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Chaudhary R, Weiskirchen R, Ehrlich M, Henis YI. Dual signaling pathways of TGF-β superfamily cytokines in hepatocytes: balancing liver homeostasis and disease progression. Front Pharmacol 2025; 16:1580500. [PMID: 40260391 PMCID: PMC12009898 DOI: 10.3389/fphar.2025.1580500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 03/25/2025] [Indexed: 04/23/2025] Open
Abstract
The transforming growth factor-β (TGF-β) superfamily (TGF-β-SF) comprises over 30 cytokines, including TGF-β, activins/inhibins, bone morphogenetic proteins (BMPs), and growth differentiation factors (GDFs). These cytokines play critical roles in liver function and disease progression. Here, we discuss Smad-dependent (canonical) and non-Smad pathways activated by these cytokines in a hepatocellular context. We highlight the connection between the deregulation of these pathways or the balance between them and key hepatocellular processes (e.g., proliferation, apoptosis, and epithelial-mesenchymal transition (EMT)). We further discuss their contribution to various chronic liver conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC). In MASLD and MASH, TGF-β signaling contributes to hepatocyte lipid accumulation, cell death and fibrosis progression through both Smad and non-Smad pathways. In HCC, TGF-β and other TGF-β-SF cytokines have a dual role, acting as tumor suppressors or promoters in early vs. advanced stages of tumor progression, respectively. Additionally, we review the involvement of non-Smad pathways in modulating hepatocyte responses to TGF-β-SF cytokines, particularly in the context of chronic liver diseases, as well as the interdependence with other key pathways (cholesterol metabolism, insulin resistance, oxidative stress and lipotoxicity) in MASLD/MASH pathogenesis. The perspectives and insights detailed in this review may assist in determining future research directions and therapeutic targets in liver conditions, including chronic liver diseases and cancer.
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Affiliation(s)
- Roohi Chaudhary
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Marcelo Ehrlich
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Yoav I. Henis
- Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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2
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Wang X, Liu Y, Zhang S, Zhang J, Lin X, Liang Y, Zong M, Hanley KL, Lee J, Karin M, Feng GS. Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by oncoprotein loss. Hepatology 2025; 81:1181-1196. [PMID: 39397357 DOI: 10.1097/hep.0000000000001037] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 07/10/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND AND AIMS The chemical carcinogen diethylnitrosamine (DEN) is often used to induce HCC in mice. Curiously, several labs have reported that the removal of oncoproteins from hepatocytes exacerbated DEN-induced HCC, with mechanisms unknown. This study aimed at deciphering molecular mechanisms underlying the tumor suppressive effect of oncoproteins. APPROACH AND RESULTS We generated mutant mouse lines with hepatocyte-specific deletions of Met , Ptpn11 / Shp2 , Ikkβ , or Ctnnb1/β-catenin and assessed DEN-induced tumorigenesis in the wild-type and mutant mice. To systematically examine genetic and molecular signaling alterations, we performed whole exome and RNA-sequencing on liver samples collected at the pre-cancer and established cancer stages. Although the mutational profiles of DEN-induced tumors were barely different in wild-type and mutant mice, oncoprotein ablation increased DEN-induced mutational burdens, especially in Shp2-deficient tumors. RNA-sequencing revealed multiple changes in signaling pathways, in particular, upregulated epithelial-mesenchymal transition, cell migration, and tumor metastasis, as well as downregulated small molecule metabolism that was affected by oncoprotein ablation. We identified key molecules and pathways that are associated with hepatic innate immunity and implicated in liver tumorigenesis. In addition, we unveiled markedly changed expression of a few miRNAs in the human HCC database. CONCLUSIONS The aggravation of DEN-induced HCC progression seen on oncoprotein ablation could be caused by common and distinct genomic and signaling alterations. This study reveals a new level of complexity in hepatocarcinogenesis and elucidates molecular mechanisms underlying tumor evolution and recurrence.
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Affiliation(s)
- Xinyi Wang
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Yingluo Liu
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Shuo Zhang
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Jiemeng Zhang
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Xiaoxue Lin
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Yan Liang
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Min Zong
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Kaisa L Hanley
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Jin Lee
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
| | - Michael Karin
- Departments of Pharmacology and Pathology, University of California at San Diego, La Jolla, California, USA
| | - Gen-Sheng Feng
- Department of Pathology, School of Medicine, La Jolla, California, USA
- Department of Molecular Biology, School of Biological Sciences, La Jolla, California, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, California, USA
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3
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Kura B, Kindernay L, Singla D, Dulova U, Bartekova M. Mechanistic insight into the role of cardiac-enriched microRNAs in diabetic heart injury. Am J Physiol Heart Circ Physiol 2025; 328:H865-H884. [PMID: 40033927 PMCID: PMC12069993 DOI: 10.1152/ajpheart.00736.2024] [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: 10/24/2024] [Revised: 11/12/2024] [Accepted: 02/26/2025] [Indexed: 03/05/2025]
Abstract
Cardiovascular complications, particularly diabetic cardiomyopathy (DCM), are the primary causes of morbidity and mortality among individuals with diabetes. Hyperglycemia associated with diabetes leads to cardiomyocyte hypertrophy, apoptosis, and myocardial fibrosis, culminating in heart failure (HF). Patients with diabetes face a 2-4 times greater risk of developing HF compared with those without diabetes. Consequently, there is a growing interest in exploring the molecular mechanisms that contribute to the development of DCM. MicroRNAs (miRNAs) are short, single-stranded, noncoding RNA molecules that participate in the maintenance of physiological homeostasis through the regulation of essential processes such as metabolism, cell proliferation, and apoptosis. At the posttranscriptional level, miRNAs modulate gene expression by binding directly to genes' mRNAs. Multiple cardiac-enriched miRNAs were reported to be dysregulated under diabetic conditions. Different studies revealed the role of specific miRNAs in the pathogenesis of diabetes and related cardiovascular complications, including cardiomyocyte hypertrophy and fibrosis, mitochondrial dysfunction, metabolic impairment, inflammatory response, or cardiomyocyte death. Circulating miRNAs have been shown to represent the potential biomarkers for early detection of diabetic heart injury. A deeper understanding of miRNAs and their role in diabetes-related pathophysiological processes could lead to new therapeutic strategies for addressing cardiac complications associated with diabetes.
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Affiliation(s)
- Branislav Kura
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lucia Kindernay
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Dinender Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
| | - Ulrika Dulova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Monika Bartekova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
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4
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Al Ageeli E. Dual Roles of microRNA-122 in Hepatocellular Carcinoma and Breast Cancer Progression and Metastasis: A Comprehensive Review. Curr Issues Mol Biol 2024; 46:11975-11992. [PMID: 39590305 PMCID: PMC11592835 DOI: 10.3390/cimb46110711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 11/28/2024] Open
Abstract
microRNA-122 (miR-122) plays crucial yet contrasting roles in hepatocellular carcinoma (HCC) and breast cancer (BC), two prevalent and aggressive malignancies. This review synthesizes current research on miR-122's functions in these cancers, focusing on its potential as a diagnostic, prognostic, and therapeutic target. A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus databases. In HCC, miR-122 is downregulated in most cases, suppressing oncogenic pathways and reducing tumor growth and metastasis. Restoring miR-122 levels has shown promising therapeutic potential, increasing sensitivity to treatments like sorafenib. In contrast, in BC, miR-122 plays a pro-metastatic role, especially in triple-negative breast cancer (TNBC) and metastatic lesions. miR-122's ability to influence key pathways, such as the Wnt/β-catenin and NF-κB pathways in HCC, and its role in enhancing the Warburg effect in BC underline its significance in cancer biology. miR-122, a key factor in breast cancer radioresistance, suppresses tumors in radiosensitive cells. Inhibiting miR-122 could reverse resistance and potentially overcome radiotherapy resistance. Given its context-dependent functions, miR-122 could serve as a potential therapeutic target, where restoring or inhibiting its expression may help in treating HCC and BC, respectively. The dual roles of miR-122 underscore its significance in cancer biology and its potential in precision medicine.
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Affiliation(s)
- Essam Al Ageeli
- Department of Basic Medical Sciences (Medical Genetics), Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia
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5
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Huang N, Fang J, Du F, Zhou J, Li Y, Zhang X. Uncovering essential anesthetics-induced exosomal miRNAs related to hepatocellular carcinoma progression: a bioinformatic investigation. BMC Med Genomics 2024; 17:154. [PMID: 38840234 PMCID: PMC11155038 DOI: 10.1186/s12920-024-01922-7] [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: 12/19/2023] [Accepted: 05/23/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the anesthetics (sevoflurane and propofol) impact the miRNA makeup within exosomes in hepatocellular carcinoma (HCC), alongside the interconnected signaling pathways linked to the tumor immune microenvironment. METHODS In this prospective study, we collected plasma exosomes from two groups of HCC patients (n = 5 each) treated with either propofol or sevoflurane, both before anesthesia and after hepatectomy. Exosomal miRNA profiles were assessed using next-generation sequencing (NGS). Furthermore, the expression data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) was used to pinpoint the differentially expressed exosomal miRNAs (DEmiRNAs) attributed to the influence of propofol or sevoflurane in the context of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to dissect the signaling pathways and biological activities associated with the identified DEmiRNAs and their corresponding target genes. RESULTS A total of 35 distinct DEmiRNAs were exclusively regulated by either propofol (n = 9) or sevoflurane (n = 26). Through TCGA-LIHC database analysis, 8 DEmiRNAs were associated with HCC. These included propofol-triggered miR-452-5p and let-7c-5p, as well as sevoflurane-induced miR-24-1-5p, miR-122-5p, miR-200a-3p, miR-4686, miR-214-3p, and miR-511-5p. Analyses revealed that among these 8 DEmiRNAs, the upregulation of miR-24-1-5p consistently demonstrated a significant association with lower histological grades (p < 0.0001), early-stage tumors (p < 0.05) and higher survival (p = 0.029). Further analyses using GSEA and GSVA indicated that miR-24-1-5p, along with its target genes, were involved in governing the tumor immune microenvironment and potentially inhibiting tumor progression in HCC. CONCLUSIONS This study provided bioinformatics evidence suggesting that sevoflurane-induced plasma exosomal miRNAs may have a potential impact on the immune microenvironment of HCC. These findings established a foundation for future research into mechanistic outcomes in cancer patients.
