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Kremer KN, Khammash HA, Miranda AM, Rutt LN, Twardy SM, Anton PE, Campbell ML, Garza-Ortiz C, Orlicky DJ, Pelanda R, McCullough RL, Torres RM. Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance. Front Immunol 2025; 15:1497788. [PMID: 39896805 PMCID: PMC11782242 DOI: 10.3389/fimmu.2024.1497788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/24/2024] [Indexed: 02/04/2025] Open
Abstract
As a metabolic center, the liver prevents inappropriate immune responses to abundant dietary antigens within the liver that could result in liver injury. This self-preservation mechanism can however decrease the efficiency of immunosurveillance of malignant cells by CD8 T cells. Hepatocellular carcinoma (HCC) is initiated by chronic viral infections, chronic alcohol consumption, and/or a fatty diet that leads to liver injury, fibrosis, and cirrhosis. HCC patients have high levels of dysfunctional and exhausted T cells, however, it is unclear which stage of HCC development contributes to T cell dysfunction. Repair of liver injury is initiated by interactions between injured hepatocytes and liver sinusoidal endothelial cells (LSEC), however, chronic injury can lead to fibrosis. Here, using a diethylnitrosamine/carbon tetrachloride (DEN/CCl4) mouse model of early HCC development, we demonstrate that chronic liver injury and fibrosis are sufficient to induce a CD8 T cell exhaustion signature with a corresponding increase in expression of immunosuppressive molecules on LSEC. We show that LSEC alter T cell function at various stages of T cell differentiation/activation. LSEC compete with dendritic cells presenting the same antigen to naïve CD8 T cells resulting in a unique T cell phenotype. Furthermore, LSEC abrogate killing of target cells, in an antigen-dependent manner, by previously activated effector CD8 T cells, and LSEC change the effector cell cytokine profile. Moreover, LSEC induce functional T cell exhaustion under low dose chronic stimulation conditions. Thus, LSEC critically regulate the balance between preventing/limiting liver injury and permitting sufficient tumor immunosurveillance with normal hepatic functions likely contributing to HCC development under conditions of chronic liver insult.
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Affiliation(s)
- Kimberly N. Kremer
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Hadeel A. Khammash
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Anjelica M. Miranda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Lauren N. Rutt
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Shannon M. Twardy
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Paige E. Anton
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Margaret L. Campbell
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Christian Garza-Ortiz
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Rebecca L. McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
| | - Raul M. Torres
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
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Njei B, Al-Ajlouni YA, Ameyaw P, Njei LP, Boateng S. Role of ammonia and glutamine in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease: A systematic review. J Gastroenterol Hepatol 2024; 39:1788-1808. [PMID: 38763916 DOI: 10.1111/jgh.16603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/10/2024] [Accepted: 04/24/2024] [Indexed: 05/21/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population, with a significant risk of advancing to liver cirrhosis and hepatocellular carcinoma. The roles of ammonia and glutamine in MASLD's pathogenesis are increasingly recognized, prompting this systematic review. This systematic review was conducted through a meticulous search of literature on December 21, 2023, across five major databases, focusing on studies that addressed the relationship between ammonia or glutamine and MASLD. The quality of the included studies was evaluated using CASP checklists. This study is officially registered in the PROSPERO database (CRD42023495619) and was conducted without external funding or sponsorship. Following PRISMA guidelines, 13 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The appraisal indicated a mainly low bias, confirming the reliability of the evidence. Glutamine's involvement in MASLD emerged as multifaceted, with its metabolic role being critical for liver function and disease progression. Variable expressions of glutamine synthetase and glutaminase enzymes highlight metabolic complexity whereas ammonia's impact through urea cycle dysfunction suggests avenues for therapeutic intervention. However, human clinical trials are lacking. This review emphasizes the necessity of glutamine and ammonia in understanding MASLD and identifies potential therapeutic targets. The current evidence, while robust, points to the need for human studies to corroborate preclinical findings. A personalized approach to treatment, informed by metabolic differences in MASLD patients, is advocated, alongside future large-scale clinical trials for a deeper exploration into these metabolic pathways.
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Affiliation(s)
- Basile Njei
- International Medicine Program, Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
| | | | - Prince Ameyaw
- Yale Affiliated Hospitals Program, Bridgeport, Connecticut, USA
| | - Lea-Pearl Njei
- University of Maryland Baltimore County, Baltimore, Maryland, USA
| | - Sarpong Boateng
- Yale Affiliated Hospitals Program, Bridgeport, Connecticut, USA
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Kumazoe M, Miyamoto E, Oka C, Kondo M, Yoshitomi R, Onda H, Shimada Y, Fujimura Y, Tachibana H. miR-12135 ameliorates liver fibrosis accompanied with the downregulation of integrin subunit alpha 11. iScience 2024; 27:108730. [PMID: 38235326 PMCID: PMC10792239 DOI: 10.1016/j.isci.2023.108730] [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: 08/17/2022] [Revised: 07/26/2023] [Accepted: 12/11/2023] [Indexed: 01/19/2024] Open
Abstract
Cirrhosis is becoming one of the most common diseases worldwide. Abnormal upregulation of transforming growth factor β (TGF-β) signaling plays a pivotal role in the excess activation of hepatic stellate cells. However, an efficient countermeasure against abnormal hepatic stellate cell activation is yet to be established because TGF-β signaling is involved in several biological processes. Herein, we demonstrated the antifibrotic effect of miR-12135, a microRNA with unknown function upregulated by isoflavone. Comprehensive transcriptome assay demonstrated that miR-12135 suppressed Integrin Subunit Alpha 11 (ITGA11) and that ITGA11 expression is correlated with alpha smooth muscle actin expression in patients with cirrhosis. miR-12135 suppressed the expression level of ITGA11 and liver fibrosis. Importantly, ITGA11 is overexpressed in activated hepatic stellate cells, whereas ITGA11 knockout mice are viable and fertile. In conclusions, the miR-12135/ITGA11 axis can be an ideal therapeutic target to suppress fibrosis by precisely targeting abnormally upregulated TGF-β signaling in hepatic stellate cells.
