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Ni W, Zhao Y, Shen J, Yin Q, Wang Y, Li Z, Tang T, Wen Y, Zhang Y, Jiang W, Jiang L, Wei J, Gan W, Zhang A, Zhou X, Wang B, Liu BC. Therapeutic role of miR-26a on cardiorenal injury in a mice model of angiotensin-II induced chronic kidney disease through inhibition of LIMS1/ILK pathway. Chin Med J (Engl) 2025; 138:193-204. [PMID: 38445356 PMCID: PMC11745862 DOI: 10.1097/cm9.0000000000002978] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
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Affiliation(s)
- Weijie Ni
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Yajie Zhao
- Department of Pediatric Nephrology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China
| | - Jinxin Shen
- Department of Neonates, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China
| | - Qing Yin
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Yao Wang
- Department of Nephrology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225100, China
| | - Zuolin Li
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Taotao Tang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Yi Wen
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Yilin Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Wei Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Liangyunzi Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Jinxuan Wei
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Weihua Gan
- Department of Pediatric Nephrology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China
| | - Aiqing Zhang
- Department of Pediatric Nephrology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, China
| | - Xiaoyu Zhou
- Department of Neonates, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China
| | - Bin Wang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210003, China
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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3
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Lv W, Wang Y. Neural Influences on Tumor Progression Within the Central Nervous System. CNS Neurosci Ther 2024; 30:e70097. [PMID: 39469896 PMCID: PMC11519750 DOI: 10.1111/cns.70097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/21/2024] [Accepted: 10/13/2024] [Indexed: 10/30/2024] Open
Abstract
For decades, researchers have studied how brain tumors, the immune system, and drugs interact. With the advances in cancer neuroscience, which centers on defining and therapeutically targeting nervous system-cancer interactions, both within the local tumor microenvironment (TME) and on a systemic level, the subtle relationship between neurons and tumors in the central nervous system (CNS) has been deeply studied. Neurons, as the executors of brain functional activities, have been shown to significantly influence the emergence and development of brain tumors, including both primary and metastatic tumors. They engage with tumor cells via chemical or electrical synapses, directly regulating tumors or via intricate coupling networks, and also contribute to the TME through paracrine signaling, secreting proteins that exert regulatory effects. For instance, in a study involving a mouse model of glioblastoma, the authors observed a 42% increase in tumor volume when neuronal activity was stimulated, compared to controls (p < 0.01), indicating a direct correlation between neural activity and tumor growth. These thought-provoking results offer promising new strategies for brain tumor therapies, highlighting the potential of neuronal modulation to curb tumor progression. Future strategies may focus on developing drugs to inhibit or neutralize proteins and other bioactive substances secreted by neurons, break synaptic connections and interactions between infiltrating cells and tumor cells, as well as disrupt electrical coupling within glioma cell networks. By harnessing the insights gained from this research, we aspire to usher in a new era of brain tumor therapies that are both more potent and precise.
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Affiliation(s)
- Wenhao Lv
- Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhouZhejiangChina
- School of PharmacyHangzhou Normal UniversityHangzhouZhejiangChina
| | - Yongjie Wang
- School of PharmacyHangzhou Normal UniversityHangzhouZhejiangChina
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4
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Li P, Ma X, Huang D, Gu X. Exploring the roles of non-coding RNAs in liver regeneration. Noncoding RNA Res 2024; 9:945-953. [PMID: 38680418 PMCID: PMC11046251 DOI: 10.1016/j.ncrna.2024.04.003] [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: 02/14/2024] [Revised: 03/26/2024] [Accepted: 04/16/2024] [Indexed: 05/01/2024] Open
Abstract
Liver regeneration (LR) is a complex process encompassing three distinct phases: priming, proliferation phase and restoration, all influenced by various regulatory factors. After liver damage or partial resection, the liver tissue demonstrates remarkable restorative capacity, driven by cellular proliferation and repair mechanisms. The essential roles of non-coding RNAs (ncRNAs), predominantly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNA (circRNA), in regulating LR have been vastly studied. Additionally, the impact of ncRNAs on LR and their abnormal expression profiles during this process have been extensively documented. Mechanistic investigations have revealed that ncRNAs interact with genes involved in proliferation to regulate hepatocyte proliferation, apoptosis and differentiation, along with liver progenitor cell proliferation and migration. Given the significant role of ncRNAs in LR, an in-depth exploration of their involvement in the liver's self-repair capacity can reveal promising therapeutic strategies for LR and liver-related diseases. Moreover, understanding the unique regenerative potential of the adult liver and the mechanisms and regulatory factors of ncRNAs in LR are crucial for improving current treatment strategies and exploring new therapeutic approaches for various liver-related diseases. This review provides a brief overview of the LR process and the ncRNA expression profiles during this process. Furthermore, we also elaborate on the specific molecular mechanisms through which multiple key ncRNAs regulate the LR process. Finally, based on the expression characteristics of ncRNAs and their interactions with proliferation-associated genes, we explore their potential clinical application, such as developing predictive indicators reflecting liver regenerative activity and manipulating LR processes for therapeutic purposes.
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Affiliation(s)
- Penghui Li
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
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Fu R, You Y, Wang Y, Wang J, Lu Y, Gao R, Pang M, Yang P, Wang H. Sanggenol L induces ferroptosis in non-small cell lung cancer cells via regulating the miR-26a-1-3p/MDM2/p53 signaling pathway. Biochem Pharmacol 2024; 226:116345. [PMID: 38852643 DOI: 10.1016/j.bcp.2024.116345] [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: 03/06/2024] [Revised: 05/28/2024] [Accepted: 06/06/2024] [Indexed: 06/11/2024]
Abstract
Ferroptosis is a regulated cell death marked by iron-dependent lipid peroxidation. Tumor cells that survive by evading chemotherapy-induced apoptosis are vulnerable to ferroptosis. Therefore, it is particularly urgent to explore active ingredients that can selectively induce ferroptosis in cancer cells. Here, we revealed that sanggenol L, the active agent of Morus Bark, predisposed non-small cell lung cancer (NSCLC) cells to ferroptosis, evidenced by reactive oxygen species (ROS) accumulation, glutathione depletion, mitochondrial shrinkage, and lipid peroxidation. Furthermore, the ferroptosis-related miRNA array showed that sanggenol L treatment upregulated the level of miR-26a-1-3p, which directly targeted the E3 ubiquitin ligase MDM2. In addition, silencing MDM2 by miR-26a-1-3p resulted in a notable increase in p53 protein levels and decrease of its downstream target SLC7A11, ultimately triggered ferroptosis. The subcutaneous xenograft model and patient-derived tumor xenograft (PDX) model of NSCLC further confirmed the anti-tumor efficacy and safety of sanggenol L in vivo. Collectively, our data suggest that miR-26a-1-3p/MDM2/p53/SLC7A11 signaling axis plays a key role in sanggenol L-induced ferroptosis, which implies that sanggenol L can serves as an anticancer therapeutic arsenal for NSCLC.
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Affiliation(s)
- Rong Fu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Yujie You
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Yuqing Wang
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China
| | - Jue Wang
- Department of Prosthodontics, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Yu Lu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Rui Gao
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Min Pang
- Department of Pulmonary and Critical Care Medicine, The First Hospital, Shanxi Medical University, Shanxi Province Key Laboratory of Respiratory Disease, Taiyuan, China.
| | - Peng Yang
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
| | - Hailong Wang
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China.
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6
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Iyer DP, Moyon L, Wittler L, Cheng CY, Ringeling FR, Canzar S, Marsico A, Bulut-Karslioğlu A. Combinatorial microRNA activity is essential for the transition of pluripotent cells from proliferation into dormancy. Genome Res 2024; 34:572-589. [PMID: 38719471 PMCID: PMC11146600 DOI: 10.1101/gr.278662.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 04/10/2024] [Indexed: 06/05/2024]
Abstract
Dormancy is a key feature of stem cell function in adult tissues as well as in embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring. How these processes are coordinated to successfully transition cells to the resting dormant state remains unclear. Here we show that microRNA activity, which is otherwise dispensable for preimplantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in the loss of pluripotent cells. Through the integration of high-sensitivity small RNA expression profiling of individual embryos and protein expression of miRNA targets with public data of protein-protein interactions, we constructed the miRNA-mediated regulatory network of mouse early embryos specific to diapause. We find that individual miRNAs contribute to the combinatorial regulation by the network, and the perturbation of the network compromises embryo survival in diapause. We further identified the nutrient-sensitive transcription factor TFE3 as an upstream regulator of diapause-specific miRNAs, linking cytoplasmic MTOR activity to nuclear miRNA biogenesis. Our results place miRNAs as a critical regulatory layer for the molecular rewiring of early embryos to establish dormancy.
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Affiliation(s)
- Dhanur P Iyer
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Lambert Moyon
- Computational Health Center, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Lars Wittler
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| | - Chieh-Yu Cheng
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Francisca R Ringeling
- Faculty of Informatics and Data Science, University of Regensburg, 93053 Regensburg, Germany
| | - Stefan Canzar
- Faculty of Informatics and Data Science, University of Regensburg, 93053 Regensburg, Germany
| | - Annalisa Marsico
- Computational Health Center, Helmholtz Center Munich, 85764 Neuherberg, Germany;
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7
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Kobayashi T, Yamazaki K, Shinada J, Mizunuma M, Furukawa K, Chuman Y. Identification of Inhibitors of the Disease-Associated Protein Phosphatase Scp1 Using Antibody Mimetic Molecules. Int J Mol Sci 2024; 25:3737. [PMID: 38612548 PMCID: PMC11011526 DOI: 10.3390/ijms25073737] [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: 02/28/2024] [Revised: 03/18/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Protein phosphorylation is a prevalent translational modification, and its dysregulation has been implicated in various diseases, including cancer. Despite its significance, there is a lack of specific inhibitors of the FCP/SCP-type Ser/Thr protein phosphatase Scp1, characterized by high specificity and affinity. In this study, we focused on adnectin, an antibody-mimetic protein, aiming to identify Scp1-specific binding molecules with a broad binding surface that target the substrate-recognition site of Scp1. Biopanning of Scp1 was performed using an adnectin-presenting phage library with a randomized FG loop. We succeeded in identifying FG-1Adn, which showed high affinity and specificity for Scp1. Ala scanning analysis of the Scp1-binding sequence in relation to the FG-1 peptide revealed that hydrophobic residues, including aromatic amino acids, play important roles in Scp1 recognition. Furthermore, FG-1Adn was found to co-localize with Scp1 in cells, especially on the plasma membrane. In addition, Western blotting analysis showed that FG-1Adn increased the phosphorylation level of the target protein of Scp1 in cells, indicating that FG-1Adn can inhibit the function of Scp1. These results suggest that FG-1Adn can be used as a specific inhibitor of Scp1.