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Affiliation(s)
- Ning Huang
- Department of anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Jie Fang
- Department of anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Fang Du
- Department of anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Jichuan Zhou
- Department of anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Yuxin Li
- Department of anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Xiaoguang Zhang
- Department of anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
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Qian D, Zhang J, Sun G, Zhang Y, Xu Q, Li J, Li H. Programmable Entropy-Driven Circuit-Cascaded Self-Feedback DNAzyme Network for Ultra-Sensitive Fluorescence and Photoelectrochemical Dual-Mode Biosensing. Anal Chem 2024; 96:7274-7280. [PMID: 38655584 DOI: 10.1021/acs.analchem.4c01168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Inspired by natural DNA networks, programmable artificial DNA networks have become an attractive tool for developing high-performance biosensors. However, there is still a lot of room for expansion in terms of sensitivity, atom economy, and result self-validation for current microRNA sensors. In this protocol, miRNA-122 as a target model, an ultrasensitive fluorescence (FL) and photoelectrochemical (PEC) dual-mode biosensing platform is developed using a programmable entropy-driven circuit (EDC) cascaded self-feedback DNAzyme network. The well-designed EDC realizes full utilization of the DNA strands and improves the atomic economy of the signal amplification system. The unique and rational design of the double-CdSe quantum-dot-released EDC substrate and the cascaded self-feedback DNAzyme amplification network significantly avoids high background signals and enhances sensitivity and specificity. Also, the enzyme-free, programmable EDC cascaded DNAzyme network effectively avoids the risk of signal leakage and enhances the accuracy of the sensor. Moreover, the introduction of superparamagnetic Fe3O4@SiO2-cDNA accelerates the rapid extraction of E2-CdSe QDs and E3-CdSe QDs, which greatly improves the timeliness of sensor signal reading. In addition to the strengths of linear range (6 orders of magnitude) and stability, the biosensor design with dual signal reading makes the test results self-confirming.
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Affiliation(s)
- Defu Qian
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, P. R. China
| | - Jingling Zhang
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, P. R. China
| | - Guoshuai Sun
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, P. R. China
| | - Yuye Zhang
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, P. R. China
| | - Qin Xu
- College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China
| | - Jing Li
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, P. R. China
| | - Hongbo Li
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, P. R. China
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7
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Al-Gazally ME, Khan R, Imran M, Ramírez-Coronel AA, Alshahrani SH, Altalbawy FMA, Turki Jalil A, Romero-Parra RM, Zabibah RS, Shahid Iqbal M, Karampoor S, Mirzaei R. The role and mechanism of action of microRNA-122 in cancer: Focusing on the liver. Int Immunopharmacol 2023; 123:110713. [PMID: 37523968 DOI: 10.1016/j.intimp.2023.110713] [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: 12/14/2022] [Revised: 07/08/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023]
Abstract
microRNA-122 (miR-122) is a highly conserved microRNA that is predominantly expressed in the liver and plays a critical role in the regulation of liver metabolism. Recent studies have shown that miR-122 is involved in the pathogenesis of various types of cancer, particularly liver cancer. In this sense, The current findings highlighted the potential role of miR-122 in regulating many vital processes in cancer pathophysiology, including apoptosis, signaling pathway, cell metabolism, immune system response, migration, and invasion. These results imply that miR-122, which has been extensively studied for its biological functions and potential therapeutic applications, acts as a tumor suppressor or oncogene in cancer development. We first provide an overview and summary of the physiological function and mode of action of miR-122 in liver cancer. We will examine the various signaling pathways and molecular mechanisms through which miR-122 exerts its effects on cancer cells, including the regulation of oncogenic and tumor suppressor genes, the modulation of cell proliferation and apoptosis, and the regulation of metastasis. Most importantly, we will also discuss the potential diagnostic and therapeutic applications of miR-122 in cancer, including the development of miRNA-based biomarkers for cancer diagnosis and prognosis, and the potential use of miR-122 as a therapeutic target for cancer treatment.
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Affiliation(s)
| | - Ramsha Khan
- MBBS, Nawaz Sharif Medical College, Gujrat, Pakistan
| | - Muhammad Imran
- MBBS, Multan Medical and Dental College, Multan, Pakistan
| | | | | | - Farag M A Altalbawy
- National Institute of Laser Enhanced Sciences (NILES), University of Cairo, Giza 12613, Egypt; Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla 51001, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Muhammad Shahid Iqbal
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, 11942 Alkharj, Saudi Arabia
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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8
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Shao JL, Wang LJ, Xiao J, Yang JF. Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury. World J Gastroenterol 2023; 29:4927-4941. [PMID: 37731999 PMCID: PMC10507504 DOI: 10.3748/wjg.v29.i33.4927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/22/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the major complication of liver surgery and liver transplantation, that may increase the postoperative morbidity, mortality, tumor progression, and metastasis. The underlying mechanisms have been extensively investigated in recent years. Among these, oxidative stress, inflammatory responses, immunoreactions, and cell death are the most studied. Non-coding RNAs (ncRNAs) are defined as the RNAs that do not encode proteins, but can regulate gene expressions. In recent years, ncRNAs have emerged as research hotspots for various diseases. During the progression of HIRI, ncRNAs are differentially expressed, while these dysregulations of ncRNAs, in turn, have been verified to be related to the above pathological processes involved in HIRI. ncRNAs mainly contain microRNAs, long ncRNAs, and circular RNAs, some of which have been reported as biomarkers for early diagnosis or assessment of liver damage severity, and as therapeutic targets to attenuate HIRI. Here, we briefly summarize the common pathophysiology of HIRI, describe the current knowledge of ncRNAs involved in HIRI in animal and human studies, and discuss the potential of ncRNA-targeted therapeutic strategies. Given the scarcity of clinical trials, there is still a long way to go from pre-clinical to clinical application, and further studies are needed to uncover their potential as therapeutic targets.
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Affiliation(s)
- Jia-Li Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Li-Juan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Ji Xiao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Feng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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Paluschinski M, Kordes C, Vucur M, Buettner V, Roderburg C, Xu HC, Shinte PV, Lang PA, Luedde T, Castoldi M. Differential Modulation of miR-122 Transcription by TGFβ1/BMP6: Implications for Nonresolving Inflammation and Hepatocarcinogenesis. Cells 2023; 12:1955. [PMID: 37566034 PMCID: PMC10416984 DOI: 10.3390/cells12151955] [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: 06/30/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
Chronic inflammation is widely recognized as a significant factor that promotes and worsens the development of malignancies, including hepatocellular carcinoma. This study aimed to explore the potential role of microRNAs in inflammation-associated nonresolving hepatocarcinogenesis. By conducting a comprehensive analysis of altered microRNAs in animal models with liver cancer of various etiologies, we identified miR-122 as the most significantly downregulated microRNA in the liver of animals with inflammation-associated liver cancer. Although previous research has indicated the importance of miR-122 in maintaining hepatocyte function, its specific role as either the trigger or the consequence of underlying diseases remains unclear. Through extensive analysis of animals and in vitro models, we have successfully demonstrated that miR-122 transcription is differentially regulated by the immunoregulatory cytokines, by the transforming growth factor-beta 1 (TGFβ1), and the bone morphogenetic protein-6 (BMP6). Furthermore, we presented convincing evidence directly linking reduced miR-122 transcription to inflammation and in chronic liver diseases. The results of this study strongly suggest that prolonged activation of pro-inflammatory signaling pathways, leading to disruption of cytokine-mediated regulation of miR-122, may significantly contribute to the onset and exacerbation of chronic liver disease.
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Affiliation(s)
- Martha Paluschinski
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Claus Kordes
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Veronika Buettner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Haifeng C. Xu
- Institute for Molecular Medicine II, Medical Faculty, Heinrich-Heine University Hospital, 40225 Dusseldorf, Germany; (H.C.X.); (P.V.S.); (P.A.L.)
| | - Prashant V. Shinte
- Institute for Molecular Medicine II, Medical Faculty, Heinrich-Heine University Hospital, 40225 Dusseldorf, Germany; (H.C.X.); (P.V.S.); (P.A.L.)
| | - Philipp A. Lang
- Institute for Molecular Medicine II, Medical Faculty, Heinrich-Heine University Hospital, 40225 Dusseldorf, Germany; (H.C.X.); (P.V.S.); (P.A.L.)
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
| | - Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (C.K.); (M.V.); (V.B.); (C.R.); (T.L.)
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10
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MicroRNA-122 in human cancers: from mechanistic to clinical perspectives. Cancer Cell Int 2023; 23:29. [PMID: 36803831 PMCID: PMC9940444 DOI: 10.1186/s12935-023-02868-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 02/09/2023] [Indexed: 02/22/2023] Open
Abstract
MicroRNAs (miRNAs) are endogenous short non-coding RNAs that can regulate the expression of target genes post-transcriptionally and interact with mRNA-coding genes. MiRNAs play vital roles in many biological functions, and abnormal miRNA expression has been linked to various illnesses, including cancer. Among the miRNAs, miR-122, miR-206, miR-21, miR-210, miR-223, and miR-424 have been extensively studied in various cancers. Although research in miRNAs has grown considerably over the last decade, much is yet to be discovered, especially regarding their role in cancer therapies. Several kinds of cancer have been linked to dysregulation and abnormal expression of miR-122, indicating that miR-122 may serve as a diagnostic and/or prognostic biomarker for human cancer. Consequently, in this review literature, miR-122 has been analyzed in numerous cancer types to sort out the function of cancer cells miR-122 and enhance patient response to standard therapy.
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11
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Costafreda MI, Sauleda S, Riveiro-Barciela M, Rico A, Llorens-Revull M, Guix S, Pintó RM, Bosch A, Rodríguez-Frías F, Rando A, Piron M, Bes M. Specific Plasma MicroRNA Signatures Underlying the Clinical Outcomes of Hepatitis E Virus Infection. Microbiol Spectr 2023; 11:e0466422. [PMID: 36695578 PMCID: PMC9927377 DOI: 10.1128/spectrum.04664-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/11/2023] [Indexed: 01/26/2023] Open
Abstract
The pathogenic mechanisms determining the diverse clinical outcomes of HEV infection (e.g., self-limiting versus chronic or symptomatic versus asymptomatic) are not yet understood. Because specific microRNA signatures during viral infection inform the cellular processes involved in virus replication and pathogenesis, we investigated plasma microRNA profiles in 44 subjects, including patients with symptomatic acute (AHE, n = 7) and chronic (CHE, n = 6) hepatitis E, blood donors with asymptomatic infection (HEV BDs, n = 9), and anti-HEV IgG+ IgM- (exposed BDs, n = 10) and anti-HEV IgG- IgM- (naive BDs, n = 12) healthy blood donors. By measuring the abundance of 179 microRNAs in AHE patients and naive BDs by reverse transcription-quantitative PCR (RT-qPCR), we identified 51 potential HEV-regulated microRNAs (P value adjusted for multiple testing by the Benjamini-Hochberg correction [PBH] < 0.05). Further analysis showed that HEV genotype 3 infection is associated with miR-122, miR-194, miR-885, and miR-30a upregulation and miR-221, miR-223, and miR-27a downregulation. AHE patients showed significantly higher levels of miR-122 and miR-194 and lower levels of miR-221, miR-27a, and miR-335 than HEV BDs. This specific microRNA signature in AHE could promote virus replication and reduce antiviral immune responses, contributing to the development of clinical symptoms. We found that miR-194, miR-335, and miR-221 can discriminate between asymptomatic HEV infections and those developing acute symptoms, whereas miR-335 correctly classifies AHE and CHE patients. Our data suggest that diverse outcomes of HEV infection result from different HEV-induced microRNA dysregulations. The specific microRNA signatures described offer novel information that may serve to develop biomarkers of HEV infection outcomes and improve our understanding of HEV pathogenesis, which may facilitate the identification of antiviral targets. IMPORTANCE There is increasing evidence that viruses dysregulate the expression and/or secretion of microRNAs to promote viral replication, immune evasion, and pathogenesis. In this study, we evaluated the change in microRNA abundance in patients with acute or chronic HEV infection and asymptomatic HEV-infected blood donors. Our results suggest that different HEV-induced microRNA dysregulations may contribute to the diverse clinical manifestations of HEV infection. The specific microRNA signatures identified in this study hold potential as predictive markers of HEV infection outcomes, which would improve the clinical management of hepatitis E patients, particularly of those developing severe symptoms or chronic infections. Furthermore, this study provides new insights into HEV pathogenesis that may serve to identify antiviral targets, which would have a major impact because no effective treatments are yet available.
