell function experiments showed that miR‐363‐3p affected multiple aspects of glioma cells. Suppressing miR‐363‐3p expression inhibited glioma cell proliferation and invasion, as well as promoted cell death via attenuating EMT and blocking the Wnt/β‐catenin pathway. These effects could be abolished by the downregulation of CELF2. Treatment with ASO‐miR‐363‐3p decreased tumour size and weight in nude mice. In conclusion, miR‐363‐3p induced the EMT, which resulted in increased migration and invasion and reduced apoptosis in glioma cell lines, via the Wnt/β‐catenin pathway by targeting CELF2.
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Affiliation(s)
- Bo Fan
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
| | - Bolun Su
- Department of urology, The Second Hospital of Baoding, Hebei, China
| | - Guoqiang Song
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
| | - Xin Liu
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
| | - Zhongjie Yan
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
| | - Shuai Wang
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
| | - Fuguang Hu
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
| | - Jiankai Yang
- Department of neurosurgery, The Second Affiliated Hospital, Hebei Medical University, Hebei, China
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Goyal T, Mitra P, Singh P, Ghosh R, Sharma S, Sharma P. Association of microRNA expression with changes in immune markers in workers with cadmium exposure. CHEMOSPHERE 2021; 274:129615. [PMID: 33545588 DOI: 10.1016/j.chemosphere.2021.129615] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/26/2020] [Accepted: 01/08/2021] [Indexed: 06/12/2023]
Abstract
Human exposure to cadmium (Cd) is known to produce severe health effects. Recently, molecular mechanism of Cd toxicity has revealed the role of Cd in causing epigenetic alterations. miRNAs are small, non-coding RNAs which are involved in translational repression of genes. Therefore, the aim of the present study was to evaluate the alterations in expression of miRNAs associated with inflammation, carcinogenesis and, further, study their possible correlation with immune profile, in occupationally Cd exposed workers of Jodhpur. 106 workers from metal handicraft and welding factories were recruited as subjects, while, 80 apparently healthy non-exposed individuals served as control for this study. Blood Cd levels (BCd) were determined by Graphite Furnace Atomic Absorption Spectroscopy (GFAAS). Lymphocyte cell subset were measured by flow cytometry, serum interleukins were assessed by ELISA and miRNA expression was determined by Real Time Polymerase Chain Reaction (RT-PCR). BCd levels were significantly higher in the exposed individuals when compared to the non-exposed, with welders reporting the highest amongst all. Among the lymphocyte subset, exposed group showed significantly higher percentage of Th17 and lower percentage of Treg population. Cytokine profile expressed by exposed workers were predominantly pro-inflammatory in nature. Among, the studied miRNAs, miR-221 was significantly higher in exposed group with a fold change of 3.05. Additionally, miR-221 and miR-155 showed significant positive correlation with Th17 cell %. Regression analysis showed duration of exposure and IL-17 to have significant effect on miR-221 in exposed group. In conclusion, miR-221 was significantly upregulated in exposed and was correlated with immune alteration making it a potential candidate for further exploration of mechanism underlying Cd toxicity.
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Affiliation(s)
- Taru Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India.
| | - Prasenjit Mitra
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India.
| | - Preeti Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Raghumoy Ghosh
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India.
| | - Shailja Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India.
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India.
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25
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Diallo I, Ho J, Laffont B, Laugier J, Benmoussa A, Lambert M, Husseini Z, Soule G, Kozak R, Kobinger GP, Provost P. Altered microRNA Transcriptome in Cultured Human Liver Cells upon Infection with Ebola Virus. Int J Mol Sci 2021; 22:ijms22073792. [PMID: 33917562 PMCID: PMC8038836 DOI: 10.3390/ijms22073792] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 02/07/2023] Open
Abstract
Ebola virus (EBOV) is a virulent pathogen, notorious for inducing life-threatening hemorrhagic fever, that has been responsible for several outbreaks in Africa and remains a public health threat. Yet, its pathogenesis is still not completely understood. Although there have been numerous studies on host transcriptional response to EBOV, with an emphasis on the clinical features, the impact of EBOV infection on post-transcriptional regulatory elements, such as microRNAs (miRNAs), remains largely unexplored. MiRNAs are involved in inflammation and immunity and are believed to be important modulators of the host response to viral infection. Here, we have used small RNA sequencing (sRNA-Seq), qPCR and functional analyses to obtain the first comparative miRNA transcriptome (miRNome) of a human liver cell line (Huh7) infected with one of the following three EBOV strains: Mayinga (responsible for the first Zaire outbreak in 1976), Makona (responsible for the West Africa outbreak in 2013–2016) and the epizootic Reston (presumably innocuous to humans). Our results highlight specific miRNA-based immunity pathways and substantial differences between the strains beyond their clinical manifestation and pathogenicity. These analyses shed new light into the molecular signature of liver cells upon EBOV infection and reveal new insights into miRNA-based virus attack and host defense strategy.
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Affiliation(s)
- Idrissa Diallo
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Jeffrey Ho
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Benoit Laffont
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Jonathan Laugier
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Abderrahim Benmoussa
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Marine Lambert
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Zeinab Husseini
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
| | - Geoff Soule
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3B 3M9, Canada; (G.S.); (R.K.)
| | - Robert Kozak
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3B 3M9, Canada; (G.S.); (R.K.)
- Division of Microbiology, Department of Laboratory Medicine & Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
| | - Gary P. Kobinger
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3B 3M9, Canada; (G.S.); (R.K.)
- Département de Microbiologie Médicale, Université du Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Patrick Provost
- CHU de Québec Research Center, Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec, QC G1V 4G2, Canada; (I.D.); (J.H.); (B.L.); (J.L.); (A.B.); (M.L.); (Z.H.); (G.P.K.)
- CHUQ Research Center/CHUL Pavilion, 2705 Blvd Laurier, Room T1-65, Quebec, QC G1V 4G2, Canada
- Correspondence: ; Tel.: +1-418-525-4444 (ext. 48842)
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miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury. Cell Death Dis 2020; 11:929. [PMID: 33116120 PMCID: PMC7595188 DOI: 10.1038/s41419-020-03135-z] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 10/10/2020] [Accepted: 10/13/2020] [Indexed: 12/19/2022]
Abstract
Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat's kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3'UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.
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