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Affiliation(s)
| | | | | | | | | | - Yoshiro Chuman
- Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181, Japan; (T.K.); (K.Y.); (J.S.); (M.M.); (K.F.)
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8
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Sun B, Meng XH, Li YM, Lin H, Xiao ZD. MicroRNA-18a prevents senescence of mesenchymal stem cells by targeting CTDSPL. Aging (Albany NY) 2024; 16:4904-4919. [PMID: 38460957 PMCID: PMC10968691 DOI: 10.18632/aging.205642] [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: 08/29/2023] [Accepted: 12/26/2023] [Indexed: 03/11/2024]
Abstract
Stem cell therapy requires massive-scale homogeneous stem cells under strict qualification control. However, Prolonged ex vivo expansion impairs the biological functions and results in senescence of mesenchymal stem cells (MSCs). We investigated the function of CTDSPL in the premature senescence process of MSCs and clarified that miR-18a-5p played a prominent role in preventing senescence of long-term cultured MSCs and promoting the self-renewal ability of MSCs. Over-expression of CTDSPL resulted in an enlarged morphology, up-regulation of p16 and accumulation of SA-β-gal of MSCs. The reduced phosphorylated RB suggested cell cycle arrest of MSCs. All these results implied that CTDSPL induced premature senescence of MSCs. We further demonstrated that miR-18a-5p was a putative regulator of CTDSPL by luciferase reporter assay. Inhibition of miR-18a-5p promoted the expression of CTDSPL and induced premature senescence of MSCs. Continuous overexpression of miR-18a-5p improved self-renewal of MSCs by reducing ROS level, increased expression of Oct4 and Nanog, and promoted growth rate and differentiation capability. We reported for the first time that the dynamic interaction of miR-18a-5p and CTDSPL is crucial for stem cell senescence.
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Affiliation(s)
- Bo Sun
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Xian-Hui Meng
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Yu-Min Li
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Hao Lin
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Zhong-Dang Xiao
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
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Li J, Pang D, Zhou L, Ouyang H, Tian Y, Yu H. miR-26a-5p inhibits the proliferation of psoriasis-like keratinocytes in vitro and in vivo by dual interference with the CDC6/CCNE1 axis. Aging (Albany NY) 2024; 16:4631-4653. [PMID: 38446584 PMCID: PMC10968694 DOI: 10.18632/aging.205618] [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: 07/14/2023] [Accepted: 02/02/2024] [Indexed: 03/08/2024]
Abstract
Psoriasis is a chronic inflammatory proliferative dermatological ailment that currently lacks a definitive cure. Employing data mining techniques, this study identified a collection of substantially downregulated miRNAs (top 10). Notably, 32 targets were implicated in both the activation of the IL-17 signaling pathway and cell cycle dysregulation. In silico analysis revealed that one of these miRNAs, miR-26a-5p, is a highly conserved cross-species miRNA. Strikingly, the miR-26a-5p sequences in humans and mice are identical, and mmu-miR-26a-5p was found to target the same 7 cell cycle targets as its human counterpart, hsa-miR-26a-5p. Among these targets, CDC6 and CCNE1 were the most effective targets of miR-26a-5p, which was further validated in vitro using a dual luciferase reporter system and qPCR assay. The therapeutic assessment of miR-26a-5p revealed its remarkable efficacy in inhibiting the proliferation and G1/S transition of keratinocytes (HaCaT and HEKs) in vitro. In vivo experiments corroborated these findings, demonstrating that miR-26a-5p effectively suppressed imiquimod (IMQ)-induced psoriasis-like skin lesions in mice over an 8-day treatment period. Histological analysis via H&E staining revealed that miR-26a-5p treatment resulted in reduced keratinocyte thickness and immune cell infiltration into the spleens of IMQ-treated mice. Mechanistic investigations revealed that miR-26a-5p induced a cascade of downregulated genes associated with the IL-23/IL-17A axis, which is known to be critical in psoriasis pathogenesis, while concomitantly suppressing CDC6 and CCNE1 expression. These findings were corroborated by qPCR and Western blot analyses. Collectively, our study provides compelling evidence supporting the therapeutic potential of miR-26a-5p as a safe and reliable endogenous small nucleic acid for the treatment of psoriasis.
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Affiliation(s)
- Jianing Li
- Key Lab for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Daxin Pang
- Key Lab for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
- Chongqing Research Institute, Jilin University, Chongqing 401123, China
- Chongqing Jitang Biotechnology Research Institute Co., Ltd., Chongqing 401123, China
| | - Lin Zhou
- Joint International Research Laboratory of Reproduction and Development, School of Basic Medicine, Chong-qing Medical University, Chongqing 400016, China
| | - Hongsheng Ouyang
- Key Lab for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
- Chongqing Research Institute, Jilin University, Chongqing 401123, China
- Chongqing Jitang Biotechnology Research Institute Co., Ltd., Chongqing 401123, China
| | - Yaping Tian
- Department of Dermatology and Venerology, First Bethune Hospital of Jilin University, Changchun 130021, China
| | - Hao Yu
- Key Lab for Zoonoses Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
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Chen W, Wu X, Hu J, Liu X, Guo Z, Wu J, Shao Y, Hao M, Zhang S, Hu W, Wang Y, Zhang M, Zhu M, Wang C, Wu Y, Wang J, Xing D. The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. Cardiovasc Diabetol 2024; 23:21. [PMID: 38195542 PMCID: PMC10777520 DOI: 10.1186/s12933-024-02119-z] [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: 11/14/2023] [Accepted: 01/02/2024] [Indexed: 01/11/2024] Open
Abstract
Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3β, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1β, IL-6, JAG2, KCNJ2, MALT1, β-MHC, NF-κB, PCK1, PLCβ1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.
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Affiliation(s)
- Wujun Chen
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Xiaolin Wu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Jianxia Hu
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xiaolei Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Zhu Guo
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Jianfeng Wu
- Department of Cardiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, 421001, Hunan, China
| | - Yingchun Shao
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Minglu Hao
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Shuangshuang Zhang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Weichao Hu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
- Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266000, Shandong, China
| | - Yanhong Wang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Miao Zhang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
| | - Meng Zhu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266071, Shandong, China
| | - Chao Wang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
| | - Yudong Wu
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
| | - Jie Wang
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
| | - Dongming Xing
- Cancer Institute, Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, 266071, Shandong, China.
- School of Life Sciences, Tsinghua University, Beijing, 100084, China.
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11
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Fattahi M, Shahrabi S, Saadatpour F, Rezaee D, Beyglu Z, Delavari S, Amrolahi A, Ahmadi S, Bagheri-Mohammadi S, Noori E, Majidpoor J, Nouri S, Aghaei-Zarch SM, Falahi S, Najafi S, Le BN. microRNA-382 as a tumor suppressor? Roles in tumorigenesis and clinical significance. Int J Biol Macromol 2023; 250:125863. [PMID: 37467828 DOI: 10.1016/j.ijbiomac.2023.125863] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/30/2023] [Accepted: 07/15/2023] [Indexed: 07/21/2023]
Abstract
MicroRNAs (miRNAs) are small single-stranded RNAs belonging to a class of non-coding RNAs with an average length of 18-22 nucleotides. Although not able to encode any protein, miRNAs are vastly studied and found to play role in various human physiologic as well as pathological conditions. A huge number of miRNAs have been identified in human cells whose expression is straightly regulated with crucial biological functions, while this number is constantly increasing. miRNAs are particularly studied in cancers, where they either can act with oncogenic function (oncomiRs) or tumor-suppressors role (referred as tumor-suppressor/oncorepressor miRNAs). miR-382 is a well-studied miRNA, which is revealed to play regulatory roles in physiological processes like osteogenic differentiation, hematopoietic stem cell differentiation and normal hematopoiesis, and liver progenitor cell differentiation. Notably, miR-382 deregulation is reported in pathologic conditions, such as renal fibrosis, muscular dystrophies, Rett syndrome, epidural fibrosis, atrial fibrillation, amelogenesis imperfecta, oxidative stress, human immunodeficiency virus (HIV) replication, and various types of cancers. The majority of oncogenesis studies have claimed miR-382 downregulation in cancers and suppressor impact on malignant phenotype of cancer cells in vitro and in vivo, while a few studies suggest opposite findings. Given the putative role of this miRNA in regulation of oncogenesis, assessment of miR-382 expression is suggested in a several clinical investigations as a prognostic/diagnostic biomarker for cancer patients. In this review, we have an overview to recent studies evaluated the role of miR-382 in oncogenesis as well as its clinical potential.
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Affiliation(s)
- Mehdi Fattahi
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; School of Engineering & Technology, Duy Tan University, Da Nang, Vietnam
| | - Saeid Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Saadatpour
- Pharmaceutical Biotechnology Lab, Department of Microbiology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Zahra Beyglu
- Department of Genetics, Qom Branch, Islamic Azad University, Qom, Iran
| | - Sana Delavari
- Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Anita Amrolahi
- Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shirin Ahmadi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Bagheri-Mohammadi
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Effat Noori
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, Faculty of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Shadi Nouri
- Department of Radiology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Shahab Falahi
- Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran.
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Binh Nguyen Le
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; School of Engineering & Technology, Duy Tan University, Da Nang, Vietnam
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12
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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13
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Zhu L, Jiao H, Gao W, Huang L, Shi C, Zhang F, Wu J, Luo J. Fatty Acid Desaturation Is Suppressed in Mir-26a/b Knockout Goat Mammary Epithelial Cells by Upregulating INSIG1. Int J Mol Sci 2023; 24:10028. [PMID: 37373175 DOI: 10.3390/ijms241210028] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
MicroRNA-26 (miR-26a and miR-26b) plays a critical role in lipid metabolism, but its endogenous regulatory mechanism in fatty acid metabolism is not clear in goat mammary epithelial cells (GMECs). GMECs with the simultaneous knockout of miR-26a and miR-26b were obtained using the CRISPR/Cas9 system with four sgRNAs. In knockout GMECs, the contents of triglyceride, cholesterol, lipid droplets, and unsaturated fatty acid (UFA) were significantly reduced, and the expression of genes related to fatty acid metabolism was decreased, but the expression level of miR-26 target insulin-induced gene 1 (INSIG1) was significantly increased. Interestingly, the content of UFA in miR-26a and miR-26b simultaneous knockout GMECs was significantly lower than that in wild-type GMECs and miR-26a- and miR-26b-alone knockout cells. After decreasing INSIG1 expression in knockout cells, the contents of triglycerides, cholesterol, lipid droplets, and UFAs were restored, respectively. Our studies demonstrate that the knockout of miR-26a/b suppressed fatty acid desaturation by upregulating the target INSIG1. This provides reference methods and data for studying the functions of miRNA families and using miRNAs to regulate mammary fatty acid synthesis.