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Affiliation(s)
- Maria I. Costafreda
- Blood and Tissue Bank of Catalonia (Banc de Sang i Teixits de Catalunya), Transfusion Safety Laboratory, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron Universitary Hospital, Barcelona, Spain
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Silvia Sauleda
- Blood and Tissue Bank of Catalonia (Banc de Sang i Teixits de Catalunya), Transfusion Safety Laboratory, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron Universitary Hospital, Barcelona, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall d’Hebron Universitary Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Angie Rico
- Blood and Tissue Bank of Catalonia (Banc de Sang i Teixits de Catalunya), Transfusion Safety Laboratory, Barcelona, Spain
| | - Meritxell Llorens-Revull
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron Universitary Hospital, Barcelona, Spain
| | - Susana Guix
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Rosa M. Pintó
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Albert Bosch
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Laboratory, Microbiology and Biochemistry Department, Vall d’Hebron Clinical Laboratories, Vall d’Hebron Universitary Hospital, Barcelona, Spain
| | - Ariadna Rando
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Laboratory, Microbiology and Biochemistry Department, Vall d’Hebron Clinical Laboratories, Vall d’Hebron Universitary Hospital, Barcelona, Spain
| | - Maria Piron
- Blood and Tissue Bank of Catalonia (Banc de Sang i Teixits de Catalunya), Transfusion Safety Laboratory, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron Universitary Hospital, Barcelona, Spain
| | - Marta Bes
- Blood and Tissue Bank of Catalonia (Banc de Sang i Teixits de Catalunya), Transfusion Safety Laboratory, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREhd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron Universitary Hospital, Barcelona, Spain
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12
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Raval M, Mishra S, Tiwari AK. Epigenetic regulons in Alzheimer's disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 198:185-247. [DOI: 10.1016/bs.pmbts.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
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13
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MicroRNA-122 mimic/microRNA-221 inhibitor combination as a novel therapeutic tool against hepatocellular carcinoma. Noncoding RNA Res 2022; 8:126-134. [DOI: 10.1016/j.ncrna.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
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14
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Park SY, Kim SJ, To PK, Zhou R, Kim K, Kim KK, Jung C, Kim H. MicroRNA-122 targets δ-catenin to suppress the tumorigenic potential of prostate cancer cells. Am J Cancer Res 2022; 12:4853-4864. [PMID: 36381334 PMCID: PMC9641389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/14/2022] [Indexed: 06/16/2023] Open
Abstract
δ-Catenin is expressed abundantly in various human cancers, including prostate, brain, breast, and lung carcinomas, and is recognized as an oncogene that promotes cancer cell growth and tumorigenesis. Although several transcriptional and post-translational pathways for δ-catenin regulation have been identified in cancer cells, the potential effects of microRNA-mediated regulation remain elusive. Here, we used a δ-catenin 3'-UTR luciferase reporter assay to identify regulatory microRNAs. Subsequent bioinformatics analyses and molecular studies revealed that overexpression of miR-122 downregulated δ-catenin expression significantly via targeted binding to a seed sequence in the 3'-UTR region of δ-catenin, and suppressed the invasion, migration, and proliferation of prostate cancer cells in vitro. In a TRAMP-C2 mouse syngeneic prostate tumor model, stable expression of miR-122 decreased both δ-catenin expression and tumor growth. Mechanistically, overexpression of miR-122 inhibited the expression of δ-catenin-mediated downstream factors significantly in prostate cancer cells, including c-myc and cyclin D1. In cells overexpressing miR-122, there was no additive or synergistic effect of siRNA-mediated knockdown of δ-catenin on cell invasiveness, and overexpression of miR-122 alone had a more pronounced suppressive effect on cell invasion than knockdown of δ-catenin alone. These results suggest that miR-122 acts as tumor suppressor in prostate cancer, mainly by downregulating δ-catenin expression, but also by targeting other factors. Indeed, subsequent experiments showed that overexpression of miR-122 reduced the levels of the mRNAs encoding myc, snail, and VEGF in prostate cancer cells. Overall, our findings demonstrate that targeting of δ-catenin by miR-122 represses the motility and tumorigenesis of prostate cancer cells, indicating a tumor suppressive effect of this miRNA in prostate cancer.
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Affiliation(s)
- So-Yeon Park
- College of Pharmacy, Sunchon National UniversitySunchon 57922, Republic of Korea
| | - Sung Jin Kim
- College of Pharmacy, Sunchon National UniversitySunchon 57922, Republic of Korea
| | - Phuong Kim To
- Department of Anatomy, Chonnam National University Medical SchoolGwangju 61469, Republic of Korea
| | - Rui Zhou
- College of Pharmacy, Sunchon National UniversitySunchon 57922, Republic of Korea
| | - Kwonseop Kim
- College of Pharmacy, Chonnam National UniversityGwangju 61186, Republic of Korea
| | - Kyung Keun Kim
- Department of Pharmacology, Chonnam National University Medical SchoolGwangju 61469, Republic of Korea
| | - Chaeyong Jung
- Department of Anatomy, Chonnam National University Medical SchoolGwangju 61469, Republic of Korea
| | - Hangun Kim
- College of Pharmacy, Sunchon National UniversitySunchon 57922, Republic of Korea
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15
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Suriya Muthukumaran N, Velusamy P, Akino Mercy CS, Langford D, Natarajaseenivasan K, Shanmughapriya S. MicroRNAs as Regulators of Cancer Cell Energy Metabolism. J Pers Med 2022; 12:1329. [PMID: 36013278 PMCID: PMC9410355 DOI: 10.3390/jpm12081329] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
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Affiliation(s)
| | - Prema Velusamy
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
| | - Charles Solomon Akino Mercy
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Dianne Langford
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
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16
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Chun KH. Molecular Targets and Signaling Pathways of microRNA-122 in Hepatocellular Carcinoma. Pharmaceutics 2022; 14:1380. [PMID: 35890276 PMCID: PMC9316959 DOI: 10.3390/pharmaceutics14071380] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading global causes of cancer mortality. MicroRNAs (miRNAs) are small interfering RNAs that alleviate the levels of protein expression by suppressing translation, inducing mRNA cleavage, and promoting mRNA degradation. miR-122 is the most abundant miRNA in the liver and is responsible for several liver-specific functions, including metabolism, cellular growth and differentiation, and hepatitis virus replication. Recent studies have shown that aberrant regulation of miR-122 is a key factor contributing to the development of HCC. In this review, the signaling pathways and the molecular targets of miR-122 involved in the progression of HCC have been summarized, and the importance of miR-122 in therapy has been discussed.
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Affiliation(s)
- Kwang-Hoon Chun
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Korea
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17
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Adipose-Derived Circulating Exosomes Promote Protection of the Pulmonary Endothelial Barrier by Inhibiting EndMT and Oxidative Stress through Down-Regulation of the TGF-β Pathway: A Potential Explanation for the Obesity Paradox in ARDS. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5475832. [PMID: 35571250 PMCID: PMC9098334 DOI: 10.1155/2022/5475832] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/11/2022] [Accepted: 03/18/2022] [Indexed: 12/15/2022]
Abstract
The “obesity paradox in acute respiratory distress syndrome” (ARDS) refers to the phenomenon in which obesity is associated with higher morbidity but lower mortality in patients with ARDS. Endothelial-to-mesenchymal transition (EndMT) represents a key link in the interaction between endothelial disruption and mesenchymal fibrosis under inflammatory and oxidative conditions, which represent the intersectional pathophysiology of ARDS. Adipose tissue is considered to constitute the major source of circulating exosomal microRNAs (miRNAs), which act as genetic forms of adipokines for cell–cell crosstalk. We aimed to demonstrate the regulation and mechanism of adipose-derived exosomes in the obesity paradox in ARDS. High-fat-induced obese mice and lean control mice were subjected to ARDS insult to investigate the effects of obesity on ARDS and microarray analysis was performed to screen for differences in circulating miRNAs. In addition, mice and pulmonary endothelial cells were administered with adipose-derived exosomal miR-122-5p to investigate the underlying molecular mechanisms. We found high-fat diet-induced obesity protected against ARDS in mice by reinforcing endothelial barrier and attenuating fibroproliferation. Circulating exosomes produced in the obese state mediated these protective effects by inhibiting EndMT and oxidative stress. Mechanistically, adipose-derived exosomal miR-122-5p promoted the integrity and function of pulmonary endothelial barrier and alleviated fibrogenesis by suppressing EndMT and oxidative stress through down-regulation of the transforming growth factor β1 (TGF-β1)/TGF-β receptor 1 (TGF-βR1)/Smad2 pathway in vivo and in vitro. In conclusion, adipose-derived circulating exosomal miR-122-5p protects against ARDS by reinforcing pulmonary endothelial barrier through inhibition of EndMT and oxidative stress via down-regulation of the TGF-β pathway, which propose a potential explanation for the obesity paradox in ARDS and indicate promising prospects for adipose-derived exosomes in cell-free therapies for ARDS.
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18
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Zhang X, Zhang R, Hao J, Huang X, Liu M, Lv M, Su C, Mu YL. miRNA-122-5p in POI ovarian-derived exosomes promotes granulosa cell apoptosis by regulating BCL9. Cancer Med 2022; 11:2414-2426. [PMID: 35229987 PMCID: PMC9189466 DOI: 10.1002/cam4.4615] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/24/2021] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
This study is to explore the therapeutic effect and potential mechanisms of exosomal microRNAs (miRNAs) derived from the ovaries with primary ovarian insufficiency (POI). The POI mouse model was established by intraperitoneal injection of cyclophosphamide (CTX) and busulfan. The apoptosis of granulosa cells (GCs) incubated with exosomes extracted from ovarian tissues of control and POI groups was analyzed by flow cytometry. Then, high-throughput sequencing was performed to detect the difference of miRNAs profile in ovarian tissue-derived exosomes between the control and POI mice. The effect of differential miRNA on the apoptosis of CTX-induced ovarian GCs was analyzed by flow cytometry. The results showed that POI mouse model was successfully established. Exosomes extracted from ovarian of normal and POI group have different effects on apoptosis of GCs induced by CTX. miRNA-seq found that exosomal miR-122-5p in POI group increased significantly. miR-122-5p as the dominant miRNA targeting BCL9 was significantly upregulated in ovarian tissues of chemotherapy-induced POI group. Exosomes derived from the ovaries in the control group and miR-122-5p inhibitor group attenuated the apoptosis of primary cultured ovarian GCs. In conclusion, exosomal miR-122-5p promoted the apoptosis of ovarian GCs by targeting BCL9, suggested that miR-122-5p may function as a potential target to restore ovarian function.