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Affiliation(s)
- Motofumi Kumazoe
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Emi Miyamoto
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Chihiro Oka
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Miyuki Kondo
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Ren Yoshitomi
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Hiroaki Onda
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Yu Shimada
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Yoshinori Fujimura
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Hirofumi Tachibana
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
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Wan S, Liu X, Sun R, Liu H, Jiang J, Wu B. Activated hepatic stellate cell-derived Bmp-1 induces liver fibrosis via mediating hepatocyte epithelial-mesenchymal transition. Cell Death Dis 2024; 15:41. [PMID: 38216590 PMCID: PMC10786946 DOI: 10.1038/s41419-024-06437-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/14/2024]
Abstract
Liver fibrosis is a reparative response to injury that arises from various etiologies, characterized by activation of hepatic stellate cells (HSCs). Periostin, a secreted matricellular protein, has been reported to participate in tissue development and regeneration. However, its involvement in liver fibrosis remains unknown. This study investigated the roles and mechanisms of Periostin in phenotypic transition of HSCs and relevant abnormal cellular crosstalk during liver fibrosis. The fate of hepatic stellate cells (HSCs) during liver fibrogenesis was investigated using single-cell and bulk RNA sequencing profiles, which revealed a significant proliferation of activated HSCs (aHSCs) in fibrotic livers of both humans and mice. αSMA-TK mice were used to demonstrate that depletion of proliferative aHSCs attenuates liver fibrosis induced by carbon tetrachloride and 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Through integrating data from single-cell and bulk sequencing, Periostin was identified as a distinctive hallmark of proliferative aHSC subpopulation. Elevated levels of Periostin were detected in fibrotic livers of both humans and mice, primarily within aHSCs. However, hepatic Periostin levels were decreased along with depletion of proliferative aHSCs. Deficiency of Periostin led to reduced liver fibrosis and suppressed hepatocyte epithelial-mesenchymal transition (EMT). Periostin-overexpressing HSCs, exhibiting a proliferative aHSC phenotype, release bone morphogenetic protein-1 (Bmp-1), which activates EGFR signaling, inducing hepatocyte EMT and contributing to liver fibrosis. In conclusion, Periostin in aHSCs drives their acquisition of a proliferative phenotype and the release of Bmp-1. Proliferative aHSC subpopulation-derived Bmp-1 induces hepatocyte EMT via EGFR signaling, promoting liver fibrogenesis. Bmp-1 and Periostin should be potential therapeutic targets for liver fibrosis.
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Affiliation(s)
- Sizhe Wan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Xianzhi Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Ruonan Sun
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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Espírito Santo J, Ladeirinha A, Alarcão A, Strelet E, Reis M, Santos R, Carvalho L. Preoperative Locoregional Therapy May Relate with Stemness and Distinct Transitions Between Epithelial and Mesenchymal States in Hepatocellular Carcinoma. J Clin Exp Hepatol 2024; 14:101268. [PMID: 38076372 PMCID: PMC10709210 DOI: 10.1016/j.jceh.2023.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/12/2023] [Indexed: 01/05/2025] Open
Abstract
Background/Objectives Locoregional therapy (LRT) might impel hepatocellular carcinoma (HCC) to exhibit different phenotypes by modulating tumoral cell adaptation. HCCs presurgically treated with LRT were studied, focusing on stemness and mesenchymal features. Methods Clinicopathological and immunohistochemical data (Ki67, p53, EpCAM, CK19, CK7, ASMA and vimentin expression) were considered in 89 HCC nodules (30 treated with LRT; 59 non-treated), comprising 46 liver transplanted/surgically resected patients. Results In LRT group, well and poorly differentiated tumors without fibrous encapsulation were predominant (P < 0.05) and peritumoral necroinflammation severity tended to be greater. Peritumoral Ki67 expression was higher (P < 0.05) and p53, EpCAM, CK19 and CK7 peritumoral expression was relevant after LRT, where ablated carcinomas displayed higher peritumoral CK19 expression (P < 0.05). Tumoral ASMA and vimentin expression was higher in non-LRT group (P < 0.05). In LRT group, an exclusive association between progenitor/cholangiocytic cell and mesenchymal markers expressed by tumoral cells was observed (P < 0.05): EpCAM tumoral expression associated with vimentin stromal expression; tumoral CK19 expression associated with stromal ASMA expression; tumoral CK7 expression associated with tumoral vimentin expression. Conclusion Peritumoral cellular proliferation and expression of progenitor/cholangiocytic cell markers seem to be more frequent after LRT, with a distinctive epithelial-mesenchymal interplay and plasticity in peritumoral and tumoral compartments.