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Affiliation(s)
- Lu Zhu
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Hongyun Jiao
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Wenchang Gao
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Lian Huang
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Chenbo Shi
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Fuhong Zhang
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Jiao Wu
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
| | - Jun Luo
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China
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14
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Ren Y, Zhang H. Emerging role of exosomes in vascular diseases. Front Cardiovasc Med 2023; 10:1090909. [PMID: 36937921 PMCID: PMC10017462 DOI: 10.3389/fcvm.2023.1090909] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/11/2023] [Indexed: 03/06/2023] Open
Abstract
Exosomes are biological small spherical lipid bilayer vesicles secreted by most cells in the body. Their contents include nucleic acids, proteins, and lipids. Exosomes can transfer material molecules between cells and consequently have a variety of biological functions, participating in disease development while exhibiting potential value as biomarkers and therapeutics. Growing evidence suggests that exosomes are vital mediators of vascular remodeling. Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts (AFs) can communicate through exosomes; such communication is associated with inflammatory responses, cell migration and proliferation, and cell metabolism, leading to changes in vascular function and structure. Essential hypertension (EH), atherosclerosis (AS), and pulmonary arterial hypertension (PAH) are the most common vascular diseases and are associated with significant vascular remodeling. This paper reviews the latest research progress on the involvement of exosomes in vascular remodeling through intercellular information exchange and provides new ideas for understanding related diseases.
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Affiliation(s)
- Yi Ren
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Honggang Zhang
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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15
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Baig MS, Deepanshu, Prakash P, Alam P, Krishnan A. In silico analysis reveals hypoxia-induced miR-210-3p specifically targets SARS-CoV-2 RNA. J Biomol Struct Dyn 2023; 41:12305-12327. [PMID: 36752331 DOI: 10.1080/07391102.2023.2175255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/01/2023] [Indexed: 02/09/2023]
Abstract
Human coronaviruses (HCoVs) until the emergence of SARS in 2003 were associated with mild cold and upper respiratory tract infections. The ongoing pandemic caused by SARS-CoV-2 has enhanced the potential for infection and transmission as compared to other known members of this family. MicroRNAs (miRNA) are 21-25 nucleotides long non-coding RNA that bind to 3' UTR of genes and regulate almost every aspect of cellular function. Several human miRNAs have been known to target viral genomes, mostly to downregulate their expression and sometimes to upregulate also. In some cases, host miRNAs could be sequestered by the viral genome to create a condition for favourable virus existence. The ongoing SARS CoV-2 pandemic is unique based on its transmissibility and severity and we hypothesised that there could be a unique mechanism for its pathogenesis. In this study, we exploited in silico approach to identify human respiratory system-specific miRNAs targeting the viral genome of three highly pathogenic HCoVs (SARS-CoV-2 Wuhan strain, SARS-CoV, and MERS-CoV) and three low pathogenic HCoVs (OC43, NL63, and HKU1). We identified ten common microRNAs that target all HCoVs studied here. In addition, we identified unique miRNAs which targeted specifically one particular HCoV. miR-210-3p was the single unique lung-specific miRNA, which was found to target the NSP3, NSP4, and NSP13 genes of SARS-CoV-2. Further miR-210-NSP3, miR-210-NSP4, and miR-210-NSP13 SARS-CoV-2 duplexes were docked with the hAGO2 protein (PDB ID 4F3T) which showed Z-score values of -1.9, -1.7, and -1.6, respectively. The role of miR-210-3p as master hypoxia regulator and inflammation regulation may be important for SARS-CoV-2 pathogenesis. Overall, this analysis advocates that miR-210-3p be investigated experimentally in SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Deepanshu
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| | - Prem Prakash
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| | - Pravej Alam
- Department of Biology, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Anuja Krishnan
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
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16
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Was N, Sauer M, Fischer U, Becker M. lncRNA Malat1 and miR-26 cooperate in the regulation of neuronal progenitor cell proliferation and differentiation. RNA (NEW YORK, N.Y.) 2022; 29:rna.079436.122. [PMID: 36302652 PMCID: PMC9808573 DOI: 10.1261/rna.079436.122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/19/2022] [Indexed: 06/16/2023]
Abstract
Neurogenesis is a finely tuned process, which depends on the balanced execution of expression programs that regulate cellular differentiation and proliferation. Different molecular players ranging from transcription factors to chromatin modulators control these programs. Adding to the complexity, also non-coding (nc)RNAs take part in this process. Here we analyzed the function of the long non-coding (lnc)RNA Malat1 during neural embryonic stem cell (ESC) differentiation. We find that deletion of Malat1 leads to inhibition of proliferation of neural progenitor cells (NPCs). Interestingly, this co-insides with an increase in the expression of miR-26 family members miR-26a and miR-26b in differentiating ESCs. Inactivation of miR-26a/b rescues the proliferative phenotype of Malat1 knockout (KO) cells and leads to accelerated neuronal differentiation of compound Malat1KO/mir-26KO ESCs. Together our work identifies a so far unknown interaction between Malat1 and miR-26 in the regulation of NPC proliferation and neuronal differentiation.
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17
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El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
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18
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Qu J, Lin Z. Autophagy Regulation by Crosstalk between miRNAs and Ubiquitination System. Int J Mol Sci 2021; 22:ijms222111912. [PMID: 34769343 PMCID: PMC8585084 DOI: 10.3390/ijms222111912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes with ~22 nucleotides which are involved in the regulation of post-transcriptional gene expression. Ubiquitination and deubiquitination are common post-translational modifications in eukaryotic cells and important pathways in regulating protein degradation and signal transduction, in which E3 ubiquitin ligases and deubiquitinases (DUBs) play a decisive role. MiRNA and ubiquitination are involved in the regulation of most biological processes, including autophagy. Furthermore, in recent years, the direct interaction between miRNA and E3 ubiquitin ligases or deubiquitinases has attracted much attention, and the cross-talk between miRNA and ubiquitination system has been proved to play key regulatory roles in a variety of diseases. In this review, we summarized the advances in autophagy regulation by crosstalk between miRNA and E3 ubiquitin ligases or deubiquitinases.
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19
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Puzanov GA, Senchenko VN. SCP Phosphatases and Oncogenesis. Mol Biol 2021. [DOI: 10.1134/s0026893321030092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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20
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Wang N, Cao S, Wang X, Zhang L, Yuan H, Ma X. lncRNA MALAT1/miR‑26a/26b/ST8SIA4 axis mediates cell invasion and migration in breast cancer cell lines. Oncol Rep 2021; 46:181. [PMID: 34278507 PMCID: PMC8273684 DOI: 10.3892/or.2021.8132] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 06/03/2021] [Indexed: 12/25/2022] Open
Abstract
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA that is overexpressed in various human cancers, including breast cancer. Evidence has associated the function of the α-2,8-sialyltransferase (ST8SIA) family with breast cancer. The present study aimed to investigate the potential roles of MALAT1 in breast cancer development and progression using analyses of both breast cancer tissues and cell lines. The mRNA levels of MALAT1, microRNA (miR)-26a/26b and ST8SIA4 were detected by reverse transcription-quantitative PCR (RT-qPCR) and the protein level of ST8SIA4 was assessed by western blot analysis. Cell proliferation, invasion and migration were detected by CCK-8, wound healing and Transwell assays, respectively. Interactions between MALAT1 and miR-26a/26b were assessed using fluorescence in situ hybridization, RNA immunoprecipitation and luciferase reporter assays. Herein, different levels of MALAT1 were primarily observed in human breast cancer samples and cells. Upregulated MALAT1 was a crucial predictor of poor breast cancer prognosis. Altered MALAT1 modulated cell progression in breast cancer. Moreover, miR-26a/26b was confirmed as a direct regulator of MALAT1, and ST8SIA4 was predicted as a target of miR-26a/26b. Functional analysis in human breast cancer cell lines demonstrated that MALAT1 modulated breast cancer cell tumorigenicity by acting as a competing endogenous lncRNA (ceRNA) to regulate ST8SIA4 levels by sponging miR-26a/26b. The identification of the MALAT1/miR-26a/26b/ST8SIA4 axis which contributes to breast cancer progression may constitute a potential new therapeutic target.
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Affiliation(s)
- Nan Wang
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Shengji Cao
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xiaoxi Wang
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Lina Zhang
- Department of Radiology Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Hong Yuan
- Department of Clinical Laboratory Medicine, Dalian Municipal Central Hospital, Dalian, Liaoning 116033, P.R. China
| | - Xiaolu Ma
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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21
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Sauer M, Was N, Ziegenhals T, Wang X, Hafner M, Becker M, Fischer U. The miR-26 family regulates neural differentiation-associated microRNAs and mRNAs by directly targeting REST. J Cell Sci 2021; 134:jcs257535. [PMID: 34151974 PMCID: PMC11443607 DOI: 10.1242/jcs.257535] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 05/11/2021] [Indexed: 01/13/2023] Open
Abstract
Repressor element 1-silencing transcription factor (REST) plays a crucial role in the differentiation of neural progenitor cells (NPCs). C-terminal domain small phosphatases (CTDSPs) are REST effector proteins that reduce RNA polymerase II activity on genes required for neurogenesis. miR-26b regulates neurogenesis in zebrafish by targeting ctdsp2 mRNA, but the molecular events triggered by this microRNA (miR) remain unknown. Here, we show in a murine embryonic stem cell differentiation paradigm that inactivation of miR-26 family members disrupts the formation of neurons and astroglia and arrests neurogenesis at the neural progenitor level. Furthermore, we show that miR-26 directly targets Rest, thereby inducing the expression of a large set of REST complex-repressed neuronal genes, including miRs required for induction of the neuronal gene expression program. Our data identify the miR-26 family as the trigger of a self-amplifying system required for neural differentiation that acts upstream of REST-controlled miRs.