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Affiliation(s)
- Xiujuan Zhang
- Department of Gynecology and Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ruihong Zhang
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Jing Hao
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Xiaoyan Huang
- Shandong Maternal and Child Health Care Hospital, Jinan, China
| | - Ming Liu
- Department of Gynecology and Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Mengxiao Lv
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chan Su
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yu-Lan Mu
- Department of Gynecology and Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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19
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Zhao X, Ji Z, Xuan R, Wang A, Li Q, Zhao Y, Chao T, Wang J. Characterization of the microRNA Expression Profiles in the Goat Kid Liver. Front Genet 2022; 12:794157. [PMID: 35082837 PMCID: PMC8784682 DOI: 10.3389/fgene.2021.794157] [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: 10/13/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
The liver is the largest digestive gland in goats with an important role in early metabolic function development. MicroRNAs (miRNA) are crucial for regulating the development and metabolism in the goat liver. In the study, we sequenced the miRNAs in the liver tissues of the goat kid to further research their regulation roles in early liver development. The liver tissues were procured at 5-time points from the Laiwu black goats of 1 day (D1), 2 weeks (W2), 4 weeks (W4), 8 weeks (W8), and 12 weeks (W12) after birth, respectively with five goats per time point, for a total of 25 goats. Our study identified 214 differential expression miRNAs, and the expression patterns of 15 randomly selected miRNAs were examined among all five age groups. The Gene ontology annotation results showed that differential expression miRNA (DE miRNA) target genes were significantly enriched in the fatty acid synthase activity, toxin metabolic process, cell surface, and antibiotic metabolic process. The KEGG analysis result was significantly enriched in steroid hormone synthesis and retinol metabolism pathways. Further miRNA-mRNA regulation network analysis reveals 9 differently expressed miRNA with important regulation roles. Overall, the DE miRNAs were mainly involved in liver development, lipid metabolism, toxin related metabolism-related biological process, and pathways. Our results provide new information about the molecular mechanisms and pathways in the goat kid liver development.
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Affiliation(s)
- Xiaodong Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Zhibin Ji
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Rong Xuan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Aili Wang
- Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Shouguang, China
| | - Qing Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Yilin Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Tianle Chao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Jianmin Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
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20
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Kang J, Song Y, Zhang Z, Wang S, Lu Y, Liu X. Identification of Key microRNAs in Diabetes Mellitus Erectile Dysfunction Rats with Stem Cell Therapy by Bioinformatic Analysis of Deep Sequencing Data. World J Mens Health 2022; 40:663-677. [PMID: 35021304 PMCID: PMC9482859 DOI: 10.5534/wjmh.210147] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/16/2021] [Accepted: 09/30/2021] [Indexed: 11/15/2022] Open
Abstract
PURPOSE Diabetes mellitus erectile dysfunction (DMED) is a common resulting complication of diabetes. Studies have shown mesenchymal stem cell (MSC)-based therapy was beneficial in alleviating erectile function of DMED rats. While the pathogenesis of DMED and the mechanism MSCs actions are unclear. MATERIALS AND METHODS We constructed a rat model of DMED with or without intracavernous injection of MSCs, and performed microRNA (miRNA) sequencing of corpora cavernosa tissues. RESULTS We identified three overlapping differentially expressed miRNAs (rno-miR-1298, rno-miR-122-5p, and rno-miR-6321) of the normal control group, DMED group, and DMED+MSCs group. We predicted 285 target genes of three miRNAs through RNAhybrid and miRanda database and constructed a miRNA-target gene network through Cytoscape. Next, we constructed protein-protein interaction networks through STRING database and identified the top 10 hub genes with highest connectivity scores. Five GO terms including cellular response to growth factor stimulus (GO:0071363), ossification (GO:0001503), response to steroid hormone (GO:0048545), angiogenesis (GO:0001525), positive regulation of apoptotic process (GO:0043065), and one Reactome pathway (Innate Immune System) were significantly enriched by 10 hub genes using the Metascape database. We selected the GSE2457 dataset to validate the expression of hub genes and found only the expression of B4galt1 was statistically different (p<0.001). B4galt1 was highly expressed in penile tissues of diabetic rats and would be negatively regulated by rno-miR-1298. CONCLUSIONS Three key miRNAs were identified in DMED rats with stem cell therapy and the miR-1298/B4GalT1 axis might exert function in stem cell therapy for ED.
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Affiliation(s)
- Jiaqi Kang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuxuan Song
- Department of Urology, Peking University People's Hospital, Beijing, China.,Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China
| | - Zhexin Zhang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shangren Wang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yi Lu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoqiang Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China.
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21
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Ahluwalia MK. Nutrigenetics and nutrigenomics-A personalized approach to nutrition. ADVANCES IN GENETICS 2021; 108:277-340. [PMID: 34844714 DOI: 10.1016/bs.adgen.2021.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The prevalence of non-communicable diseases has been on an upward trajectory for some time and this puts an enormous burden on the healthcare expenditure. Lifestyle modifications including dietary interventions hold an immense promise to manage and prevent these diseases. Recent advances in genomic research provide evidence that focussing these efforts on individual variations in abilities to metabolize nutrients (nutrigenetics) and exploring the role of dietary compounds on gene expression (nutrigenomics and nutri-epigenomics) can lead to more meaningful personalized dietary strategies to promote optimal health. This chapter aims to provide examples on these gene-diet interactions at multiple levels to support the need of embedding targeted dietary interventions as a way forward to prevent, avoid and manage diseases.
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22
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Cui S, Yu Y, Zhan T, Zhang C, Zhuang S. 2,6-Di-tert-butylphenol and its quinone metabolite trigger aberrant transcriptional responses in C57BL/6 mice liver. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 778:146322. [PMID: 33714818 DOI: 10.1016/j.scitotenv.2021.146322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 06/12/2023]
Abstract
2,6-Di-tert-butylphenol (2,6-DTBP) is used as an antioxidant with wide commercial applications and its residues have been detected in various environmental matrices. 2,6-DTBP may enter human body via ingestion, inhalation or other exposure pathways. However, its susceptibility to biotransformation and potential of the metabolic products to trigger aberrant transcriptional responses remain unclear. Here, we investigated in vitro and in vivo biotransformation of 2,6-DTBP and characterized the RNA-Seq based transcriptional profiling of C57BL/6 mice liver after the exposure to 2,6-DTBP and its metabolites. 2,6-DTBP was metabolized into hydroxylated (2,6-DTBH) and para-quinone (2,6-DTBQ) products with residues detected in serum and liver of C57BL/6 mice. 2,6-DTBP and 2,6-DTBQ induced the aberrant transcription in C57BL/6 mice liver featured with 373-2861 differentially expressed genes (DEGs). They also up-regulated 1.09-2.92 fold mRNA expression of carcinogenesis-related genes such as Ccnd1, TGFβ1 and FOS in C57BL/6 mice liver. Our study indicated potential carcinogenic risk of 2,6-DTBP and its metabolites, beneficial to further evaluation of health risk of TBPs-related contaminants.
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Affiliation(s)
- Shixuan Cui
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yang Yu
- Solid Waste and Chemicals Management Center, Ministry of Ecology and Environment (MEE), Beijing 100029, China
| | - Tingjie Zhan
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Chunlong Zhang
- Department of Environmental Sciences, University of Houston-Clear Lake, TX 77058, United States
| | - Shulin Zhuang
- Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
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Yang H, Shi G, Ge C, Huang J, Wan L, Wang Z, Liu Y, Jia R, Wang M, Zhang L, Zhang Z, Yan X. Functionalized graphene oxide as a nanocarrier for multiple suppressive miRNAs to inhibit human intrahepatic cholangiocarcinoma. NANO SELECT 2021. [DOI: 10.1002/nano.202000130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Hui Yang
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
- Institute of Health Service and Transfusion Medicine Stem Cell and Regenerative Medicine Lab AMMS Beijing 100850 China
| | - Gaona Shi
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine Hainan Medical University Haikou 571101 China
| | - Chen Ge
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Jie Huang
- CAS Key Laboratory of Nano‐Bio Interface Division of Nanobiomedicine Suzhou Institute of Nano‐Tech & Nano‐bionics Chinese Academy of Sciences Suzhou 215123 China
| | - Lingfei Wan
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Zhaohai Wang
- Department of Hepatobiliary surgery Fifth Medical Center of Chinese PLA General Hospital Beijing 100039 China
| | - Yunhui Liu
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Runqing Jia
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Minglian Wang
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
| | - Liming Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine Hainan Medical University Haikou 571101 China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano‐Bio Interface Division of Nanobiomedicine Suzhou Institute of Nano‐Tech & Nano‐bionics Chinese Academy of Sciences Suzhou 215123 China
| | - Xinlong Yan
- College of Life Science and Bioengineering Faculty of Environmental and Life Sciences Beijing University of Technology Beijing 100124 China
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24
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Yang Y, Liu Y, Liu W, Li C, Liu Y, Hu W, Song H. miR-122 Inhibits the Cervical Cancer Development by Targeting the Oncogene RAD21. Biochem Genet 2021; 60:303-314. [PMID: 34191246 DOI: 10.1007/s10528-021-10098-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/09/2021] [Indexed: 12/20/2022]
Abstract
Cervical cancer (CC) is one of the most frequently diagnosed tumors in female. miR-122 has been proved to be dominant in CC. The particular role of miR-122 in CC is unclear. Thus, we attempted to investigate the prognostic role of miR-122 in CC. We used the database of Kaplan-Meier curve plot. Growth and apoptosis of C33A cells were detected by CCK-8, colony formation assay, transwell assays and flow cytometry analysis. The target gene of miR-122 was identified using bioinformatics, q-PCR, western blot and luciferase assay. It showed that CC patients with overexpression of miR-122 have a better prognosis in the Kaplan-Meier plot database analysis. Overexpressed miR-122 inhibited the malignant growth and induced apoptosis of CC. miR-122 targeting of RAD21 cohesin complex component (RAD21) was identified using bioinformatics, Q-PCR, western blot and luciferase assay analyses. Moreover, we found miR-122 conduct its functions via RAD21 via the PI3K/AKT signaling pathway. Importantly, overexpression of RAD21 restored the roles of miR-122 in CC. Our data suggested that miR-122 could block malignant growth and promoted apoptosis by targeting RAD21 in CC. Our finding indicates miR-122 could potentially participate in the pathogenesis and be a biomarker or the potential therapeutic target of CC.
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Affiliation(s)
- Yanling Yang
- Xuzhou Maternal and Child Health Hospital, Xuzhou Medical University, Xuzhou, 221000, China
| | - Yang Liu
- Xuzhou Maternal and Child Health Hospital, Xuzhou Medical University, Xuzhou, 221000, China
| | - Wei Liu
- Xuzhou Maternal and Child Health Hospital, Xuzhou Medical University, Xuzhou, 221000, China
| | - Chunyang Li
- Xuzhou Maternal and Child Health Hospital, Xuzhou Medical University, Xuzhou, 221000, China
| | - Yuan Liu
- Xuzhou Maternal and Child Health Hospital, Xuzhou Medical University, Xuzhou, 221000, China
| | - Wenyang Hu
- College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Hongjuan Song
- Xuzhou Maternal and Child Health Hospital, Xuzhou Medical University, Xuzhou, 221000, China.