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Affiliation(s)
- Joana Espírito Santo
- Coimbra Hospital and University Centre, Adult Liver Transplantation Unit, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - Ana Ladeirinha
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - Ana Alarcão
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - Eugeniu Strelet
- Chemical Process Engineering and Forest Products Research Centre, University of Coimbra, Department of Chemical Engineering, Rua Sílvio Lima, Pólo II – Pinhal de Marrocos, 3030-790 Coimbra, Portugal
| | - Marco Reis
- Chemical Process Engineering and Forest Products Research Centre, University of Coimbra, Department of Chemical Engineering, Rua Sílvio Lima, Pólo II – Pinhal de Marrocos, 3030-790 Coimbra, Portugal
| | - Rui Santos
- Coimbra Hospital and University Centre, Internal Medicine Department, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal
| | - Lina Carvalho
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Coimbra Hospital and University Centre, Pathology Department, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal
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Li F, Zhao Y, Nie G. Nanotechnology-based combinational strategies toward the regulation of myofibroblasts and diseased microenvironment in liver fibrosis and hepatic carcinoma. NANO RESEARCH 2023; 16:13042-13055. [DOI: 10.1007/s12274-023-5809-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 01/03/2025]
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Noah AA, El-Mezayen NS, El-Ganainy SO, Darwish IE, Afify EA. Reversal of fibrosis and portal hypertension by Empagliflozin treatment of CCl 4-induced liver fibrosis: Emphasis on gal-1/NRP-1/TGF-β and gal-1/NRP-1/VEGFR2 pathways. Eur J Pharmacol 2023; 959:176066. [PMID: 37769984 DOI: 10.1016/j.ejphar.2023.176066] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 10/03/2023]
Abstract
To date, liver fibrosis has no clinically approved treatment. Empagliflozin (EMPA), a highly selective sodium-glucose-cotransporter-2 (SGLT2) inhibitor, has shown ameliorative potential in liver diseases without revealing its full mechanisms. Neuropilin-1 (NRP-1) is a novel regulator of profibrogenic signaling pathways related to hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs) that modulates intrahepatic profibrogenic and angiogenic pathways. Herein, EMPA's antifibrotic potentials and effects on galactin-1 (Gal-1)/NRP-1 signaling pathways have been evaluated in an experimental liver fibrosis rat model by testing different EMPA dose regimens. EMPA treatment brought a dose-dependent decrease in Gal-1/NRP-1 hepatic expression. This was coupled with suppression of major HSCs pro-fibrotic pathways; transforming growth factor-β (TGF-β)/TGF-βRI/Smad2 and platelet-derived growth factor-beta (PDGF-β) with a diminution of hepatic Col 1A1 level. In addition, EMPA prompted a protuberant suppression of the angiogenic pathway; vascular endothelial growth factor (VEGF)/VEGF-receptor-2 (VEGFR-2)/SH2-Domain Containing Adaptor Protein-B (Shb), and reversal of altered portal hypertension (PHT) markers; endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS). The amelioration of liver fibrosis was coupled with a remarkable improvement in liver aminotransferases and histologic hepatic fibrosis Ishak scores. The highest EMPA dose showed a good safety profile with minimal changes in renal function and glycemic control. Thus, the current study brought about novel findings for a potential liver fibrosis treatment modality via targeting NRP-1 signaling pathways by EMPA.
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Affiliation(s)
- Ashraf A Noah
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Clinical Research Administration, Alexandria Directorate of Health Affairs, Egyptian Ministry of Health and Population, Alexandria, Egypt
| | - Nesrine S El-Mezayen
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Samar O El-Ganainy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Inas E Darwish
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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8
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Kandhi R, Yeganeh M, Yoshimura A, Menendez A, Ramanathan S, Ilangumaran S. Hepatic stellate cell-intrinsic role of SOCS1 in controlling hepatic fibrogenic response and the pro-inflammatory macrophage compartment during liver fibrosis. Front Immunol 2023; 14:1259246. [PMID: 37860002 PMCID: PMC10582746 DOI: 10.3389/fimmu.2023.1259246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Introduction Hepatic stellate cells (HSC) become activated, differentiate to myofibroblasts and produce extracellular fibrillar matrix during liver fibrosis. The hepatic fibrogenic response is orchestrated by reciprocal interactions between HSCs and macrophages and their secreted products. SOCS1 can regulate several cytokines and growth factors implicated in liver fibrosis. Here we investigated the role of SOCS1 in regulating HSC activation. Methods Mice lacking SOCS1 in HSCs (Socs1ΔHSC) were generated by crossing Socs1fl/fl and LratCre mice. Liver fibrosis was induced by carbon tetrachloride and evaluated by Sirius red staining, hydroxyproline content and immunostaining of myofibroblasts. Gene expression of pro-fibrogenic factors, cytokines, growth factors and chemokines were quantified by RT-qPCR. The phenotype and the numbers of intrahepatic leukocyte subsets were studied by flow cytometry. The impact of fibrosis on the development of diethyl nitrosamine-induced hepatocellular carcinoma was evaluated. Results Socs1ΔHSC mice developed more severe liver fibrosis than control Socs1fl/fl mice that was characterized by increased collagen deposition and myofibroblast differentiation. Socs1ΔHSC mice showed a significant increase in the expression of smooth muscle actin, collagens, matrix metalloproteases, cytokines, growth factors and chemokines in the liver following fibrosis induction. The fibrotic livers of Socs1ΔHSC mice displayed heightened inflammatory cell infiltration with increased proportion and numbers of Ly6ChiCCR2+ pro-inflammatory macrophages. This macrophage population contained elevated numbers of CCR2+CX3CR1+ cells, suggesting impaired transition towards restorative macrophages. Fibrosis induction following exposure to diethyl nitrosamine resulted in more numerous and larger liver tumor nodules in Socs1ΔHSC mice than in Socs1fl/fl mice. Discussion Our findings indicate that (i) SOCS1 expression in HSCs is a critical to control liver fibrosis and development of hepatocaellular carcinoma, and (ii) attenuation of HSC activation by SOCS1 regulates pro-inflammatory macrophage recruitment and differentiation during liver fibrosis.