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Affiliation(s)
- Mark Sauer
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, D-97078 Würzburg, Germany
| | - Nina Was
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, D-97078 Würzburg, Germany
| | - Thomas Ziegenhals
- Department of Biochemistry, Theodor Boveri-Institute, University of Würzburg, D-97074 Würzburg, Germany
| | - Xiantao Wang
- RNA Molecular Biology Group, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD 20892, USA
| | - Markus Hafner
- RNA Molecular Biology Group, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD 20892, USA
| | - Matthias Becker
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, D-97078 Würzburg, Germany
| | - Utz Fischer
- Department of Biochemistry, Theodor Boveri-Institute, University of Würzburg, D-97074 Würzburg, Germany
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22
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Yang X, Chen Y, Zhou Y, Wu C, Li Q, Wu J, Hu WW, Zhao WQ, Wei W, Wu CP, Jiang JT, Ji M. GPC5 suppresses lung cancer progression and metastasis via intracellular CTDSP1/AhR/ARNT signaling axis and extracellular exosome secretion. Oncogene 2021; 40:4307-4323. [PMID: 34079082 DOI: 10.1038/s41388-021-01837-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 04/09/2021] [Accepted: 05/10/2021] [Indexed: 12/13/2022]
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Glypican-5 (GPC5) is a member of heparan sulfate proteoglycans, and its biological importance in initiation and progression of lung cancer remains controversial. In the present study, we revealed that GPC5 transcriptionally enhanced the expression of CTDSP1 (miR-26b host gene) via AhR-ARNT pathway, and such up-regulation of CTDSP1 intracellularly contributed to the inhibited proliferation of lung cancer cells. Moreover, exosomes derived from GPC5-overexpressing human lung cancer cells (GPC5-OE-derived exosomes) had an extracellular repressive effect on human lymphatic endothelial cells (hLECs), leading to decreased tube formation and migration. Comparison between GPC5-WT- and GPC5-OE-derived exosomes showed that miR-26b (embedded within introns of CTDSP1 gene) was significantly up-regulated in GPC5-OE-derived exosomes and critical to the influence on hLECs. On the mechanism, we demonstrated that miR-26b transferred into hLECs directly targeted to PTK2 3'-UTR and led to PTK2 down-regulation, resulting in defects in tube formation and migration of hLECs. By uncovering the regulation network among GPC5, miR-26b, miR-26b host gene (CTDSP1), and target gene (PTK2), our findings demonstrated that GPC5 functioned as a tumor suppressor in human lung cancer.
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Affiliation(s)
- Xin Yang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, P.R. China.
- Institute of Cell Therapy, Soochow University, Changzhou, P.R. China.
| | - Yan Chen
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - You Zhou
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, P.R. China
- Institute of Cell Therapy, Soochow University, Changzhou, P.R. China
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Chen Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Qing Li
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Wen Wei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Wei Qing Zhao
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Wei Wei
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Chang Ping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China
| | - Jing Ting Jiang
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, P.R. China.
- Institute of Cell Therapy, Soochow University, Changzhou, P.R. China.
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China.
| | - Mei Ji
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, P.R. China.
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Zeng H, Sun W, Ren X, Xia N, Zheng S, Xu H, Tian Y, Fu X, Tian J. AP2-microRNA-26a overexpression reduces visceral fat mass and blood lipids. Mol Cell Endocrinol 2021; 528:111217. [PMID: 33667597 DOI: 10.1016/j.mce.2021.111217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 01/21/2021] [Accepted: 02/16/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND MicroRNA-26a (miR-26a) is a key player in tumor suppression and plays important roles in glucose and lipid metabolism. However, its function in adipose tissue is not well defined. OBJECTIVE The study aimed to examine the effect on fat expansion and function of miR-26a in adipose tissue. METHODS Adipose-specific miR-26a transgenic mice (Ap2-miR-26a) were firstly generated by breeding miR-26a floxed (Mir26aloxP/loxP) mice with Ap2-Cre recombinase transgenic mice. The effects of miR-26a adipose-specific overexpression on body weight, body fat composition, fat pad weight, adipocyte size, blood lipid levels, glucose metabolism, and adipogenesis were investigated in mice on a chow diet and a high fat diet. White adipose tissue browning was evaluated by energy expenditure, adipocyte morphology and browning related genes expression levels both at room temperature and after cold exposure. Gene expression was determined by Real-Time quantitative PCR and western blotting. RESULTS MiR-26a was specifically overexpressed in adipose by ~4 folds. Ap2-miR-26a mice had a moderate decrease in body weight, body fat composition, epididymal white adipose (eWAT) weight and blood lipid levels, along with smaller adipocytes in eWAT. The favorable phenotype was not due to white adipose tissue browning (even after cold exposure) or adipogenesis or lipolysis. Ap2-miR-26a mice exhibited no significant metabolic phenotype under high-fat-diet feeding. CONCLUSION This study suggests that adipose-specific overexpression of miR-26a could moderately reduce visceral fat pad mass and lipid levels independent of white adipose tissue browning, adipogenesis and adipose lipolysis based on the gene expression level.
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Affiliation(s)
- Hailuan Zeng
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Weihong Sun
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai, 200031, China
| | - Xinping Ren
- State Key Laboratory of Medical Genomics, Department of Ultrasound, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Nan Xia
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Sheng Zheng
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Haixia Xu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Yan Tian
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Xianghui Fu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China.
| | - Jingyan Tian
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Cho JS, Lee J, Park KC, Yang KJ, Cho EJ. The relationship between miRNA-26b and connective tissue growth factor in rat models of aortic banding and debanding. Korean J Intern Med 2021; 36:596-607. [PMID: 31875666 PMCID: PMC8137408 DOI: 10.3904/kjim.2019.120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 07/23/2019] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Connective tissue growth factor (CTGF) is a profibrotic factor implicated in pressure overload-mediated myocardial fibrosis. In this study, we determined the role of predicted CTGF-targeting microRNAs (miRNAs) in rat models of aortic stenosis and reverse cardiac remodeling. METHODS Minimally invasive ascending aortic banding was performed in 24 7-week-old male Sprague-Dawley rats, which were divided into three groups. The banding group consisted of eight rats that were sacrificed immediately after 6 weeks of aortic constriction. The debanding group underwent aortic constriction for 4 weeks and was sacrificed 2 weeks after band removal. The third group underwent sham surgery. We investigated the expression of CTGF, transforming growth factor-β1 (TGFβ1), and matrix metalloproteinase-2 using ELISA and examined miRNA-26b, miRNA-133a, and miRNA-19b as predicted CTGF-targeting miRNAs based on miRNA databases in 24-hour TGFβ-stimulated and TGFβ- washed fibroblasts and myocardial tissues from all subjects. RESULTS CTGF was elevated in 24-hour TGFβ-stimulated fibroblasts and decreased in 24-hour TGFβ-washed fibroblasts. miRNA-26b was significantly increased in TGFβ-washed fibroblasts compared with control and TGFβ-stimulated fibroblasts (p < 0.05). CTGF expression was significantly higher in the banding group than that in the sham and debanding groups. The relative expression levels of miRNA-26b were higher in the debanding group than in the banding group. CONCLUSION The results of our study using models of aortic banding and debanding suggested that miRNA-26b was significantly increased after aortic debanding. The in vitro model yielded the same results: miRNA-26b was upregulated after removal of TGFβ from fibroblasts.
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Affiliation(s)
- Jung Sun Cho
- Division of Cardiology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Korea
| | - Jongho Lee
- Department of Thoracic and Cardiovascular Surgery, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Korea
| | - Ki Cheol Park
- Clinical Research Institute, College of Medicine, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Korea
| | - Keum-Jin Yang
- Clinical Research Institute, College of Medicine, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Korea
| | - Eun Joo Cho
- Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Correspondence to Eun Joo Cho, M.D. Division of Cardiology, Department of Internal Medicine, College of Medicine, Yeouido St. Mary’s Hospital, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Korea Tel: +82-2-3779-1335 Fax: +82-2-780-9114 E-mail:
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25
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Chen E, Li E, Liu H, Zhou Y, Wen L, Wang J, Wang Y, Ye L, Liang T. miR-26b enhances the sensitivity of hepatocellular carcinoma to Doxorubicin via USP9X-dependent degradation of p53 and regulation of autophagy. Int J Biol Sci 2021; 17:781-795. [PMID: 33767588 PMCID: PMC7975695 DOI: 10.7150/ijbs.52517] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/16/2021] [Indexed: 12/30/2022] Open
Abstract
Multi-drug resistance is a major challenge to hepatocellular carcinoma (HCC) treatment, and the over-expression or deletion of microRNA (miRNA) expression is closely related to the drug-resistant properties of various cell lines. However, the underlying molecular mechanisms remain unclear. CCK-8, EdU, flow cytometry, and transmission electron microscopy were performed to determine cell viability, proliferation, apoptosis, autophagic flow, and nanoparticle characterization, respectively. In this study, the results showed that the expression of miR-26b was downregulated following doxorubicin treatment in human HCC tissues. An miR-26b mimic enhanced HCC cell doxorubicin sensitivity, except in the absence of p53 in Hep3B cells. Delivery of the proteasome inhibitor, MG132, reversed the inhibitory effect of miR-26b on the level of p53 following doxorubicin treatment. Tenovin-1 (an MDM2 inhibitor) protected p53 from ubiquitination-mediated degradation only in HepG2 cells with wild type p53. Tenovin-1 pretreatment enhanced HCC cell resistance to doxorubicin when transfected with an miR-26b mimic. Moreover, the miR-26b mimic inhibited doxorubicin-induced autophagy and the autophagy inducer, rapamycin, eliminated the differences in the drug sensitivity effect of miR-26b. In vivo, treatment with sp94dr/miR-26b mimic nanoparticles plus doxorubicin inhibited tumor growth. Our current data indicate that miR-26b enhances HCC cell sensitivity to doxorubicin through diminishing USP9X-mediated p53 de-ubiquitination caused by DNA damaging drugs and autophagy regulation. This miRNA-mediated pathway that modulates HCC will help develop novel therapeutic strategies.