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25
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Inhibition of miR-122 reduced atherosclerotic lesion formation by regulating NPAS3-mediated endothelial to mesenchymal transition. Life Sci 2020; 265:118816. [PMID: 33278397 DOI: 10.1016/j.lfs.2020.118816] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/14/2020] [Accepted: 11/20/2020] [Indexed: 12/30/2022]
Abstract
AIMS Endothelial to mesenchymal transition (EndMT) is closely related to atherosclerosis. Herein, we aim to determine whether miR-122 is involved in EndMT and the underlying mechanism in atherosclerosis. MAIN METHODS qRT-PCR was performed to detect miR-122 expression in ApoE-/- mice and cellular EndMT model induced by H2O2. MiR-122 expression in vivo was modulated by lenti-virus injection and by genetic manipulation. Hematoxylin and eosin (HE) and Oil-red O staining were used to observe the plaque size and lipid accumulation in the aortic roots. F4/80 staining, elastin staining, and masson staining were used to observe the components of atherosclerotic lesions. MiR-122 expression in endothelial cells was modulated by transfection of miR-122 mimic and inhibitor. Western blotting and co-localization of endothelial markers (VE-cadherin, CD31) and mesenchymal markers (Vimentin, α-SMA) were carried out to determine EndMT. KEY FINDINGS MiR-122 was upregulated in the aortic intima and serum of ApoE-/- mice induced by HFD and in cellular EndMT model. Inhibition of miR-122 repressed the atherosclerotic plaque progression and vulnerable plaque formation in ApoE-/- mice. In vitro, endothelial cells acquired a spindle-shaped morphology accompanying decrease of the endothelial markers (VE-cadherin, CD31) and increase of the mesenchymal markers (Vimentin, α-SMA) in the presence of H2O2, which was inhibited by miR-122 inhibitor. Furthermore, NPAS3 functions as a target of miR-122, and NPAS3 silencing abolished the anti-EndMT effect of miR-122 inhibitor. SIGNIFICANCE Inhibition of miR-122 prevents atherosclerosis and regulates NPAS3-mediated EndMT, suggesting that miR-122 may be a novel target in the treatment of EndMT-associated diseases including atherosclerosis.
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26
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Teng KY, Barajas JM, Hu P, Jacob ST, Ghoshal K. Role of B Cell Lymphoma 2 in the Regulation of Liver Fibrosis in miR-122 Knockout Mice. BIOLOGY 2020; 9:biology9070157. [PMID: 32650615 PMCID: PMC7408427 DOI: 10.3390/biology9070157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/25/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022]
Abstract
MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.
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Affiliation(s)
- Kun-Yu Teng
- Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA;
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Juan M. Barajas
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Peng Hu
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Samson T. Jacob
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA
| | - Kalpana Ghoshal
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
- Correspondence: ; Tel.: +614-292-8865; Fax: +614-688-4245
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27
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Yang X, Ma L, Wei R, Ye T, Zhou J, Wen M, Men R, Aqeilan RI, Peng Y, Yang L. Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway. Signal Transduct Target Ther 2020; 5:75. [PMID: 32499481 PMCID: PMC7272438 DOI: 10.1038/s41392-020-0169-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 01/07/2020] [Accepted: 01/07/2020] [Indexed: 02/05/2023] Open
Abstract
The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl4-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl4-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.
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Affiliation(s)
- Xiaoxue Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liping Ma
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China.,School of Bioscience and Technology, Chengdu medical college, Chengdu, 610500, China
| | - Rong Wei
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China
| | - Tinghong Ye
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - JianKang Zhou
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China
| | - Maoyao Wen
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ruoting Men
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rami I Aqeilan
- Department of Immunology & Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Yong Peng
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China.
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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28
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Guo Q, Yu Y, Zhang H, Cai C, Shen Q. Electrochemical Sensing of Exosomal MicroRNA Based on Hybridization Chain Reaction Signal Amplification with Reduced False-Positive Signals. Anal Chem 2020; 92:5302-5310. [PMID: 32148013 DOI: 10.1021/acs.analchem.9b05849] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) in cancer cell-derived exosomes are important cancer biomarkers. Herein, a sensitive hybridization chain reaction (HCR) electrochemical assay was fabricated for the detection of exosomal microRNA-122 (miR-122). The hairpin DNA (hpDNA) probes were first immobilized on the surface of a gold electrode. In the presence of miR-122, the hairpin structure of the hpDNA could be opened and triggered the HCR through the cross-opening and hybridization of two helper DNA hairpins. Long nicked double helixes generated from HCR are used to capture more RuHex and increase the signal of differential pulse voltammetry (DPV). In this assay, the density of the hpDNA probes on the surface of the gold electrode was precisely controlled by the simultaneous immobilization of hpDNA and short 12 nucleotides single-stranded DNA (S-12), providing a very high amplification efficiency. More importantly, the false positive signal could be reduced or completely eliminated by applying exonuclease I (Exo I) before the introduction of target miR-122. Under optimal conditions, the assay offers very high sensitivity with an attomolar level detection limit, a linear range with 9 orders of magnitude, and specificity in single mismatch discrimination. This sensitive electrochemical assay could successfully evaluate the miR-122 concentration in different cancer-derived exosomes, indicating its potential use in cancer diagnostics.
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Affiliation(s)
- Qunqun Guo
- Jiangsu Key Laboratory of New Power Batteries, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, National and Local Joint Engineering Research Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, People's Republic of China
| | - Yongqi Yu
- Jiangsu Key Laboratory of New Power Batteries, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, National and Local Joint Engineering Research Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, People's Republic of China
| | - Hui Zhang
- Jiangsu Key Laboratory of New Power Batteries, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, National and Local Joint Engineering Research Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, People's Republic of China.,Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials, Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, People's Republic of China
| | - Chenxin Cai
- Jiangsu Key Laboratory of New Power Batteries, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, National and Local Joint Engineering Research Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, People's Republic of China
| | - Qingming Shen
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials, Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, People's Republic of China
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29
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Chen Q, Gao Y, Yu Q, Tang F, Zhao PW, Luo SK, Lin JS, Mei H. miR-30a-3p inhibits the proliferation of liver cancer cells by targeting DNMT3a through the PI3K/AKT signaling pathway. Oncol Lett 2019; 19:606-614. [PMID: 31897176 PMCID: PMC6924113 DOI: 10.3892/ol.2019.11179] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 03/28/2019] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) are crucial for normal development and maintenance of homeostasis. Dysregulated miRNA expression contributes to numerous pathological conditions, including cancer tumorigenesis. However, a limited number of studies have examined the regulatory effects of miR-30a-3p in tumorigenesis. Therefore, the present study investigated the mechanistic process of tumorigenesis in liver cancer. The results revealed a high expression of DNA methyltransferase 3a (DNMT3a) and a low expression of miR-30a-3p in HepG2 cells compared with that in the L02 cell line. A luciferase reporter assay demonstrated that DNMT3a is a direct target of miR-30a-3p. In addition, DNMT3a overexpression significantly enhanced cell proliferation, which was reversed by a miR-30a-3p mimic. Similarly, the miR-30a-3p mimic blocked DNMT3a-triggered cell cycle processes and apoptosis by attenuating active p-AKT and p-PI3K in HepG2 cells. In summary, the results of the present study demonstrate that miR-30a-3p is essential for cell proliferation regulation via its association with AKT/PI3K signaling in liver cancer. These results provide insight into the molecular mechanism by which miR-30a-3p inhibits liver cancer cell proliferation and provides a foundation for its clinical development and application.
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Affiliation(s)
- Qiong Chen
- Department of Gastroenterology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Yuan Gao
- Department of Gastroenterology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Qin Yu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Feng Tang
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Pei-Wei Zhao
- Clinical Research Center, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Su-Kun Luo
- Clinical Research Center, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Ju-Sheng Lin
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Hong Mei
- Department of Gastroenterology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
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30
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Su J, Wu F, Xia H, Wu Y, Liu S. Accurate cancer cell identification and microRNA silencing induced therapy using tailored DNA tetrahedron nanostructures. Chem Sci 2019; 11:80-86. [PMID: 32110359 PMCID: PMC7012044 DOI: 10.1039/c9sc04823e] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 10/30/2019] [Indexed: 12/16/2022] Open
Abstract
Accurate cancer cell identification and efficient therapy are extremely desirable and challenging in clinics. Here, we reported the first example of DNA tetrahedron nanostructures (DTNSs) to real-time monitor and image three intracellular miRNAs based on the fluorescence "OFF" to "ON" mode, as well as to realize cancer therapy induced by miRNA silencing. DTNSs were self-assembled by seven customized single-stranded nucleic acid chains containing three recognition sequences for target miRNAs. In the three vertexes of DTNSs, fluorophores and quenchers were brought into close proximity, inducing fluorescence quenching. In the presence of target miRNAs, fluorophores and quenchers would be separated, resulting in fluorescence recovery. Owing to the unique tetrahedron-like spatial structure, DTNSs displayed improved resistance to enzymatic digestion and high cellular uptake efficiency, and exhibited the ability to simultaneously monitor three intracellular miRNAs. DTNSs not only effectively distinguished tumor cells from normal cells, but also identified cancer cell subtypes, which avoided false-positive signals and significantly improved the accuracy of cancer diagnosis. Moreover, the DTNSs could also act as an anti-cancer drug; antagomir-21 (one recognition sequence) was detached from DTNSs to silence endogenous miRNA-21 inside cells, which would suppress cancer cell migration and invasion, and finally induce cancer cell apoptosis; the result was demonstrated by experiments in vitro and in vivo. It is anticipated that the development of smart nanoplatforms will open a door for cancer diagnosis and treatment in clinical systems.