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Affiliation(s)
- Rajani Kandhi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Mehdi Yeganeh
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Alfredo Menendez
- Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Batudeligen, Han Z, Chen H, Narisu, Xu Y, Anda, Han G. Luteolin Alleviates Liver Fibrosis in Rat Hepatic Stellate Cell HSC-T6: A Proteomic Analysis. Drug Des Devel Ther 2023; 17:1819-1829. [PMID: 37360572 PMCID: PMC10285022 DOI: 10.2147/dddt.s402864] [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: 12/27/2022] [Accepted: 05/23/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Traditional Chinese medicine (TCM) with single or compound materials is an effective cure for liver fibrosis. Hepatic stellate cells (HSCs) play a key role in liver fibrosis pathology and have become a novel drug target for this condition. METHODS CCK-8 assay was used to determine the cytotoxicity of four components, SYPA, HSYPA, Apigenin, and Luteolin, from Deduhonghua-7 powder on HSC-T6 cells. Transforming Growth Factor β 1 (TGFβ1)-induced fibrotic cell model and CCI4-induced fibrotic rat model were constructed, the expression of fibrosis-related genes, the pathological changes and serum biochemical markers were evaluated. Proteomic analysis was performed to determine the mechanism by which luteolin attenuated liver fibrosis, which were further confirmed by Western blot. RESULTS Luteolin attenuates liver fibrosis in HSC-T6 cells and luteolin decreases the liver fibrosis index level in vivo. A total of 5000 differentially expressed proteins (DEPs) were obtained using proteomic analysis. KEGG analysis found that DEPs were concentrated in various metabolic pathways, including DNA replication and repair and lysosomal signaling. GO analysis showed that molecular functions included the activity and binding of various enzymes, related cellular components included the extracellular space, lysosomal lumen, mitochondrial matrix, and nucleus, and biological processes included collagen organization and biosynthesis and the positive regulation of cell migration. Western blot results showed that CCR1, CD59, and NAGA were downregulated in TGFβ1 treatment, while upregulated both in Lut2 and Lut10 treatment. Meanwhile, eight proteins, ITIH3, MKI67, KIF23, DNMT1, P4HA3, CCDC80, APOB, FBLN2, that were upregulated in TGFβ1 treatment, while downregulated both in Lut2 and Lut10 treatment. CONCLUSION Luteolin was shown to have a strong protective effect on liver fibrosis. CCR1, CD59, and NAGA may promote liver fibrosis while ITIH3, MKI67, KIF23, DNMT1, P4HA3, CCDC80, APOB, and FBLN2 may facilitate protection against fibrosis.
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Affiliation(s)
- Batudeligen
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Zhiqiang Han
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Hongmei Chen
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Narisu
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Yanhua Xu
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Anda
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
| | - Gegentaoli Han
- Institute of Clinical Pharmacology of Traditional Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao City, Inner Mongolia, People’s Republic of China
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10
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Kim S, Lee SY, Seo HR. Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models. BMB Rep 2023; 56:225-233. [PMID: 36814078 PMCID: PMC10140482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal. Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo. However, the information provided by an multicelluar tumor spheroid (MCTS) model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases. [BMB Reports 2023; 56(4): 225-233].
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Affiliation(s)
- Sanghwa Kim
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
| | - Su-Yeon Lee
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
| | - Haeng Ran Seo
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
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Kim S, Lee SY, Seo HR. Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models. BMB Rep 2023; 56:225-233. [PMID: 36814078 PMCID: PMC10140482 DOI: 10.5483/bmbrep.2023-0010] [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: 01/20/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 03/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal. Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo. However, the information provided by an multicelluar tumor spheroid (MCTS) model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases. [BMB Reports 2023; 56(4): 225-233].
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Affiliation(s)
- Sanghwa Kim
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
| | - Su-Yeon Lee
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
| | - Haeng Ran Seo
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
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12
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Yao M, Liang S, Cheng B. Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine. Front Pharmacol 2023; 14:1110922. [PMID: 36733504 PMCID: PMC9886889 DOI: 10.3389/fphar.2023.1110922] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) usually occurs on the basis of chronic liver inflammatory diseases and cirrhosis. The liver microenvironment plays a vital role in the tumor initiation and progression. Exosomes, which are nanometer-sized membrane vesicles are secreted by a number of cell types. Exosomes carry multiple proteins, DNAs and various forms of RNA, and are mediators of cell-cell communication and regulate the tumor microenvironment. In the recent decade, many studies have demonstrated that exosomes are involved in the communication between HCC cells and the stromal cells, including endothelial cells, macrophages, hepatic stellate cells and the immune cells, and serve as a regulator in the tumor proliferation and metastasis, immune evasion and immunotherapy. In addition, exosomes can also be used for the diagnosis and treatment HCC. They can potentially serve as specific biomarkers for early diagnosis and drug delivery vehicles of HCC. Chinese herbal medicine, which is widely used in the prevention and treatment of HCC in China, may regulate the release of exosomes and exosomes-mediated intercellular communication. In this review, we summarized the latest progresses on the role of the exosomes in the initiation, progression and treatment of HCC and the potential value of Traditional Chinese medicine in exosomes-mediated biological behaviors of HCC.
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Affiliation(s)
- Man Yao
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Shufang Liang
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China,Faculty of Traditional Chinese Medicine, Naval Medical University (The Second Military Medical University), Shanghai, China,*Correspondence: Binbin Cheng,
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Design of Nanoparticles in Cancer Therapy Based on Tumor Microenvironment Properties. Pharmaceutics 2022; 14:pharmaceutics14122708. [PMID: 36559202 PMCID: PMC9785496 DOI: 10.3390/pharmaceutics14122708] [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: 10/19/2022] [Revised: 11/23/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and battling cancer has always been a challenging subject in medical sciences. All over the world, scientists from different fields of study try to gain a deeper knowledge about the biology and roots of cancer and, consequently, provide better strategies to fight against it. During the past few decades, nanoparticles (NPs) have attracted much attention for the delivery of therapeutic and diagnostic agents with high efficiency and reduced side effects in cancer treatment. Targeted and stimuli-sensitive nanoparticles have been widely studied for cancer therapy in recent years, and many more studies are ongoing. This review aims to provide a broad view of different nanoparticle systems with characteristics that allow them to target diverse properties of the tumor microenvironment (TME) from nanoparticles that can be activated and release their cargo due to the specific characteristics of the TME (such as low pH, redox, and hypoxia) to nanoparticles that can target different cellular and molecular targets of the present cell and molecules in the TME.