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Affiliation(s)
- Enjiang Chen
- The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Enliang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Liu
- Department of Medical Oncology, Tongde hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China
| | - Yue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
- Department of Medical Oncology, Tongde hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Tingbo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Disease, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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27
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Nomura K, Kitanaka A, Iwama H, Tani J, Nomura T, Nakahara M, Ohura K, Tadokoro T, Fujita K, Mimura S, Yoneyama H, Kobara H, Morishita A, Okano K, Suzuki Y, Tsutsi K, Himoto T, Masaki T. Association between microRNA-527 and glypican-3 in hepatocellular carcinoma. Oncol Lett 2021; 21:229. [PMID: 33613718 PMCID: PMC7856685 DOI: 10.3892/ol.2021.12490] [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: 09/27/2019] [Accepted: 09/19/2020] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to identify the specific microRNAs (miRNAs/miRs) and their corresponding target genes involved in hepatocellular carcinomas (HCCs). Microarray analysis was performed to examine the miRNA expression profiles of four paired HCC and corresponding non-cancerous (N) liver tissues using 985 miRNA probes. The Human miRNA Target database was used to identify the target genes of differentially expressed miRNAs between the HCC and N tissues. The protein expression levels of target genes in the HCC tissues and cell lines were evaluated using western blotting. miRNA-mediated suppression of target gene expression was evaluated by transiently transfecting the miRNA into the HCC cell lines. Of the 985 miRNAs evaluated, four miRNAs were differentially expressed (three upregulated and one downregulated miRNAs). Of these four miRNAs, miRNA-527 was highly downregulated in the HCC tissues. Glypican-3 (GPC-3) was predicted as a target gene of miRNA-527. Western blotting revealed that GPC-3 protein is highly expressed in the HCC tissues and HCC cell lines compared with N and normal cell lines. Transfection with miR-527 resulted in suppression of GPC-3 protein expression in the Cos7 cells. Furthermore, transfection with miR-527 also inhibited the intrinsic expression of GPC-3 in the Huh-7 cell line. This indicated that miR-527 in the HCC tissues may be an important novel miRNA that targets the GPC-3 gene expression. GPC-3, whose expression is regulated by miR-527, may be involved in the development and progression of HCC.
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Affiliation(s)
- Kei Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Akira Kitanaka
- Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Hisakazu Iwama
- Information Technology Center, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Kyoko Ohura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Kunihiko Tsutsi
- Department of Healthy Science, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Clinical Examination, Faculty of Health Sciences, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
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MALAT1 sponges miR-26a and miR-26b to regulate endothelial cell angiogenesis via PFKFB3-driven glycolysis in early-onset preeclampsia. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:897-907. [PMID: 33614238 PMCID: PMC7868745 DOI: 10.1016/j.omtn.2021.01.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 01/10/2021] [Indexed: 11/20/2022]
Abstract
6-phosphofructo-2-kinase (PFKFB3) is a crucial regulator of glycolysis that has been implicated in angiogenesis and the development of diverse diseases. However, the functional role and regulatory mechanism of PFKFB3 in early-onset preeclampsia (EOPE) remain to be elucidated. According to previous studies, noncoding RNAs play crucial roles in EOPE pathogenesis. The goal of this study was to investigate the functional roles and co-regulatory mechanisms of the metastasis-associated lung adenocarcinoma transcript-1 (MALAT1)/microRNA (miR)-26/PFKFB3 axis in EOPE. In our study, decreased MALAT1 and PFKFB3 expression in EOPE tissues correlates with endothelial cell (EC) dysfunction. The results of in vitro assays revealed that PFKFB3 regulates the proliferation, migration, and tube formation of ECs by modulating glycolysis. Furthermore, MALAT1 regulates PFKFB3 expression by sponging miR-26a/26b. Finally, MALAT1 knockout reduces EC angiogenesis by inhibiting PFKFB3-mediated glycolysis flux, which is ameliorated by PFKFB3 overexpression. In conclusion, decreased MALAT1 expression in EOPE tissues reduces the glycolysis of ECs in a PFKFB3-dependent manner by sponging miR-26a/26b and inhibits EC proliferation, migration, and tube formation, which may contribute to abnormal angiogenesis in EOPE. Thus, strategies targeting PFKFB3-driven glycolysis may be a promising approach for the treatment of EOPE.
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Li C, Li Y, Lu Y, Niu Z, Zhao H, Peng Y, Li M. miR-26 family and its target genes in tumorigenesis and development. Crit Rev Oncol Hematol 2021; 157:103124. [PMID: 33254041 DOI: 10.1016/j.critrevonc.2020.103124] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 08/27/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
The microRNA-26 family, including miR-26a, miR-26b, miR-1297 and miR-4465, is a group of broadly conserved small RNAs with identical sequences at the seed region. The expression of miR-26 could be induced by hypoxia via a HIF-dependent mechanism, and up-regulated during multiple cell differentiation. Accumulating studies have demonstrated that miR-26 family members could be detected in many different kinds of tumors, and their validated target genes are involved in cell metabolism, proliferation, differentiation, apoptosis, invasion and metastasis. The expression of miR-26 might be a potentially valuable biomarker and a new target for cancer therapy. In this review, miR-26 family and its target genes in tumorigenesis and development will be summarized as follows.
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Affiliation(s)
- Chuangang Li
- The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China.
| | - Yongyi Li
- University of Virginia, Charlottesville, VA 22903, USA
| | - Yufeng Lu
- Dalian Medical University, Dalian 116044, China
| | - Zhaorui Niu
- Dalian Medical University, Dalian 116044, China
| | - Henan Zhao
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Yan Peng
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Molin Li
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
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Tumor suppressor properties of the small C-terminal domain phosphatases in non-small cell lung cancer. Biosci Rep 2020; 39:221348. [PMID: 31774910 PMCID: PMC6911153 DOI: 10.1042/bsr20193094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/17/2019] [Accepted: 11/19/2019] [Indexed: 02/07/2023] Open
Abstract
Non-Small Cell Lung Cancer (NSCLC) is responsible for the majority of deaths caused by cancer. Small C-terminal domain (CTD) phosphatases (SCP), CTDSP1, CTDSP2 and CTDSPL (CTDSPs) belong to SCP/CTDSP subfamily and are involved in many vital cellular processes and tumorigenesis. High similarity of their structures suggests similar functions. However their role in NSCLC remains insufficiently understood. For the first time we revealed the suppressor function of CTDSPs leading to a significant growth slowdown and senescence of A549 lung adenocarcinoma (ADC) cells in vitro. Their tumor-suppressive activity can be realized through increasing the proportion of the active form of Rb protein dephosphorylated at Ser807/811, Ser780, and Ser795 (P<0.05) thereby negatively regulating cancer cell proliferation. Moreover, we observed that a frequent (84%, 39/46) and highly concordant (Spearman's rank correlation coefficient (rs) = 0.53-0.62, P≤0.01) down-regulation of CTDSPs and RB1 is characteristic of primary NSCLC samples (n=46). A clear difference in their mRNA levels was found between lung ADCs with and without lymph node metastases, but not in squamous cell carcinomas (SCCs) (P≤0.05). Based on The Cancer Genome Atlas (TCGA) data and the results obtained using the CrossHub tool, we suggest that the well-known oncogenic cluster miR-96/182/183 could be a common expression regulator of CTDSPs. Indeed, according to our qPCR, the expression of CTDSPs negatively correlates with these miRs, but positively correlates with their intronic miR-26a/b. Our results reflect functional association of CTDSP1, CTDSP2, and CTDSPL, expand knowledge about their suppressor properties through Rb dephosphorylation and provide new insights into the regulation of NSCLC growth.
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Li L, Li H, Tian Y, Hu M, Le F, Wang L, Liu X, Jin F. Differential microRNAs expression in seminal plasma of normospermic patients with different sperm DNA fragmentation indexes. Reprod Toxicol 2020; 94:8-12. [PMID: 32259568 DOI: 10.1016/j.reprotox.2020.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 03/17/2020] [Accepted: 03/21/2020] [Indexed: 11/30/2022]
Abstract
Sperm DNA fragmentation index (SDF), as an important supplement to routine semen parameters, has been proposed to discriminate between fertile and infertile men, and predicts the outcomes of natural conception and in vitro fertilization. Unfortunately there are uncertainty and contradictory evidences regarding the importance of SDF. An important reason is the fact that significant and fundamental research about SDF is rare. This study was designed to characterize the microRNA (miRNA) expression profile in seminal plasma of normospermic patients with different SDF and their implications in human fertility. Using next-generation sequencing (NGS), a total of 897 human miRNAs were detected from 10 seminal plasma samples, out of which 431 differentially expressed miRNAs in 5 pairs of seminal plasma samples (each pair of seminal plasma samples obtained from the same male), with 14 miRNAs were identified in all the pairs. According to the fold change and expression level, 7 miRNAs including miR-374b-5p, miR-429, hsa-miR-26b-5p, miR-21-5p, miR-4257, miR-135b-5p and miR-134-5p were selected for further excavation. MiR-374b-5p and miR-26b-5p were significantly different in 3 sets of individual seminal plasma samples with different SDF from total 90 infertile patients (30 patients each set). Our results demonstrate that the profile of miR-374b and miR-26b with significantly decreased expression could be used as a first indication of increased SDF. And miR-374b and miR-26b could serve as adjunct biomarkers for the diagnosis of idiopathic infertile males.
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Affiliation(s)
- Lejun Li
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hongping Li
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yonghong Tian
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Minhao Hu
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fang Le
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liya Wang
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaozhen Liu
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fan Jin
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou, China.
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Wei Z, Chang K, Fan C, Zhang Y. MiR-26a/miR-26b represses tongue squamous cell carcinoma progression by targeting PAK1. Cancer Cell Int 2020; 20:82. [PMID: 32190006 PMCID: PMC7071636 DOI: 10.1186/s12935-020-1166-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/04/2020] [Indexed: 12/13/2022] Open
Abstract
Background Tongue squamous cell carcinoma (TSCC) is the most common oral malignancy. Previous studies found that microRNA (miR)-26a and miR-26b were downregulated in TSCC tissues. The current study was designed to explore the effects of miR-26a/miR-26b on TSCC progression and the potential mechanism. Methods Expression of miR-26a, miR-26b and p21 Activated Kinase 1 (PAK1) in TSCC tissues and cell lines was detected by reverse transcription- quantitative polymerase chain reaction (RT-qPCR). Flow cytometry analysis was performed to examine cell cycle and apoptosis. Transwell assay was conducted to evaluate the migrated and invasive abilities of SCC4 and Cal27 cells. In addition, western blot assay was employed to analyze the protein level. Glucose assay kit and lactate assay kit were utilized to analyze glycolysis. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were applied to explore the relationship between miR-26a/miR-26b and PAK1. Xenograft tumor model was constructed to explore the role of miR-26a/miR-26b in vivo. Results Both miR-26a and miR-26b were underexpressed, while PAK1 was highly enriched in TSCC. Overexpression of miR-26a and miR-26b inhibited TSCC cell cycle, migration invasion and glycolysis, while promoted cell apoptosis. Both miR-26a and miR-26b directly targeted and negatively regulated PAK1 expression. Introduction of PAK1 partially reversed miR-26a/miR-26b upregulation-mediated cellular behaviors in TSCC cells. Gain of miR-26a/miR-26b blocked TSCC tumor growth in vivo. Conclusion MiR-26a/miR-26b repressed TSCC progression via targeting PAK1 in vitro and in vivo, which enriched our understanding about TSCC development and provided new insights into the its treatment.