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Affiliation(s)
- Juan Su
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device , School of Chemistry and Chemical Engineering , Southeast University , Nanjing 211189 , China
| | - Fubing Wu
- Department of Pathology , School of Basic Medical Sciences , Department of Oncology , The Affiliated Sir Run Run Hospital , State Key Laboratory of Reproductive Medicine , Key Laboratory of Antibody Technique of National Health Commission , Nanjing Medical University , Nanjing 211166 , China
| | - Hongping Xia
- Department of Pathology , School of Basic Medical Sciences , Department of Oncology , The Affiliated Sir Run Run Hospital , State Key Laboratory of Reproductive Medicine , Key Laboratory of Antibody Technique of National Health Commission , Nanjing Medical University , Nanjing 211166 , China
| | - Yafeng Wu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device , School of Chemistry and Chemical Engineering , Southeast University , Nanjing 211189 , China
| | - Songqin Liu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device , School of Chemistry and Chemical Engineering , Southeast University , Nanjing 211189 , China
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31
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Cao Z, Duan F, Huang X, Liu Y, Zhou N, Xia L, Zhang Z, Du M. A multiple aptasensor for ultrasensitive detection of miRNAs by using covalent-organic framework nanowire as platform and shell-encoded gold nanoparticles as signal labels. Anal Chim Acta 2019; 1082:176-185. [PMID: 31472706 DOI: 10.1016/j.aca.2019.07.062] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/24/2019] [Accepted: 07/29/2019] [Indexed: 01/03/2023]
Abstract
We report herein a novel multiple electrochemical aptasensor based on covalent-organic framework (COF) for sensitive and simultaneous detection of miRNA 155 and miRNA 122, by using shell-encoded gold nanoparticles (Au NPs) as signal labels (AgNCs@AuNPs and Cu2O@AuNPs, respectively, NCs = nanoclusters). A new COF nanowire was synthesized via condensation polymerization of 1,3,6,8-tetra(4-carboxylphenyl)pyrene and melamine (represented by TBAPy-MA-COF-COOH) for multiple aptasensor fabrication. The nanowire was then used as a platform for anchoring single-strand DNA (ssDNA), which was hybridized with the complementary aptamer (cApt) probes of miRNA 155 and miRNA 122. AgNCs@AuNPs and Cu2O@AuNPs modified with cApts show separated differential pulse voltammetry (DPV) peaks at 0.08 and -0.1 V, respectively. The signal labels immobilized with cApts were released from the hybridized DNA complex and bound to their corresponding targets when contacting miRNAs. This phenomenon results in the substantial decline of the DPV peak current density of the signal labels. The developed TBAPy-MA-COF-COOH-based aptasensor has superior performance for sensing miRNA 155 and miRNA 122 simultaneously, with ultrasensitive low detection limits of 6.7 and 1.5 fM (S/N = 3), respectively, a wide linear range of 0.01-1000 pM, and high selectivity and applicability for serum samples. The proposed TBAPy-MA-based aptasensor demonstrates potential for simultaneous detection of multiple cancer biomarkers by replacing other ssDNA and aptamer strands.
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Affiliation(s)
- Zhengming Cao
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, PR China
| | - Fenghe Duan
- Henan Provincial Key Laboratory of Surface and Interface Science, Zhengzhou, University of Light Industry, No. 136, Science Avenue, Zhengzhou, 450001, PR China
| | - Xiaoyu Huang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, PR China
| | - Yang Liu
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, PR China
| | - Nan Zhou
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, PR China.
| | - Lei Xia
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, PR China
| | - Zhihong Zhang
- Henan Provincial Key Laboratory of Surface and Interface Science, Zhengzhou, University of Light Industry, No. 136, Science Avenue, Zhengzhou, 450001, PR China.
| | - Miao Du
- Henan Provincial Key Laboratory of Surface and Interface Science, Zhengzhou, University of Light Industry, No. 136, Science Avenue, Zhengzhou, 450001, PR China.
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32
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miR-122 promotes hepatic lipogenesis via inhibiting the LKB1/AMPK pathway by targeting Sirt1 in non-alcoholic fatty liver disease. Mol Med 2019; 25:26. [PMID: 31195981 PMCID: PMC6567918 DOI: 10.1186/s10020-019-0085-2] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 04/17/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disease with an increasing prevalence but an unclear aetiology. This study aimed to investigate the functional implications of microRNA-122 (miR-122) in the pathogenesis of NAFLD and the possible molecular mechanisms. METHODS Both in vitro and in vivo models of NAFLD were generated by treating HepG2 and Huh-7 cells with free fatty acids (FFA) and by feeding mice a high-fat diet (HFD), respectively. HE and Oil Red O staining were used to examine liver tissue morphology and lipid deposition, respectively. Immunohistochemical (IHC) staining was used to examine Sirt1 expression in liver tissues. qRT-PCR and Western blotting were employed to measure the expression of miR-122, Sirt1, and proteins involved in lipogenesis and the AMPK pathway. Enzyme-linked immunosorbent assay (ELISA) was used to quantify triglyceride (TG) levels in HepG2 and Huh-7 cells and in liver tissues. The interaction between miR-122 and the Sirt1 gene was further examined by a dual luciferase reporter assay and RNA-immunoprecipitation (RIP). RESULTS NAFLD hepatic tissues and FFA-treated HepG2 and Huh-7 cells presented excess lipid production and TG secretion, accompanied by miR-122 upregulation, Sirt1 downregulation, and potentiated lipogenesis-related genes. miR-122 suppressed Sirt1 expression via binding to its 3'-untranslated region (UTR). Knockdown of miR-122 effectively mitigated excessive lipid production and suppressed the expression of lipogenic genes in FFA-treated HepG2 and Huh-7 cells via upregulating Sirt1. Furthermore, miR-122 knockdown activated the LKB1/AMPK signalling pathway. CONCLUSION The inhibition of miR-122 protects hepatocytes from lipid metabolic disorders such as NAFLD and suppresses lipogenesis via elevating Sirt1 and activating the AMPK pathway. These data support miR-122 as a promising biomarker and drug target for NAFLD.
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Yang C, Yin M, Xu G, Lin W, Chen J, Zhang Y, Feng T, Huang P, Chen C, Yong K. Biodegradable Polymers as a Noncoding miRNA Nanocarrier for Multiple Targeting Therapy of Human Hepatocellular Carcinoma. Adv Healthc Mater 2019; 8:e1801318. [PMID: 30829008 DOI: 10.1002/adhm.201801318] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 01/26/2019] [Indexed: 12/21/2022]
Abstract
Therapeutic strategy based on the restoration of tumor suppressor-microRNAs (miRNAs) is a promising approach for cancer therapy, but the low delivery efficiency of miRNA remains a huge hurdle due to the lack of safe and efficient nonviral carriers. In this work, with the use of newly developed PEGylated biodegradable charged polyester-based vectors (PEG-BCPVs) as the carrier, the miR26a and miR122 codelivering therapeutic strategy (PEG-BCPVs/miR26a/miR122 as the delivery formulation) is successfully developed for efficient treatment of human hepatocellular carcinoma (HCC). In vitro study results show that PEG-BCPVs are capable of effectively facilitating miRNA cellular uptake via a cell endocytosis pathway. Consequently, the restoration of miR26a and miR122 remarkably inhibit the cell growth, migration, invasion, colony formation, and induced apoptosis of HepG2 cells. More importantly, the chemosensitivity of HepG2 to anticancer drug is also considerably enhanced. After treatment with the PEG-BCPV-based miRNA delivery system, the expression of the multiple targeted genes corresponding to miR26a and miR122 in HepG2 cells is greatly downregulated. Accordingly, the newly developed miRNA restoration therapeutic strategy via biodegradable PEG-BCPVs as the carrier should be a promising modality for combating HCC.
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Affiliation(s)
- Chengbin Yang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound ImagingSchool of Biomedical EngineeringHealth Science CenterShenzhen University Shenzhen 518060 China
| | - Mingjie Yin
- School of Electrical and Electronic EngineeringNanyang Technological University Singapore 639798 Singapore
| | - Gaixia Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound ImagingSchool of Biomedical EngineeringHealth Science CenterShenzhen University Shenzhen 518060 China
| | - Wei‐Jen Lin
- Department of Fiber and Composite MaterialsFeng Chia University Taichung 40724 Republic of China, Taiwan
| | - Jiajie Chen
- School of MedicineHealth Science CenterShenzhen University Shenzhen 518060 China
| | - Yinling Zhang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound ImagingSchool of Biomedical EngineeringHealth Science CenterShenzhen University Shenzhen 518060 China
| | - Tao Feng
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound ImagingSchool of Biomedical EngineeringHealth Science CenterShenzhen University Shenzhen 518060 China
| | - Peng Huang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound ImagingSchool of Biomedical EngineeringHealth Science CenterShenzhen University Shenzhen 518060 China
| | - Chih‐Kuang Chen
- Department of Chemical and Materials EngineeringNational Yunlin University of Science and Technology Yunlin 64002 Republic of China, Taiwan
| | - Ken‐Tye Yong
- School of Electrical and Electronic EngineeringNanyang Technological University Singapore 639798 Singapore
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Yang L, Liu Z, Wen T. Multiplex fluorescent immunohistochemistry quantitatively analyses microvascular density (MVD) and the roles of TGF-β signalling in orchestrating angiogenesis in colorectal cancer. Transl Cancer Res 2019; 8:429-438. [PMID: 35116775 PMCID: PMC8797362 DOI: 10.21037/tcr.2019.02.09] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 12/07/2018] [Indexed: 12/28/2022]
Abstract
Background Advances in multiplex fluorescent immunohistochemistry (mfIHC) techniques and digital pathology platforms allow the quantification of multiple proteins in the same tissue section and produce continuous data. Previously, we used mfIHC to establish the expressed profiles of proteins involved in TGF-β signalling in colorectal cancer (CRC). Methods We used mfIHC to show microvascular density (MVD) by staining CD31 in the tissues from CRC patients. We further investigated the relationship between MVD and TGF-β signalling. Results We found that the levels of MVD were significantly higher in cancer tissues than in paired normal tissues. Prognostic analysis revealed that the survival time for CRC patients with high levels of MVD was significantly shorter than that for those with low levels of MVD. Systematic analysis of the levels of MVD and TGF-β signalling proteins revealed that TGF-β signalling showed contradictory roles in sustained tumour angiogenesis. In CRC cells, the expression of VEGFA was increased by low concentrations of TGFB1 but decreased by high concentrations of TGFB1. Vessel-forming assays demonstrated that low-dose TGFB1 stimulated but high-dose TGFB1 inhibited HUVECs to form vessel tubes. Conclusions Our analysis based on mfIHC staining in CRC tissues supports the concept that TGF-β signalling either promotes or inhibits tumour angiogenesis.
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Affiliation(s)
- Lei Yang
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zheng Liu
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Tao Wen
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
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Tajmirriahi N, Razavi SM, Shirani S, Homayooni S, Gasemzadeh G. Evaluation of metastasis and 5-year survival in oral squamous cell carcinoma patients in Isfahan (2001-2015). Dent Res J (Isfahan) 2019; 16:117-121. [PMID: 30820206 PMCID: PMC6364350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Frequency analysis of metastasis in patients with oral squamous cell carcinoma (OSCC) helps to partly anticipate the upcoming chance of metastasis in the patients following primary diagnosis. This study was conducted to determine the evaluation of metastasis and 5-year survival in OSCC. MATERIALS AND METHODS This was a retrospective, descriptive study. A total of 96 OSCC patients were studied. Demographic data and clinical view of lesion as well as histopathological grade of patients were recorded in previously prepared forms of pathology centers. These findings were then evaluated in relation to the 5-year survival. The obtained data were fed into SPSS and analyzed by Chi-square test, t-test, one-way ANOVA, and Scheffé test. A significant level of α = 0.05 was used. RESULTS The 5-year survival of patients was 41.7%. From among the patients, 44% were found to have local recurrence and 36% were reported to have distant metastasis. There was no significant association between the 5-year survival rate and primary grade (P = 0.105). However, it revealed a significant relationship between the 5-year survival rate and distant metastasis (P = 0. 001). CONCLUSION This study showed that the 5-year survival is dependent on the primary site of involvement, local recurrence, regional and distant metastasis, and mean age. However, gender (P = 0.89), grade (P = 0.105), and stage (P = 0.242) have no effect on the 5-year survival of patients.