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14
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Hussein MA, Radwan AFM, Fawzi MM, Rashed LA, Saad EHAI. MicroRNA 21as a novel biomarker in hepatitis C virus-related hepatocellular carcinoma. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2022. [DOI: 10.1186/s43162-022-00136-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatocellular carcinoma is considered one of the most common cancers occurring in human population all over the world. It became an increasingly threatening malignancy due to both morbidity and mortality. Chronic viral hepatitis B and hepatitis C are two risk factors, which account for 80–90% of all HCC cases worldwide. Alfa Feto protien is used as a tumor marker for HCC diagnosis and prognosis prediction; however, its false negative rate when used alone is as high as 40% for patients with early-stage HCC. AFP levels remain normal in 15–30% of all the patients, even patients with advanced HCC. It has been demonstrated that miRNAs (MicroRNAs) are an important class of non-coding RNAs. They act as tumor oncogenes or suppressors and are involved in the HCC development. MiRNAs are endogenous nucleotides that can be found in intra- and extracellular spaces, such as the blood, urine, and saliva.
The study evaluated the miRNA 21 as a novel biomarker in patients with HCV related hepatocellular carcinoma.
Results
The study was conducted on three groups. Group (1) included 25 patients with liver cirrhosis due to hepatitis C virus infection. Group (2) included 25 patients with hepatocellular carcinoma (HCC) on top of liver cirrhosis due to hepatitis C virus infection. Group (3) included 10 normal control subjects. There was a significant difference in the mean level of miRNA between the three groups with p value < 0.001 with the highest value in group 2 ( 8.28 ± 2.55), then in group1 (5.04 ± 2.11) and the lowest in group 3 (control) (1.02 ± 0.07). MiRNA 21 has a sensitivity of 68% and a specificity of 96%, to differentiate between the liver cirrhosis group and HCC group.
Conclusion
miRNA 21 can be a promising marker for detection of patients with HCV-related hepatocellular carcinoma, with higher specificity compared to α feto protein; however, its cost is higher.
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Sarantis P, Trifylli EM, Koustas E, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors. Int J Mol Sci 2022; 23:13612. [PMID: 36362398 PMCID: PMC9655697 DOI: 10.3390/ijms232113612] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
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Affiliation(s)
- Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Wang PW, Lin TY, Yang PM, Yeh CT, Pan TL. Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms231810777. [PMID: 36142683 PMCID: PMC9503407 DOI: 10.3390/ijms231810777] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/29/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.
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Affiliation(s)
- Pei-Wen Wang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, Taiwan
| | - Tung-Yi Lin
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung 20401, Taiwan
| | - Pei-Ming Yang
- TMU Research Center of Cancer Translational Medicine, Taipei 11042, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11042, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33375, Taiwan
| | - Tai-Long Pan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33375, Taiwan
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Cosmetic Science, Research Center for Food and Cosmetic Safety, and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan
- Correspondence: ; Tel.: +886-3-211-8800 (ext. 5105); Fax: +886-3-211-8700
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Zhang L, Xu JY, Yuan L, Yin XB, Li YH, Qin LQ. Protective effects of epigallocatechin-3-o-gallate combined with organic selenium against transforming growth factor-beta 1-induced fibrosis in LX-2 cells. J Food Biochem 2022; 46:e14223. [PMID: 35586925 DOI: 10.1111/jfbc.14223] [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: 01/06/2022] [Revised: 04/14/2022] [Accepted: 04/19/2022] [Indexed: 11/25/2022]
Abstract
In this study, we investigated the protective effects and possible mechanism of epigallocatechin-3-o-gallate (EGCG) combined with organic selenium in transforming growth factor (TGF)-β1-activated LX-2 cells. After 12 h of starvation, LX-2 cells were treated with 10 ng/ml of recombinant TGF-β1 and different concentrations of EGCG, L-selenomethionine (L-SeMet), or L-selenomethylcysteine (L-SeMC) for 24 h. We found that 100 and 200 μM EGCG combined with 1 mM L-SeMet or L-SeMC showed a synergistic effect in decreasing the survival rate of activated LX-2 cells. In addition, the combination of 100 mM EGCG and 1 mM L-SeMet or L-SeMC promoted the apoptosis of activated LX-2 cells. Compared with the EGCG treatment group, the combination intervention group had significantly suppressed levels of hepatic stellate cell activation markers including alpha-smooth muscle actin, collagen type I alpha 1, collagen type III alpha 1, 5-hydroxytryptophan (5-HT), and 5-HT receptors 2A and 2B. Moreover, interleukin-10 levels were decreased, while TGF-β1 levels were increased after TGF-β1 activation in LX-2 culture medium, whereas the combin1ation intervention reversed this phenomenon. The combination treatment had a more pronounced effect than any single treatment at the same dose. These results demonstrated that the combination of EGCG and organic selenium synergistically improves the TGF-β1-induced fibrosis of LX-2 cells to some extent by promoting apoptosis and inhibiting cell activation. PRACTICAL APPLICATIONS: Here, we found that the effects of epigallocatechin-3-o-gallate (EGCG) + L-selenomethionine or L-selenomethylcysteine were more pronounced than those of EGCG alone. Future studies should investigate the protective effects of green tea and selenium-enriched green tea against hepatic fibrosis and explore the differences in their molecular mechanisms. The results of this study will be helpful for the development and utilization of selenium-enriched tea for food processing and health supplement production.
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Affiliation(s)
- Lin Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Linxi Yuan
- Department of Health and Environmental Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Xue-Bin Yin
- Key Laboratory for Functional Agriculture, Suzhou Research Institute, University of Science and Technology of China, Suzhou, China
| | - Yun-Hong Li
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
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18
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Rojas Á, García-Lozano MR, Gil-Gómez A, Romero-Gómez M, Ampuero J. Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies. J Clin Transl Hepatol 2022; 10:356-362. [PMID: 35528989 PMCID: PMC9039703 DOI: 10.14218/jcth.2021.00247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/29/2021] [Accepted: 10/14/2021] [Indexed: 12/04/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.