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Affiliation(s)
- Zhenxing Wei
- Department of Otorhinolaryngology-Head and Neck Surgery, The Luoyang Central Hospital Affiliated to Zhengzhou University, No. 288 Middle Zhongzhou Road, Xigong District, Luoyang, 471000 Henan China
| | - Kunpeng Chang
- Department of Otorhinolaryngology-Head and Neck Surgery, The Luoyang Central Hospital Affiliated to Zhengzhou University, No. 288 Middle Zhongzhou Road, Xigong District, Luoyang, 471000 Henan China
| | - Chongsheng Fan
- Department of Otorhinolaryngology-Head and Neck Surgery, The Luoyang Central Hospital Affiliated to Zhengzhou University, No. 288 Middle Zhongzhou Road, Xigong District, Luoyang, 471000 Henan China
| | - Yang Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, The Luoyang Central Hospital Affiliated to Zhengzhou University, No. 288 Middle Zhongzhou Road, Xigong District, Luoyang, 471000 Henan China
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Zhang Z, Huang J, Wang G, Jin F, Zheng J, Xiao H, Lei L, Luo J, Chen C. Serum miRNAs, a potential prognosis marker of loco-regionally advanced nasopharyngeal carcinoma patients treated with CCRT. BMC Cancer 2020; 20:183. [PMID: 32131777 PMCID: PMC7057605 DOI: 10.1186/s12885-020-6689-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 02/27/2020] [Indexed: 12/26/2022] Open
Abstract
Background Serum miRNA was once found as potential disease survival index,thus we investigated the role of miRNA in predicting prognosis in loco-regionally advanced NPC patients treated with CCRT. Methods This study included two phases: (i) We enrolled 3 NPC patients with recurrence or distant metastasis (experimental group, EG) and 3 NPC patients in clinical remission (control group, CG),who were treated with CCRT within 5 years. The paired serum was collected before and after treatment and biomarkers were discovered by LNA-TaqMan Human MicroRNA Arrays. (ii) we used the bioinformatic analysis, marker selection and an independent validation by qRT-PCR to analyse the serums of 29 NPC patients with recurrent disease or distant metastasis and 19 NPC patients in clinical remission treated with CCRT. Using the Kaplan-Meier method, log-rank test and Cox regression model to estimate the accuracy of the miRNAs to predict PFS and OS, and identified factors significantly associated with prognosis, respectively. Results Using fold change≥2.0 or ≤ 0.5 and p ≤ 0.05 as cutoff levels, we identified 1 up-regulated and 6 down-regulated miRNAs, 1 up-regulated and 9 down-regulated miRNAs in EG versus CG before and after CCRT, respectively. After these down-regulated miRNAs were dealed with bioinformatics analysis and normalization, only 5 different miRNAs were significantly reduced, which there were no significant difference in the expression of miRNA-26b, miRNA-29a and miRNA-125b before CCRT, and the expression of miRNA-143 and miRNA-29b after CCRT in the serum samples of 48 NPC patients. Based on this, we calculated a risk score with the expression of miRNA-26b、miRNA-29a、miRNA-125b、miRNA-29b、miRNA-143 and then classified patients as high or low risk group. Cox regression model suggested that combining miRNA-29a and miRNA-125b before CCRT with miRNA-26b after CCRT was independent prognostic factors for PFS (HR = 3.149, 95%CI:1.018–9.115, p = 0.034), whereas combining the former two is independent for OS (HR = 5.146, 95%CI:1.674–15.817, p = 0.04). Conclusions For loco-regionally advanced NPC patients treated with CCRT, especially high-risk patients- serum miRNAs, such as miRNA-29a, miRNA-125b and miRNA-26b etc., play an important role in predicting prognosis factors of PFS and OS, which will contribute to the strategic direction for future research.
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Affiliation(s)
- Zhimin Zhang
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China.,Department of Oncology, General Hospital of Central Theater Command, People's Liberation Army, Wuhan, 430070, Hubei, China
| | - Jiangbiao Huang
- Medical College, Wuhan University of science and technology, Wuhan, 430065, Hubei, China
| | - Ge Wang
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Feng Jin
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Jijun Zheng
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - He Xiao
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Lin Lei
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Jia Luo
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Chuan Chen
- Cancer Center, Institute of Surgery Research, Daping Hospital, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China.
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Du J, Gao R, Wang Y, Nguyen T, Yang F, Shi Y, Liu T, Liao W, Li R, Zhang F, Ge X, Zhao B. MicroRNA-26a/b have protective roles in oral lichen planus. Cell Death Dis 2020; 11:15. [PMID: 31907356 PMCID: PMC6944705 DOI: 10.1038/s41419-019-2207-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/11/2019] [Accepted: 12/12/2019] [Indexed: 12/19/2022]
Abstract
Oral lichen planus (OLP) is a kind of oral epithelial disorder featured with keratinocyte apoptosis and inflammatory reaction. The pathogenesis of OLP remains an enigma. Herein, we showed that the levels of miR-26a/b were robustly down-regulated in oral mucosal biopsies, serum and saliva in OLP patients compared with healthy control. Moreover, we found the binding sites of vitamin D receptor (VDR) in the promoter regions of miR-26a/b genes and proved that the induction of miR-26a/b was VDR dependent. The reduction of miR-26a/b expression was also detected in the oral epithelium of vitamin D deficient or VDR knockout mice. miR-26a/b inhibitors enhanced apoptosis and Type 1T helper (Th1) cells-related cytokines production in oral keratinocytes, whereas miR-26a/b mimics were protective. Mechanistically, we analyzed miRNA target genes and confirmed that miR-26a/b blocked apoptosis by directly targeting Protein Kinase C δ (PKCδ) which promotes cellular apoptotic processes. Meanwhile, miR-26a/b suppressed Th1-related cytokines secretion through targeting cluster of the differentiation 38 (CD38). In accordant with miR-26a/b decreases, PKCδ and CD38 levels were highly elevated in OLP patients’ samples. Taken together, our present investigations suggest that vitamin D/VDR-induced miR-26a/b take protective functions in OLP via both inhibiting apoptosis and impeding inflammatory response in oral keratinocytes.
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Affiliation(s)
- Jie Du
- Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China. .,Institute of Biomedical Research, Shanxi Medical University, Taiyuan, Shanxi, China.
| | - Ruifang Gao
- Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Yimei Wang
- Department of Endodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Tivoli Nguyen
- Division of Biological Sciences, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Fang Yang
- Department of Periodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Yongyan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tianjing Liu
- Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wang Liao
- Department of Cardiology, Hainan General Hospital, Hainan Clinical Medicine Research Institution, Haikou, China
| | - Ran Li
- Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Fang Zhang
- Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Xuejun Ge
- Department of Periodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Bin Zhao
- Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China. .,Department of prosthodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.
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Linck-Paulus L, Hellerbrand C, Bosserhoff AK, Dietrich P. Dissimilar Appearances Are Deceptive-Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma. Cells 2020; 9:E114. [PMID: 31906510 PMCID: PMC7017070 DOI: 10.3390/cells9010114] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/20/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022] Open
Abstract
: In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs-melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these-at first sight-dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.
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Affiliation(s)
- Lisa Linck-Paulus
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany; (L.L.-P.); (C.H.)
| | - Claus Hellerbrand
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany; (L.L.-P.); (C.H.)
- Comprehensive Cancer Center (CCC) Erlangen-EMN, 91054 Erlangen, Germany
| | - Anja K. Bosserhoff
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany; (L.L.-P.); (C.H.)
- Comprehensive Cancer Center (CCC) Erlangen-EMN, 91054 Erlangen, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany; (L.L.-P.); (C.H.)
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
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Zhang K, Zhang B, Bai Y, Dai L. E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma. J Cancer 2020; 11:301-310. [PMID: 31897226 PMCID: PMC6930434 DOI: 10.7150/jca.33983] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 09/18/2019] [Indexed: 12/26/2022] Open
Abstract
Cisplatin is an essential chemotherapy drug in esophageal squamous cell carcinoma (ESCC). Some studies suggested that the expression of E2F1 is increased in ESCC cells after cisplatin treatment, but its mechanism remains obscure. Here, we found that miR-26b is upregulated in ESCC cell lines with cisplatin treatment, and it relies on the expression of E2F1 because E2F1 directly binds to the promoter of the miR-26b gene, thus activating the transcriptional activity of miR-26b. Cell cycle analysis suggested that miR-26b inhibits the G1/S phase transition, thus inhibiting the cell growth of ESCC cells. The cisplatin-induced cycle arrest also closely depends on the expression of miR-26b. In vivo assays revealed that the sensitivity of ESCC cells to cisplatin is decreased when the E2F1/miR-26b pathway is disturbed. A nude mouse xenograft model of cisplatin treatment showed that the tumor volume was increased in the Si-E2F1 group compared with that in the group with cisplatin treatment alone. The effect may be due to the cellular DNA damage response, because that miR-26b could target the mRNA of ATM and Rb genes via binding to their 3'UTRs, thus leading to decreased protein expression of ATM and Rb. In conclusion, our results indicate that E2F1 promotes the chemosensitization to cisplatin in ESCC. The effect may be due to the upregulation of miR-26b because cisplatin-induced cycle arrest depends on miR-26b, which may also disturb the DNA damage response by reducing the expression of ATM and Rb.
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Affiliation(s)
- Kun Zhang
- Department of Pathogenic Biology, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
| | - Bo Zhang
- Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
| | - Yun Bai
- Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
| | - Limeng Dai
- Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China
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MicroRNAs in Animal Models of HCC. Cancers (Basel) 2019; 11:cancers11121906. [PMID: 31805631 PMCID: PMC6966618 DOI: 10.3390/cancers11121906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.
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miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2. J Transl Med 2019; 99:1484-1500. [PMID: 31201367 DOI: 10.1038/s41374-019-0270-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/23/2019] [Accepted: 04/28/2019] [Indexed: 12/13/2022] Open
Abstract
A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.