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Affiliation(s)
- Nabet Tajmirriahi
- Department of Dermatology, Skin Diseases and Leishmaniasis Research Centre, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Mohamad Razavi
- Department of Oral and Maxillofacial Pathology, Dental Implants Research Center, Isfahan, Iran
| | - Samaneh Shirani
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, International Campus, Tehran, Iran,Address for correspondence: Dr. Samaneh Shirani, Department of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, International Campus, Tehran, Iran. E-mail:
| | - Solmaz Homayooni
- Department of Oral and Maxillofacial Pathology, Dental Research Center, Isfahan, Iran
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Single Nucleotide Polymorphisms in miR-122 Are Associated with the Risk of Hepatocellular Carcinoma in a Southern Chinese Population. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1540201. [PMID: 30662901 PMCID: PMC6313975 DOI: 10.1155/2018/1540201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 11/20/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
Abstract
Single nucleotide polymorphisms (SNPs) in microRNA may affect its expression and regulation of target genes, which may consequently alter individual susceptibility to cancer. In this study we aimed to investigate associations between miR-122 polymorphisms and hepatocellular carcinoma (HCC) in a southern Chinese population. Three selected SNPs in miR-122 (rs9966765, rs1135519, and rs17669) were genotyped in 1050 HCC patients and 1079 cancer-free controls using Sequenom MassARRAY platform and the associations of the three SNPs and HCC risk were evaluated. We found that individuals with the rs1135519 CC genotypes had a significant increased risk of HCC than those with TT genotypes (adjusted OR=2.71, 95% CI=1.15-6.36, and P=0.022), while the rs9966765 CC genotypes showed a borderline significant association with increased risk of HCC when compared with the GG genotypes (adjusted OR=2.38, 95% CI=0.99-5.75, and P=0.052). There was also a significant increased risk of HCC when combining risk genotypes of these loci, i.e., rs1135519 CC and rs9966765 CC. Compared with the low-risk group (0 risk genotype), the high risk group (1-2 risk genotypes) had significantly increased risk of HCC (OR=1.61, 95% CI=1.05-2.44, and P=0.028). Further genotype-expression analysis revealed that cases carrying the CC genotype of rs1135519 had lower levels of miR-122 expression than those with the TT genotype. Our results suggest that SNP of rs1135519 modulates miR-122 expression and contributes to the genetic susceptibility of HCC, either independently or together with rs9966765 in miR-122. Further well-designed studies with lager sample sizes are needed to confirm our findings.
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Chen QQ, Zhang C, Qin MQ, Li J, Wang H, Xu DX, Wang JQ. Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice. Front Pharmacol 2018; 9:1344. [PMID: 30538632 PMCID: PMC6277551 DOI: 10.3389/fphar.2018.01344] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/31/2018] [Indexed: 12/12/2022] Open
Abstract
Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.
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Affiliation(s)
- Qian-Qian Chen
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Cheng Zhang
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Ming-Qiang Qin
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Jian Li
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - De-Xiang Xu
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Jian-Qing Wang
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
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Yamasaki Y, Kobayashi K, Okuya F, Kajitani N, Kazuki K, Abe S, Takehara S, Ito S, Ogata S, Uemura T, Ohtsuki S, Minegishi G, Akita H, Chiba K, Oshimura M, Kazuki Y. Characterization of P-Glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans. Drug Metab Dispos 2018; 46:1756-1766. [PMID: 29777024 DOI: 10.1124/dmd.118.081216] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/16/2018] [Indexed: 12/31/2022] Open
Abstract
P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the Mdr1a/1b genes in rodents, is expressed in numerous tissues and performs as an efflux pump to limit the distribution and absorption of many drugs. Owing to species differences of P-gp between humans and rodents, it is difficult to predict the impact of P-gp on pharmacokinetics and the tissue distribution of P-gp substrates in humans from the results of animal experiments. Therefore, we generated a novel P-gp humanized mouse model by using a mouse artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]. The results showed that hMDR1 mRNA was expressed in various tissues of hMDR1-MAC mice. Furthermore, the expression of human P-gp was detected in the brain capillary fraction and plasma membrane fraction of intestinal epithelial cells isolated from hMDR1-MAC mice, although the expression levels of intestinal P-gp were extremely low. Thus, we evaluated the function of human P-gp at the blood-brain barrier of hMDR1-MAC mice. The brain-to-plasma ratios of P-gp substrates in hMDR1-MAC mice were much lower than those in Mdr1a/1b-knockout mice, and the brain-to-plasma ratio of paclitaxel was significantly increased by pretreatment with a P-gp inhibitor in hMDR1-MAC mice. These results indicated that the hMDR1-MAC mice are the first P-gp humanized mice expressing functional human P-gp at the blood-brain barrier. This mouse is a promising model with which to evaluate species differences of P-gp between humans and mice in vivo and to estimate the brain distribution of drugs in humans while taking into account species differences of P-gp.
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Affiliation(s)
- Yuki Yamasaki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Kaoru Kobayashi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Fuka Okuya
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Naoyo Kajitani
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Kanako Kazuki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Satoshi Abe
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Shoko Takehara
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Shingo Ito
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Seiryo Ogata
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Tatsuki Uemura
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Sumio Ohtsuki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Genki Minegishi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Hidetaka Akita
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Kan Chiba
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Mitsuo Oshimura
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
| | - Yasuhiro Kazuki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (Y.Y., K.Ko., F.O., G.M., H.A., K.C.); Chromosome Engineering Research Center (N.K., K.Ka., S.A., S.T., M.O., Y.K.) and Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science (Y.K.), Tottori University, Tottori, Japan; and Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.I., S.Og., T.U., S.Oh.)
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KSHV oral shedding and plasma viremia result in significant changes in the extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite. PLoS One 2018; 13:e0192659. [PMID: 29425228 PMCID: PMC5806893 DOI: 10.1371/journal.pone.0192659] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/26/2018] [Indexed: 01/06/2023] Open
Abstract
Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS). Both KSHV and HIV infections are endemic in Uganda, where KS is among the most common cancers in HIV-infected individuals. Recent studies examined the use of small RNAs as biomarkers of disease, including microRNAs (miRNAs), with viral and tumor-derived miRNAs being detected in exosomes from individuals with KSHV-associated malignancies. In the current study, the host and viral extracellular mature miRNA expression profiles were analyzed in blood of KS-negative individuals in Uganda, comparing those with or without KSHV detectable from the oropharynx. We observed increased levels of cellular oncogenic miRNAs and decreased levels of tumor-suppressor miRNAs in plasma of infected individuals exhibiting oral KSHV shedding. These changes in host oncomiRs were exacerbated in people co-infected with HIV, and partially reversed after 2 years of anti-retroviral therapy. We also detected KSHV miRNAs in plasma of KSHV infected individuals and determined that their expression levels correlated with KSHV plasma viremia. Deep sequencing revealed an expected profile of small cellular RNAs in plasma, with miRNAs constituting the major RNA biotype. In contrast, the composition of small RNAs in exosomes was highly atypical with high levels of YRNA and low levels of miRNAs. Mass spectrometry analysis of the exosomes revealed eleven different peptides derived from the malaria parasite, Plasmodium falciparum, and small RNA sequencing confirmed widespread plasmodium co-infections in the Ugandan cohorts. Proteome analysis indicated an exosomal protein profile consistent with erythrocyte and keratinocyte origins for the plasma exosomes. A strong correlation was observed between the abundance of Plasmodium proteins and cellular markers of malaria. As Plasmodium falciparum is an endemic pathogen in Uganda, our study shows that co-infection with other pathogens, such as KSHV, can severely impact the small RNA repertoire, complicating the use of exosome miRNAs as biomarkers of disease.
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SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis. Cell Death Dis 2018; 9:151. [PMID: 29396446 PMCID: PMC5833407 DOI: 10.1038/s41419-017-0205-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 11/10/2017] [Accepted: 12/05/2017] [Indexed: 12/13/2022]
Abstract
Canonical TGF-β signals are transduced from the cell surface to the cytoplasm, and then translocated into the nucleus, a process that involves ligands (TGF-β1), receptors (TGFBR2/1), receptor-activated SMADs (SMAD2/3), and the common SMAD (SMAD4). Here we provide evidence that SMAD4, a core component of the canonical TGF-β signaling pathway, regulates the canonical TGF-β signaling pathway in porcine granulosa cells (GCs) through a feedback mechanism. Genome-wide analysis and qRT-PCR revealed that SMAD4 affected miRNA biogenesis in GCs. Interestingly, TGFBR2, the type II receptor of the canonical TGF-β signaling pathway, was downregulated in SMAD4-silenced GCs and found to be a common target of SMAD4-inhibited miRNAs. miR-425, the most significantly elevated miRNA in SMAD4-silenced GCs, mediated the SMAD4 feedback regulation of the TGF-β signaling pathway. This was accomplished through a direct interaction between the transcription factor SMAD4 and the miR-425 promoter, and a direct interaction between miR-425 and the TGFBR2 3′-UTR. Furthermore, miR-425 enhanced GC apoptosis by targeting TGFBR2 and the canonical TGF-β signaling pathway, which was rescued by SMAD4 and TGF-β1. Overall, our findings demonstrate that a positive feedback mechanism exists within the canonical TGF-β signaling pathway. This study also provides new insights into mechanism underlying the canonical TGF-β signaling pathway, which regulates GC function and follicular development.
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41
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Novel miR-122 delivery system based on MS2 virus like particle surface displaying cell-penetrating peptide TAT for hepatocellular carcinoma. Oncotarget 2018; 7:59402-59416. [PMID: 27449085 PMCID: PMC5312320 DOI: 10.18632/oncotarget.10681] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 07/01/2016] [Indexed: 12/19/2022] Open
Abstract
Current treatments for hepatocellular carcinoma (HCC) have shown inadequate. MicroRNA-122 (miR-122) mediated RNA interference brings new prospects. A safe, efficient miRNA delivery system is an indispensable assurance. Previously, we developed an MS2 bacteriophage virus-like particle (VLP)-based microRNA delivery system crosslinked with the HIV TAT peptide, which served as an effective inhibitor in the treatments of systemic lupus erythematosus and osteoporosis. However, defects, such as low crosslinking efficiency, high cost, and potential toxicity of the crosslinking agent, needed to be confronted. Therefore, TAT peptide was designed to display on the surface of MS2 VLPs, instead of being chemically crosslinked, using the platform of phage surface display. The results reflected that MS2 VLPs displaying TAT could effectively penetrate the cytomembrane and deliver miR-122. Additionally, its inhibitory effects on HCC were significant in Hep3B, HepG2, and Huh7 cells and Hep3B related animal models. Thus, we have established a novel miR-122 delivery system based on MS2 VLPs surface displaying TAT peptide, which could effectively perform the function of penetrating cytomembrane and the inhibition of HCC.