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Affiliation(s)
- Ángela Rojas
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - María Rosario García-Lozano
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071, Seville, Spain
| | - Antonio Gil-Gómez
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Manuel Romero-Gómez
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Javier Ampuero
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Correspondence to: Javier Ampuero, Digestive Disease Department and CIBERehd, Virgen del Rocio University Hospital, Avenida Manuel Siurot s/n, Sevilla 41013, Spain. ORCID: https://orcid.org/0000-0002-8332-2122. Tel: +34-955-015761, Fax: +34-955-015899, E-mail:
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The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications. Cancers (Basel) 2022; 14:cancers14040940. [PMID: 35205692 PMCID: PMC8870127 DOI: 10.3390/cancers14040940] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have paradoxical implications. While acting as a potent tumor suppressor pathway in the early stages of malignancy, TGF-β diverts to a promoter of tumor progression in the late stages, reflecting its bright and dark natures, respectively. Within this context, targeting TGF-β represents a promising therapeutic option for HCC treatment. We discuss here the molecular properties of TGF-β signaling in HCC, attempting to provide an overview of its effects on tumor cells and the stroma. We also seek to evaluate the dysregulation mechanisms that mediate the functional switch of TGF-β from a tumor suppressor to a pro-tumorigenic signal. Finally, we reconcile its biphasic nature with the therapeutic implications. Abstract Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.
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Bai K, Ma Y, Li J. Circular RNA circ_0001955 promotes hepatocellular carcinoma tumorigenesis by up-regulating alkaline ceramidase 3 expression through microRNA-655-3p. Bioengineered 2022; 13:2099-2113. [PMID: 35034572 PMCID: PMC8973869 DOI: 10.1080/21655979.2021.2023797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The involvement of certain circular RNAs (circRNAs) in the development of hepatocellular carcinoma (HCC) has been reported. Herein, this study aimed to investigate the function and mechanism of circ_0001955 in HCC tumorigenesis. Expression of circ_0001955, miR-655-3p, and alkaline ceramidase 3 (ACER3) was evaluated by quantitative real-time PCR and Western blot. Cell counting kit-8, colony formation, transwell, tube formation, flow cytometry and tumor xenograft assays were adopted to perform in vitro and in vivo experiments. The direct interaction between miR-655-3p and circ_0001955 or ACER3 was verified using dual-luciferase reporter and RNA immunoprecipitation assays. Circ_0001955 was highly expression in HCC tissues and cells. Functionally, circ_0001955 deletion suppressed HCC tumorigenesis in vitro by suppressing cell growth, metastasis and angiogenesis. Mechanistically, circ_0001955 could competitively sponge miR-655-3p, which targeted ACER3. Besides that, miR-655-3p silencing abolished the anticancer action of circ_0001955 silencing on HCC cells. Moreover, miR-655-3p overexpression inhibited HCC cell oncogenic phenotypes mentioned above, which were attenuated by ACER3 up-regulation. Additionally, circ_0001955 knockdown also impeded HCC growth in a mouse model. In all, this study suggested a novel circ_0001955/miR-655-3p/ACER3 pathway in HCC progression.
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Affiliation(s)
- Kai Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yubo Ma
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Luo N, Li J, Wei Y, Lu J, Dong R. Hepatic Stellate Cell: A Double-Edged Sword in the Liver. Physiol Res 2021; 70:821-829. [PMID: 34717063 DOI: 10.33549/physiolres.934755] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatic stellate cells (HSCs) are located in the space of Disse, between liver sinusoidal endothelia cells (LSECs) and hepatocytes. They have surprised and excited hepatologists for their biological characteristics. Under physiological quiescent conditions, HSCs are the major vitamin A-storing cells of the liver, playing crucial roles in the liver development, regeneration, and tissue homeostasis. Upon injury-induced activation, HSCs convert to a pro-fibrotic state, producing the excessive extracellular matrix (ECM) and promoting angiogenesis in the liver fibrogenesis. Activated HSCs significantly contribute to liver fibrosis progression and inactivated HSCs are key to liver fibrosis regression. In this review, we summarize the comprehensive understanding of HSCs features, including their roles in normal liver and liver fibrosis in hopes of advancing the development of emerging diagnosis and treatment for hepatic fibrosis.
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Affiliation(s)
- Nianan Luo
- Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. ,
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22
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Niu G, Zhang X, Hong R, Yang X, Gu J, Song T, Hu Z, Chen L, Wang X, Xia J, Ke Z, Ren J, Hong L. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial-mesenchymal transition of hepatic stellate cells. Open Med (Wars) 2021; 16:1459-1471. [PMID: 34693020 PMCID: PMC8486017 DOI: 10.1515/med-2021-0344] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 08/12/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction Gap junction protein, alpha 1 (GJA1), which is correlated with recurrences and unfavorable prognoses in hepatocellular carcinomas (HCCs), is one of the specific proteins expressed by activated hepatic stellate cells (HSCs). Methods Expression of GJA1 was compared between HCCs and nontumor tissues (NTs), between hepatic cirrhosis and NTs, and between primary and metastatic HCCs using transcriptomic datasets from the Gene Expression Omnibus and the Integrative Molecular Database of Hepatocellular Carcinoma. The in vitro activities of GJA1 were investigated in cultured HSCs and HCC cells. The underlying mechanism was characterized using Gene Set Enrichment Analysis and validated by western blotting. Results The expression of GJA1 was significantly increased in HCCs and hepatic cirrhosis compared to that in NTs. GJA1 was also overexpressed in pulmonary metastases from HCCs when compared with HCCs without metastasis. Overexpression of GJA1 promoted while knockdown of GJA1 inhibited proliferation and transforming growth factor (TGF)-β-mediated activation and migration of cultured HSCs. Overexpression of GJA1 by lentivirus infection promoted proliferation and migration, while conditioned medium from HSCs overexpressing GJA1 promoted migration but inhibited proliferation of Hep3B and PLC-PRF-5 cells. Lentivirus infection with shGJA1 or conditioned medium from shGJA1-infected HSCs inhibited the proliferation and migration of HCCLM3 cells that had a high propensity toward lung metastasis. Mechanistically, GJA1 induced the epithelial–mesenchymal transition (EMT) in HSCs and HCCLM3 cells. Conclusion GJA1 promoted HCC progression by inducing HSC activation and the EMT in HSCs. GJA1 is potentially regulated by TGF-β and thus may be a therapeutic target to inhibit HCC progression.