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Yang J, Lin Y, Huang Y, Jin J, Zou S, Zhang X, Li H, Feng T, Chen J, Zuo Z, Zheng J, Li Y, Gao G, Wu C, Tan W, Lin D. Genome landscapes of rectal cancer before and after preoperative chemoradiotherapy. Am J Cancer Res 2019; 9:6856-6866. [PMID: 31660073 PMCID: PMC6815957 DOI: 10.7150/thno.37794] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 07/29/2019] [Indexed: 12/14/2022] Open
Abstract
Resistance to preoperative chemoradiotherapy (CRT) is a major obstacle to cancer treatment in patients with locally advanced rectal cancer. This study was to explore genome alterations in rectal cancer under CRT stress. Methods: Whole-exome sequencing (WES) was performed on 28 paired tumors collected before and after CRT from the same patients who did not respond to CRT treatment. Somatic point mutations and copy number variations were detected by VarScan2 and Exome CNVs respectively using paired tumor and blood samples. Somatic alterations associated with CRT resistance were inferred considering differences in significantly mutated genes, mutation counts and cancer cell fraction between matched pre- and post-CRT tumors. We employed SignatureAnalyzer to infer mutation signatures and PyClone to decipher clonal evolution and examine intratumoral heterogeneity in tumors before and after CRT. The associations between intratumoral heterogeneity and patients' survival were analyzed using the log-rank test and the Cox regression model. Results: (i) Recurrent mutations in CTDSP2, APC, KRAS, TP53 and NFKBIZ confer selective advantages on cancer cells and made them resistant to CRT treatment. (ii) CRT alters the genomic characteristics of tumors at both the somatic mutation and the copy number variation levels. (iii) CRT-resistant tumors exhibit either a branched or a linear evolution pattern. (iv) Different recurrent mutation signatures in pre-CRT and post-CRT patients implicate mutational processes underlying the evolution of CRT-resistant tumors. (v) High intratumoral heterogeneity in pre- or post-CRT is associated with poor patients' survival. Conclusion: Our study reveals genome landscapes in rectal cancer before and after CRT and tumors evolution under CRT stress. The treatment-associated characteristics are useful for further investigations of CRT resistance in rectal cancer.
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Xu X, Zou H, Luo L, Wang X, Wang G. MicroRNA-9 exerts antitumor effects on hepatocellular carcinoma progression by targeting HMGA2. FEBS Open Bio 2019; 9:1784-1797. [PMID: 31408273 PMCID: PMC6768112 DOI: 10.1002/2211-5463.12716] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/24/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence has demonstrated that the aberrant expression of microRNAs (miRs or miRNAs) may contribute to the initiation and progression of various types of human cancer and may also constitute biomarkers for cancer diagnosis and therapy. However, the specific function of miR‐9 in hepatocellular carcinoma (HCC) remains unclear, and the mechanisms that underlie HCC are incompletely understood. Here, we report that miR‐9 expression was significantly decreased in clinical tumor tissue samples, as well as in a cohort of HCC cell lines. In addition, it was demonstrated that overexpression of miR‐9 suppressed the proliferative and migratory capacity of HCC cells and impaired cell cycle progression. Furthermore, high mobility group AT‐hook 2 (HMGA2) was verified as a downstream target gene of miR‐9 using a luciferase reporter assay. Quantitative RT‐PCR and western blotting implicated HMGA2 in the miR‐9‐mediated reduction of HCC cell growth. In vivo, transfection with miR‐9 mimics down‐regulated the expression of HMGA2, thus leading to a dramatic reduction in tumor growth in a mouse xenograft model. These results suggest that miR‐9 may exert critical antitumor effects on HCC by directly targeting HMGA2, and the miR9/HMGA2 signaling pathway may be of use for the diagnosis and prognosis of patients with HCC.
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Affiliation(s)
- Xiangang Xu
- Department of Hepatobiliary Surgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Haibo Zou
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Lanyun Luo
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiankui Wang
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Guan Wang
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
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Dai X, Chen C, Xue J, Xiao T, Mostofa G, Wang D, Chen X, Xu H, Sun Q, Li J, Wei Y, Chen F, Quamruzzaman Q, Zhang A, Liu Q. Exosomal MALAT1 derived from hepatic cells is involved in the activation of hepatic stellate cells via miRNA-26b in fibrosis induced by arsenite. Toxicol Lett 2019; 316:73-84. [PMID: 31513886 DOI: 10.1016/j.toxlet.2019.09.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 07/28/2019] [Accepted: 09/08/2019] [Indexed: 12/15/2022]
Abstract
In the liver microenvironment, interactions among diverse types of hepatic cells are involved in liver fibrosis. In fibrotic tissues, exosomes act as transporters in intercellular communication. Long non-coding RNAs (lncRNAs) are involved in the activation of hepatic stellate cells (HSCs), which are participants in liver fibrosis. However, the functions of exosomal lncRNAs in liver fibrosis induced by arsenite are undefined. The purposes of the present study were (a) to determine if lncRNAs secreted from human hepatic (L-02) cells exposed to arsenite are shuttled to hepatic stellate LX-2 cells and (b) to establish their effects on LX-2 cells. In mice, MALAT1 was overexpressed in the progression of liver fibrosis induced by arsenite as well as in L-02 cells exposed to arsenite. Co-cultures with arsenite-treated L-02 cells induced the activation of LX-2 cells and overexpression of MALAT1. Arsenite-treated L-02 cells transported MALAT1 into LX-2 cells. Downregulation of MALAT1, which reduced the MALAT1 levels in exosomes derived from arsenite-treated L-02 cells, inhibited the activation of LX-2 cells. Additionally, exosomal MALAT1 derived from arsenite-treated L-02 cells promoted the activation of LX-2 cells via microRNA-26b regulation of COL1A2. Furthermore, circulating exosomal MALAT1 was up-regulated in people exposed to arsenite. In sum, exosomes derived from arsenite-treated hepatic cells transferred MALAT1 to HSCs, which induced their activation. These findings support the concept that, during liver fibrosis induced by arsenite, exosomal lncRNAs are involved in cell-cell communication.
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Affiliation(s)
- Xiangyu Dai
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Chao Chen
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, people's Republic of China
| | - Junchao Xue
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Tian Xiao
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Golam Mostofa
- Dhaka Community Hospital Trust, Dhaka 1217, Bangladesh
| | - Dapeng Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, People's Republic of China
| | - Xiong Chen
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, People's Republic of China
| | - Hui Xu
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Qian Sun
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Junjie Li
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Yongyue Wei
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Feng Chen
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | | | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, People's Republic of China
| | - Qizhan Liu
- Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
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Snezhkina AV, Lukyanova EN, Fedorova MS, Kalinin DV, Melnikova NV, Stepanov OA, Kiseleva MV, Kaprin AD, Pudova EA, Kudryavtseva AV. Novel Genes Associated with the Development of Carotid Paragangliomas. Mol Biol 2019. [DOI: 10.1134/s0026893319040137] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Asghariazar V, Sakhinia E, Mansoori B, Mohammadi A, Baradaran B. Tumor suppressor microRNAs in lung cancer: An insight to signaling pathways and drug resistance. J Cell Biochem 2019; 120:19274-19289. [DOI: 10.1002/jcb.29295] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 06/27/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Vahid Asghariazar
- Department of Medical Genetics, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
- Immunology Research Center Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Ebrahim Sakhinia
- Department of Medical Genetics, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | - Behzad Mansoori
- Immunology Research Center Tabriz University of Medical Sciences Tabriz Iran
- Aging Research Institute, Physical Medicine and Rehabilitation Research Center Tabriz University of Medical Sciences Tabriz Iran
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine University of Southern Denmark Odense Denmark
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine University of Southern Denmark Odense Denmark
| | - Behzad Baradaran
- Immunology Research Center Tabriz University of Medical Sciences Tabriz Iran
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Wang CJ, Zhu CC, Xu J, Wang M, Zhao WY, Liu Q, Zhao G, Zhang ZZ. The lncRNA UCA1 promotes proliferation, migration, immune escape and inhibits apoptosis in gastric cancer by sponging anti-tumor miRNAs. Mol Cancer 2019; 18:115. [PMID: 31272462 PMCID: PMC6609402 DOI: 10.1186/s12943-019-1032-0] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 05/22/2019] [Indexed: 12/21/2022] Open
Abstract
Background UCA1 is a long non-coding RNA which was found overexpressed in various human cancers including gastric cancer (GC). It is identified that UCA1 promotes GC cells proliferation, migration and invasion, however, the role of UCA1 during the processes of immune escape is still not unclear. Methods We collected 40 paired GC and non-tumor tissue samples. The level of UCA1 in GC and control tissue samples were determined by in situ hybridization and qRT-PCR. Cell viability was determined by MTT assay. GC cells’ migration capacities were examined by transwell assay. To understand the roles of UCA1 during immune escape, wildtype or UCA1 KO GC cells co-cultured with peripheral blood mononuclear cells or cytokine-induced killer cells in vitro. Mouse model was used to examine the function of UCA1 in vivo. Results UCA1 promoted GC cells proliferation and migration, and inhibit apoptosis. UCA1 repressed miR-26a/b, miR-193a and miR-214 expression through direct interaction and then up-regulated the expression of PDL1. UCA1-KO GC cells could induce a higher IFNγ expression when co-cultured with peripheral blood mononuclear cells (PBMCs), and have a lower survival rate when co-cultured with cytokine-induced killer (CIK) cells in vitro. UCA1-KO GC cells formed smaller tumors, had higher miR-26a, −26b, −193a and − 214 level, reduced cell proliferation and increased apoptosis in xenograft mouse model. Conclusions UCA1 overexpression protected PDL1 expression from the repression of miRNAs and contributed to the GC cells immune escape. UCA1 could serve as a potential novel therapeutic target for GC treatment. Electronic supplementary material The online version of this article (10.1186/s12943-019-1032-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chao-Jie Wang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Chun-Chao Zhu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Jia Xu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Wen-Yi Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Qiang Liu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China
| | - Zi-Zhen Zhang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, China.