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42
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Yang L, Liu Z, Tan J, Dong H, Zhang X. Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer. Cancer Biol Ther 2017; 19:105-112. [PMID: 29219668 DOI: 10.1080/15384047.2017.1395116] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Advances in multiplex immunohistochemistry (IHC) techniques and digital pathology platforms allow quantification of multiple proteins at same tissue section and produce continuous data. TGF-β signaling plays crucial and complex roles in colorectal cancer (CRC). We here aimed to investigate clinical pathological relevant of proteins involved in TGF-β signaling at CRC tissues. Multiplex fluorescent IHC was used to quantitative analysis. The levels of eight proteins (TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD2/3, p-SMAD2/3, SMAD1/5/9, and p-SMAD1/5/9) were determined in TMA sections. Quantitative analysis was carried out by a scoring system by InForm software. It revealed that TGF-β signaling was hyper active. The levels of TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD1/5/9 and p-SMAD2/3 were significantly increased in cancer tissues when compared their levels in normal tissues. Furthermore, the levels of eight proteins in stroma were significantly lower than the levels that in cancer tissues. Clinical pathological relevant analysis exhibited that TGF-β signaling inclined to suppress the progression of tumor. SMAD1/5/9, TGFBRII, SMAD2/3 were confirmed as significant predictors for overall survival. In conclusion, we established a method based on multispectral imaging to extensively explore the clinical relevant of TGF-β signaling proteins. These results provided an opportunity to consider the novel application for proteins involving TGF-β signaling that used as diagnostic or prognostic biomarkers to conduct tumor therapy.
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Affiliation(s)
- Lei Yang
- a Medical Research Center, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Zheng Liu
- a Medical Research Center, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Jinjing Tan
- b Department of Cellular and Molecular Biology, Beijing Chest Hospital , Capital Medical University , Beijing , P.R. China
| | - Hongwei Dong
- c Oncology Department, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Xiaojing Zhang
- c Oncology Department, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
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43
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Alamoudi AA, Alnoury A, Gad H. miRNA in tumour metabolism and why could it be the preferred pathway for energy reprograming. Brief Funct Genomics 2017; 17:157-169. [DOI: 10.1093/bfgp/elx023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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44
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Zhang F, Wan M, Xu Y, Li Z, Leng K, Kang P, Cui Y, Jiang X. Long noncoding RNA PCAT1 regulates extrahepatic cholangiocarcinoma progression via the Wnt/β-catenin-signaling pathway. Biomed Pharmacother 2017; 94:55-62. [PMID: 28753454 DOI: 10.1016/j.biopha.2017.07.025] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 06/21/2017] [Accepted: 07/06/2017] [Indexed: 01/09/2023] Open
Abstract
Extrahepatic cholangiocarcinoma (ECC) is a deadly disease that often responds poorly to conventional chemotherapy or radiotherapy. Long noncoding RNAs (lncRNAs) play important roles in human cancers, including ECC, and recent studies indicated that the lncRNA prostate cancer-associated transcript 1 (non-protein coding) (PCAT1) is involved in multiple cancers. However, the role of PCAT1 in ECC is unclear. Previously, we showed that PCAT1 is up-regulated in both ECC tissue samples and cell lines. Here, we showed that downregulation of PCAT1 following transfection with silencing RNA reduced ECC cell growth and increased cell apoptosis. Additionally, PCAT1 suppression inhibited ECC cell migration and invasion as determined by transwell assay. Furthermore, we determined that PCAT1 is a competing endogenous for microRNA (miR)-122, with bioinformatics analysis and luciferase-reporter assay results demonstrating that PCAT1 regulated WNT1 expression via miR-122. Moreover, PCAT1 downregulation increased levels of glycogen synthase kinase 3β and significantly decreased β-catenin levels in whole cell lysates and nuclear fractions, indicating that PCAT1 silencing inhibited the Wnt/β-catenin-signaling pathway. We also observed that exogenous expression of WNT1 reversed PCAT1-silencing-induced inhibition of ECC cell growth inhibition. These results indicated that PCAT1 silencing inhibited ECC progression by reducing Wnt/β-catenin signaling through miR-122 repression and WNT1 expression. Our findings revealed an important role of PCAT1 in ECC and suggested that PCAT1 might be a potential ECC-related therapeutic target.
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Affiliation(s)
- Fumin Zhang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China; Department of General Surgery, Daqing Oilfield General Hospital, Daqing, 163000, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin 150086, Heilongjiang Province, China
| | - Ming Wan
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Zhenglong Li
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Kaiming Leng
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Pengcheng Kang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
| | - Xingming Jiang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
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45
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Wei S, Fan Q, Yang L, Zhang X, Ma Y, Zong Z, Hua X, Su D, Sun H, Li H, Liu Z. Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling. Oncol Rep 2017; 38:1902-1908. [PMID: 28731193 DOI: 10.3892/or.2017.5840] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/06/2017] [Indexed: 11/06/2022] Open
Abstract
The long non-coding RNA HOX transcript antisense RNA (HOTAIR) plays a key role in the progression of various carcinomas. However, whether or not HOTAIR influences glucose metabolism and the specific underlying mechanism in hepatocellular carcinoma (HCC) cells remain unclear. In the present study, we found markedly increased HOTAIR expression in 84 HCC tissues and demonstrated that HOTAIR overexpression promoted cell proliferation using Cell Counting Kit-8. The effect on glucose metabolism regulated by HOTAIR in HCC cells was determined by detecting lactate and glucose levels: HOTAIR promoted glycolysis by upregulating glucose transporter isoform 1 (GLUT1) and activating mammalian target of rapamycin (mTOR) signaling, whereas knockdown of HOTAIR suppressed this effect. Our research reveals a novel relationship between HOTAIR and glucose metabolism in HCC cells, and it may be a therapeutic target for diagnosing and treating HCC.
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Affiliation(s)
- Shibo Wei
- Department of General Surgery, The Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Qing Fan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Xiaodong Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yingbo Ma
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Zhihong Zong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiangdong Hua
- Department of General Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China
| | - Dongming Su
- Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hongzhi Sun
- Department of General Surgery, The First Hospital Affiliated to Jinzhou Medical College, Jinzhou, Liaoning 121001, P.R. China
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Zhen Liu
- Department of General Surgery, The Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, P.R. China
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46
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Demerdash HM, Hussien HM, Hassouna E, Arida EA. Detection of MicroRNA in Hepatic Cirrhosis and Hepatocellular Carcinoma in Hepatitis C Genotype-4 in Egyptian Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1806069. [PMID: 28642869 PMCID: PMC5469990 DOI: 10.1155/2017/1806069] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Revised: 04/05/2017] [Accepted: 04/19/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND In Egypt, the prevalence of chronic hepatitis C (CHC) infection is 13.8% of whole population and about 80% of the patients with hepatocellular carcinoma have underling hepatitis C. AIM This study was designed to assess the diagnostic value of plasma miR-122 and miR-21 in patients with CHC, genotype-4, to detect fibrosis progression versus noninvasive indices and their diagnostic value in detection of early stages of hepatocellular carcinoma (HCC). METHODOLOGY A prospective study that included 180 patients, divided into 3 groups: healthy controls (group I), CHC patients (group II), and hepatitis C patients with HCC (group III); all cases were subjected to thorough clinical, radiological, and laboratory investigations. Selected biomarkers were evaluated and correlated with degree of liver damage. Results revealed that miR-122 followed by miR-21 had the highest efficiency in prediction of liver cell damage. Also, miR-21 was strongly correlated with vascular endothelial growth factor (VEGF) and alpha fetoprotein (α-FP) in HCC patients. CONCLUSIONS Plasma miR-122 and miR-21 had strong correlation with degree fibrosis in HCV genotype-4 patients; consequently they can be considered as potential biomarker for early detection of hepatic fibrosis. Moreover, miR-21 can be used as a potential biomarker, for early detection of HCC combined with VEGF and α-FP.
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Affiliation(s)
- Hala M. Demerdash
- Department of Clinical Pathology, Alexandria University Hospitals, Alexandria, Egypt
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Drug Manufacturing, Pharos University, Alexandria, Egypt
| | - Hend M. Hussien
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Drug Manufacturing, Pharos University, Alexandria, Egypt
| | - Ehab Hassouna
- Department of Internal Medicine, Hepatology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Emad A. Arida
- Department of Anesthesia and Surgical Intensive Care, Alexandria University Faculty of Medicine, Chamblion Street, Elazareeta, District-Zip Code 21526, Alexandria, Egypt
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47
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Yang J, Brown ME, Zhang H, Martinez M, Zhao Z, Bhutani S, Yin S, Trac D, Xi JJ, Davis ME. High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction. Am J Physiol Heart Circ Physiol 2017; 312:H1002-H1012. [PMID: 28235791 DOI: 10.1152/ajpheart.00685.2016] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 02/01/2017] [Accepted: 02/15/2017] [Indexed: 01/09/2023]
Abstract
Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases.NEW & NOTEWORTHY NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening to identify microRNAs that target Nox2 and improve cardiac function after infarction.
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Affiliation(s)
- Junyu Yang
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.,Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia
| | - Milton E Brown
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia
| | - Hanshuo Zhang
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China
| | - Mario Martinez
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia
| | - Zhihua Zhao
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China
| | - Srishti Bhutani
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia
| | - Shenyi Yin
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China
| | - David Trac
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia
| | - Jianzhong Jeff Xi
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.,Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.,State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.,State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University, Beijing, China; and
| | - Michael E Davis
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China; .,Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.,Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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48
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Liu Y, Jin L, Lou P, Gu Y, Li M, Li X. Dynamic microRNAome profiles in the developing porcine liver. Biosci Biotechnol Biochem 2017; 81:127-134. [DOI: 10.1080/09168451.2016.1240602] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abstract
Increasing evidence suggests that micro (mi)RNAs play important roles in various biological process. To evaluate the roles of miRNA in the porcine liver, we investigated the dynamic profiles of microRNAomes using liver tissue from pigs during the embryonic period (embryonic day 90), weaning stage (postnatal day 30), and adult stage (7 years old). A total of 186 unique miRNAs were differentially expressed during liver development. We also identified that 17, 13, and 6 miRNAs were specifically abundant at embryonic day 90, postnatal day 30, and at 7 years, respectively. Besides regulating basic cellular roles in development, miRNAs expressed at the three developmental stages also participated in regulating “embryonic liver development,” “early hepatic growth and generating a functioning liver,” and “energy metabolic processes,” respectively. Our study indicates that miRNAs are extensively involved in liver development, and provides a valuable resource for the further elucidation of miRNA regulatory roles during liver development.
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Affiliation(s)
- Yihui Liu
- College of Animal Science & Technology, Sichuan Agricultural University, Chengdu, China
| | - Long Jin
- College of Animal Science & Technology, Sichuan Agricultural University, Chengdu, China
| | - Pengbo Lou
- College of Animal Science & Technology, Sichuan Agricultural University, Chengdu, China
| | - Yiren Gu
- Genetics of the Pigs, Sichuan Animal Science Academy, Chengdu, China
| | - Mingzhou Li
- College of Animal Science & Technology, Sichuan Agricultural University, Chengdu, China
| | - Xuewei Li
- College of Animal Science & Technology, Sichuan Agricultural University, Chengdu, China
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In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone. Int J Mol Sci 2016; 17:ijms17091405. [PMID: 27571063 PMCID: PMC5037685 DOI: 10.3390/ijms17091405] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/10/2016] [Accepted: 08/19/2016] [Indexed: 12/27/2022] Open
Abstract
Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps.
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