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Affiliation(s)
- Gengming Niu
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Xiaotian Zhang
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Runqi Hong
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Ximin Yang
- Department of Radiology, Dongying New District Hospital, Dongying, Shandong Province, 257000, People's Republic of China
| | - Jiawei Gu
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Tao Song
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Zhiqing Hu
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Liang Chen
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Xin Wang
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Jie Xia
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Shanghai, 200240, People's Republic of China
| | - Zhongwei Ke
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Jun Ren
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Liang Hong
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
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23
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Kang MJ, Lee S, Jung U, Mandal C, Park H, Stetler-Stevenson WG, Kim YS, Moon JW, Park SH, Oh J. Inhibition of Hepatic Stellate Cell Activation Suppresses Tumorigenicity of Hepatocellular Carcinoma in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:2219-2230. [PMID: 34428424 PMCID: PMC8747013 DOI: 10.1016/j.ajpath.2021.08.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/27/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022]
Abstract
Transdifferentiation (or activation) of hepatic stellate cells (HSCs) to myofibroblasts is a key event in liver fibrosis. Activated HSCs in the tumor microenvironment reportedly promote tumor progression. This study analyzed the effect of an inhibitor of HSC activation, retinol-binding protein–albumin domain III fusion protein (R-III), on protumorigenic functions of HSCs. Although conditioned medium collected from activated HSCs enhanced the migration, invasion, and proliferation of the hepatocellular carcinoma cell line Hepa-1c1c7, this effect was not observed in Hepa-1c1c7 cells treated with conditioned medium from R-III–exposed HSCs. In a subcutaneous tumor model, larger tumors with increased vascular density were formed in mice transplanted with Hepa-1c1c7+HSC than in mice transplanted with Hepa-1c1c7 cells alone. Intriguingly, when Hepa-1c1c7+HSC–transplanted mice were injected intravenously with R-III, a reduction in vascular density and extended tumor necrosis were observed. In an orthotopic tumor model, co-transplantation of HSCs enhanced tumor growth, angiogenesis, and regional metastasis accompanied by increased peritumoral lymphatic vessel density, which was abolished by R-III. In vitro study showed that R-III treatment affected the synthesis of pro-angiogenic and anti-angiogenic factors in activated HSCs, which might be the potential mechanism underlying the R-III effect. These findings suggest that the inhibition of HSC activation abrogates HSC-induced tumor angiogenesis and growth, which represents an attractive therapeutic strategy.
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Affiliation(s)
- Min-Jung Kang
- Department of Biomedical Science, Korea University Graduate School, Seoul, Korea
| | - Soovin Lee
- Laboratory Animal Research Center, College of Medicine, Korea University, Seoul, Korea
| | - Usuk Jung
- Department of Biomedical Science, Korea University Graduate School, Seoul, Korea
| | - Chanchal Mandal
- Department of Biomedical Science, Korea University Graduate School, Seoul, Korea
| | - Heekyung Park
- Department of Biomedical Science, Korea University Graduate School, Seoul, Korea
| | - William G Stetler-Stevenson
- Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Young-Sik Kim
- Department of Pathology, College of Medicine, Korea University, Seoul, Korea
| | - Ji Wook Moon
- Department of Anatomy, College of Medicine, Korea University, Seoul, Korea
| | - Sun-Hwa Park
- Department of Anatomy, College of Medicine, Korea University, Seoul, Korea
| | - Junseo Oh
- Department of Biomedical Science, Korea University Graduate School, Seoul, Korea; Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
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24
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Wu M, Miao H, Fu R, Zhang J, Zheng W. Hepatic Stellate Cell: A Potential Target for Hepatocellular Carcinoma. Curr Mol Pharmacol 2021; 13:261-272. [PMID: 32091349 DOI: 10.2174/1874467213666200224102820] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/11/2020] [Accepted: 01/16/2020] [Indexed: 12/24/2022]
Abstract
Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Mengna Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Huajie Miao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Rong Fu
- Department of Pathology, Affiliated Haian Hospital of Nantong University, 17 Zhongba Road, 226600, Haian, Jiangsu, China
| | - Jie Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
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25
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Wu SC, Cheng HT, Wang YC, Tzeng CW, Hsu CH, Muo CH. Decreased risk of liver and intrahepatic cancer in non-H. pylori-infected perforated peptic ulcer patients with truncal vagotomy: a nationwide study. Sci Rep 2021; 11:15594. [PMID: 34341400 PMCID: PMC8329055 DOI: 10.1038/s41598-021-95142-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 07/16/2021] [Indexed: 11/09/2022] Open
Abstract
The vagal nervous system is central to the physiological responses and systemic diseases of the liver. We evaluated the subsequent risk of liver and intrahepatic cancer (HCC/ICC) in non-H. pylori (HP)-infected perforated peptic ulcer (PPU) patients with and without vagotomy. Hospitalized PPU patients who underwent simple closure or truncal vagotomy/pyloroplasty (TVP) in the National Health Insurance Research Database from 2000 to 2008 were enrolled. The exclusion criteria included: (1) Multiple surgeries for PPU were received at the same admission; (2) Any cancer history; (3) Previous peptic ulcer-associated surgery; (4) HP infection history; (5) Viral hepatitis infection history; (6) Follow-up duration < 1 year; and (7) Age < 18 years. The risks of developing HCC/ICC in PPU patients with and without vagotomy were assessed at the end of 2013. To balance the baseline condition between groups, we used the propensity score matched method to select study subjects. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence interval (CI) of HCC/ICC. Before propensity score matching, 675 simple suture patients and 54 TVP patients had HCC/ICC, which corresponded to incidences of 2.11 and 0.88 per 1000 person-years, respectively. After propensity score matching, 145 simple suture patients and 54 TVP patients experienced HCC/ICC, which corresponded to incidences of 1.45 and 0.88 per 1000 person-years, respectively. The TVP patients had a 0.71 (95% CI 0.54-0.95)- and 0.69 (95% CI 0.49-0.97)-fold risk of developing HCC/ICC compared to simple suture patients before and after propensity score matching. Our findings reported that, in the Asian population, TVP decreases the risk of HCC/ICC in non-HP-infected PPU patients compared to simple closure patients. However, further studies are warranted.