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Wang Y, Liu J, Yang J, Yu X, Chen Z, Chen Y, Kuang M, Zhu Y, Zhuang S. Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation. Hepatology 2019; 70:259-275. [PMID: 30865310 PMCID: PMC6618099 DOI: 10.1002/hep.30613] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 03/10/2019] [Indexed: 12/22/2022]
Abstract
Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been functionally characterized. Here, we identified an oncogenic lncRNA, named lnc-UCID (lncRNA up-regulating CDK6 by interacting with DHX9). Lnc-UCID was up-regulated in hepatocellular carcinoma (HCC), and a higher lnc-UCID level was correlated with shorter recurrence-free survival of HCC patients. Both gain-of-function and loss-of function studies revealed that lnc-UCID enhanced cyclin-dependent kinase 6 (CDK6) expression and thereby promoted G1/S transition and cell proliferation. Studies from mouse xenograft models revealed that tumors derived from lnc-UCID-silenced HCC cells had a much smaller size than those from control cells, and intratumoral injection of lnc-UCID small interfering RNA suppressed xenograft growth. Mechanistically, the 850-1030-nt domain of lnc-UCID interacted physically with DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), an RNA helicase. On the other hand, DHX9 post-transcriptionally suppressed CDK6 expression by binding to the 3'-untranslated region (3'UTR) of CDK6 mRNA. Further investigation disclosed that lnc-UCID enhanced CDK6 expression by competitively binding to DHX9 and sequestering DHX9 from CDK6-3'UTR. In an attempt to explore the mechanisms responsible for lnc-UCID up-regulation in HCC, we found that the lnc-UCID gene was frequently amplified in HCC. Furthermore, miR-148a, whose down-regulation was associated with an increase of lnc-UCID in HCC, could bind lnc-UCID and inhibit its expression. Conclusion: Up-regulation of lnc-UCID, which may result from amplification of its gene locus and down-regulation of miR-148a, can promote HCC growth by preventing the interaction of DHX9 with CDK6 and subsequently enhancing CDK6 expression. These findings provide insights into the biological functions of lncRNAs, the regulatory network of cell cycle control, and the mechanisms of HCC development, which may be exploited for anticancer therapy.
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Affiliation(s)
- Yun‐Long Wang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Jin‐Yu Liu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Jin‐E Yang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina,Key Laboratory of Liver Disease of Guangdong ProvinceThe Third Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Xiao‐Man Yu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Zhan‐Li Chen
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Ya‐Jing Chen
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Ming Kuang
- Department of Liver SurgeryThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Ying Zhu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Shi‐Mei Zhuang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen UniversityGuangzhouChina,Key Laboratory of Liver Disease of Guangdong ProvinceThe Third Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
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Li X, Pan X, Fu X, Yang Y, Chen J, Lin W. MicroRNA-26a: An Emerging Regulator of Renal Biology and Disease. Kidney Blood Press Res 2019; 44:287-297. [PMID: 31163420 DOI: 10.1159/000499646] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that modulate many key biological processes by simultaneously suppressing multiple target genes. Among them, miR-26a, a conserved miRNA among vertebrates, is highly expressed in various tissues. Accumulating evidence demonstrates that miR-26a plays pivotal roles in cellular differentiation, cell growth, apoptosis, and metastasis, thereby participating in the initiation and development of various human diseases, such as metabolic disease and cancer. More recently, miR-26a was found as a versatile regulator of renal biology and disease. miR-26a is intensively involved in the maintenance of podocyte homeostasis and the actin cytoskeleton. It is also able to modulate the homeostasis and function of mesangial cells. In addition, miR-26a affects the expansion of regulatory T cells in the context of ischemia-reperfusion injury and autoimmune diabetes and thus protects the renal system from immune attack. These available data strongly suggest that renal miR-26a possesses critical pathological functions and represents a potential target for renal disease therapies. This review summarizes current knowledge of miR-26a in renal biology and disease, laying the foundation for exploring its previously unknown functions and mechanisms in the renal system.
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Affiliation(s)
- Xiaoyan Li
- Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Pan
- Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianghui Fu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Yang
- Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiqiang Lin
- Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, .,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China,
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Toh TB, Lim JJ, Chow EKH. Epigenetics of hepatocellular carcinoma. Clin Transl Med 2019; 8:13. [PMID: 31056726 PMCID: PMC6500786 DOI: 10.1186/s40169-019-0230-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 04/08/2019] [Indexed: 12/13/2022] Open
Abstract
In recent years, large scale genomics and genome-wide studies using comprehensive genomic tools have reshaped our understanding of cancer evolution and heterogeneity. Hepatocellular carcinoma, being one of the most deadly cancers in the world has been well established as a disease of the genome that harbours a multitude of genetic and epigenetic aberrations during the process of liver carcinogenesis. As such, in depth understanding of the cancer epigenetics in cancer specimens and biopsy can be useful in clinical settings for molecular subclassification, prognosis, and prediction of therapeutic responses. In this review, we present a concise discussion on recent progress in the field of liver cancer epigenetics and some of the current works that contribute to the progress of liver cancer therapeutics.
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Affiliation(s)
- Tan Boon Toh
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore
| | - Jhin Jieh Lim
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore. .,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Level 5, Singapore, 117597, Singapore.
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Lin H, Zhang Z. Diagnostic value of a microRNA signature panel in exosomes for patients with hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:1478-1487. [PMID: 31933965 PMCID: PMC6947065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 02/22/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide and the second most frequent cause of cancer death. The aim of this study is to investigate the early diagnostic value of a panel of peripheral blood exosomal micro-RNAs (miRNAs) in patients with HCC compared with patients with Hepatitis B virus (HBV) and hepatocirrhosis. PATIENTS AND METHODS Blood samples from 72 patients with HCC, 72 patients with hepatocirrhosis and 72 patients with HBV were obtained at Beijing Friendship Hospital, Capital Medical University. The miRNA expression levels were detected by real-time polymerase chain reaction (RT-PCR). Areas under curve (AUCs) were used to compare diagnostic values of plasmic and exosomal miRNAs. RESULTS We screened plasmic and exosomal solutions of 3 HCC, 3 cirrhosis and 3 HBV patients to perform miRNA microarray analysis. Three distinctly differential microRNAs including miRNA-26a, miRNA-29c, and miRNA-21 were selected to perform further evaluation. First, we found that the expressions of miRNA-26a, miRNA-29c, and miRNA-21 were significantly lower in patients with HCC compared with cirrhotic and HBV group in both exosomes and plasma. Second, we found miRNA-26a, miRNA-29c, and miRNA-21 were significantly down-regulated in HCC tumor tissues compared with normal tissues. Thirdly, we found miRNAs in exosomes had better diagnostic value for patients with HCC compared with plasmic miRNAs among different groups. CONCLUSIONS In conclusion, we found that the expression of miRNA-26a, miRNA-29c, and miRNA-21 were significantly lower in patients with HCC, and we confirmed miRNA-26a, miRNA-29c, and miRNA-21 could be identified as independent diagnostic biomarkers for patients with HCC.
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Affiliation(s)
- Huajun Lin
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University Beijing, People's Republic of China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University Beijing, People's Republic of China
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Stefan-Lifshitz M, Karakose E, Cui L, Ettela A, Yi Z, Zhang W, Tomer Y. Epigenetic modulation of β cells by interferon-α via PNPT1/mir-26a/TET2 triggers autoimmune diabetes. JCI Insight 2019; 4:126663. [PMID: 30721151 DOI: 10.1172/jci.insight.126663] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 01/29/2019] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β cells. Mounting evidence supports a central role for β cell alterations in triggering the activation of self-reactive T cells in T1D. However, the early deleterious events that occur in β cells, underpinning islet autoimmunity, are not known. We hypothesized that epigenetic modifications induced in β cells by inflammatory mediators play a key role in initiating the autoimmune response. We analyzed DNA methylation (DNAm) patterns and gene expression in human islets exposed to IFN-α, a cytokine associated with T1D development. We found that IFN-α triggers DNA demethylation and increases expression of genes controlling inflammatory and immune pathways. We then demonstrated that DNA demethylation was caused by upregulation of the exoribonuclease, PNPase old-35 (PNPT1), which caused degradation of miR-26a. This in turn promoted the upregulation of ten-eleven translocation 2 (TET2) enzyme and increased 5-hydroxymethylcytosine levels in human islets and pancreatic β cells. Moreover, we showed that specific IFN-α expression in the β cells of IFNα-INS1CreERT2 transgenic mice led to development of T1D that was preceded by increased islet DNA hydroxymethylation through a PNPT1/TET2-dependent mechanism. Our results suggest a new mechanism through which IFN-α regulates DNAm in β cells, leading to changes in expression of genes in inflammatory and immune pathways that can initiate islet autoimmunity in T1D.
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Affiliation(s)
- Mihaela Stefan-Lifshitz
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
| | | | - Lingguang Cui
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
| | - Abora Ettela
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
| | - Zhengzi Yi
- Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Weijia Zhang
- Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yaron Tomer
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
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50
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Andrew AS, Karagas MR, Schroeck FR, Marsit CJ, Schned AR, Pettus JR, Armstrong DA, Seigne JD. MicroRNA Dysregulation and Non-Muscle-Invasive Bladder Cancer Prognosis. Cancer Epidemiol Biomarkers Prev 2019; 28:782-788. [PMID: 30700445 DOI: 10.1158/1055-9965.epi-18-0884] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/20/2018] [Accepted: 01/23/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The high rate of non-muscle-invasive bladder cancer recurrence is a major challenge in patient management. miRNAs functionally regulate tumor cell proliferation and invasion, and have strong potential as biomarkers because they are robust to degradation. The objective of this project was to identify reproducible prognostic miRNAs in resected non-muscle-invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype. METHODS We utilized patients diagnosed with primary non-muscle-invasive bladder cancer in three independent cohorts for a biomarker discovery/validation approach. Baseline tumor tissue from patients with the clinically challenging, non-muscle-invasive primary low stage (Ta), high grade, and T1 tumors (tumors extending into the lamina propria) comprised the discovery cohort (n = 38). We isolated the tumor tissue RNA and assessed a panel of approximately 800 miRNAs. RESULTS miR-26b-5p was the top-ranking prognostic tumor tissue miRNA, with a time-to-recurrence HR 0.043 for levels above versus below median, (P adj = 0.0003). miR-26b-5p was related to a dose-response reduction in tumor recurrence, and levels above the median were also associated with reduced time-to-progression (P adj = 0.02). We used two independent longitudinal cohorts that included both low-grade and high-grade Ta and T1 tumors for validation and found a consistent relationship between miR-26b-5p and recurrence and progression. CONCLUSIONS Our results suggest that miR-26b-5p levels may be prognostic for non-muscle-invasive bladder cancer recurrence, and can feasibly be assessed in baseline tumor tissue from a wide variety of clinical settings. IMPACT Early identification of those non-muscle-invasive bladder tumor patients with refractory phenotypes would enable individualized treatment and surveillance.
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Affiliation(s)
- Angeline S Andrew
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
| | - Margaret R Karagas
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Florian R Schroeck
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth and White River Junction VA Medical Center, White River Junction, Vermont
| | - Carmen J Marsit
- Department of Environmental Health and Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Alan R Schned
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Jason R Pettus
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - David A Armstrong
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - John D Seigne
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
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