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Affiliation(s)
- Shih-Chi Wu
- School of Medicine, China Medical University, Taichung, Taiwan. .,Trauma and Emergency Center, China Medical University Hospital, No. 2 Yuh-Der Road, Taichung, 404, Taiwan.
| | - Han-Tsung Cheng
- Department of Trauma and Emergency Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Chun Wang
- Department of Trauma and Emergency Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Wei Tzeng
- Department of Trauma and Emergency Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hao Hsu
- Department of Trauma and Emergency Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Hsin Muo
- Management Office for Health Data, China Medical University and Hospital, Taichung, Taiwan
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26
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Esparza-Baquer A, Labiano I, Sharif O, Agirre-Lizaso A, Oakley F, Rodrigues PM, Zhuravleva E, O'Rourke CJ, Hijona E, Jimenez-Agüero R, Riaño I, Landa A, La Casta A, Zaki MYW, Munoz-Garrido P, Azkargorta M, Elortza F, Vogel A, Schabbauer G, Aspichueta P, Andersen JB, Knapp S, Mann DA, Bujanda L, Banales JM, Perugorria MJ. TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms. Gut 2021; 70:1345-1361. [PMID: 32907830 PMCID: PMC8223629 DOI: 10.1136/gutjnl-2019-319227] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis. DESIGN TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2-/- mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted. RESULTS TREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2-/- mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2-/- animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2-/- livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion. CONCLUSION TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.
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Affiliation(s)
- Aitor Esparza-Baquer
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Ibone Labiano
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Omar Sharif
- Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
- Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Aloña Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Ekaterina Zhuravleva
- Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Colm J O'Rourke
- Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Elizabeth Hijona
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Ioana Riaño
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Marco Y W Zaki
- Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Patricia Munoz-Garrido
- Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Mikel Azkargorta
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Proteomics Platform, CIC bioGUNE, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain
| | - Felix Elortza
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Proteomics Platform, CIC bioGUNE, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain
| | - Andrea Vogel
- Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
- Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Gernot Schabbauer
- Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
- Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Patricia Aspichueta
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Lejona, Spain
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Sylvia Knapp
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Lejona, Spain
| | - Jesus Maria Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Maria Jesus Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Lejona, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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27
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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28
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Mezawa Y, Orimo A. Phenotypic heterogeneity, stability and plasticity in tumor-promoting carcinoma-associated fibroblasts. FEBS J 2021; 289:2429-2447. [PMID: 33786982 DOI: 10.1111/febs.15851] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/15/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022]
Abstract
Reciprocal interactions between cancer cells and stromal cells in the tumor microenvironment (TME) are essential for full-blown tumor development. Carcinoma-associated fibroblasts (CAFs) are a key component of the TME together with a wide variety of stromal cell types including vascular, inflammatory, and immune cells in the extracellular matrix. CAFs not only promote tumor growth, invasion, and metastasis, but also dampen the efficacy of various therapies including immune checkpoint inhibitors. CAFs are composed of distinct fibroblast populations presumably with diverse activated fibroblastic states and tumor-promoting phenotypes in a tumor, indicating intratumor heterogeneity in these fibroblasts. Given that CAFs have been implicated in both disease progression and therapeutic responses, elucidating the functional roles of each fibroblast population in CAFs and the molecular mechanisms mediating their phenotypic stability and plasticity in the TME would be crucial for understanding tumor biology. We herein discuss how distinct fibroblast populations comprising CAFs establish their cell identities, in terms of cells-of-origin, stimuli from the TME, and the phenotypes characteristic of activated states.
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Affiliation(s)
- Yoshihiro Mezawa
- Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akira Orimo
- Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan
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29
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Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells 2020; 9:cells9092027. [PMID: 32899119 PMCID: PMC7563527 DOI: 10.3390/cells9092027] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 08/26/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.
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30
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Li J, Yan Y, Ang L, Li X, Liu C, Sun B, Lin X, Peng Z, Zhang X, Zhang Q, Wu H, Zhao M, Su C. Extracellular vesicles-derived OncomiRs mediate communication between cancer cells and cancer-associated hepatic stellate cells in hepatocellular carcinoma microenvironment. Carcinogenesis 2020; 41:223-234. [PMID: 31140556 DOI: 10.1093/carcin/bgz096] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/08/2019] [Accepted: 05/28/2019] [Indexed: 01/10/2023] Open
Abstract
Tumor microenvironment (TME) is a critical determinant for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) are main interstitial cells in TME and play a vital role in early intrahepatic invasion and metastasis of HCC. The potential mechanism on the interactions between HSCs and HCC cells remains unclear. In this study, the effects of extracellular vesicles (EVs)-derived OncomiRs that mediate communication between HCC cells and cancer-associated hepatic stellate cells (caHSCs) and remold TME were investigated. The results found that the HCC cells-released EVs contained more various OncomiRs, which could activate HSCs (LX2 cells) and transform them to caHSCs, the caHSCs in turn exerted promotion effects on HCC cells through HSCs-released EVs. To further simulate the effects of OncomiRs in EVs on construction of pro-metastatic TME, a group of OncomiRs, miR-21, miR-221 and miR-151 was transfected into HCC cells and LX2 cells. These microRNAs in the EVs from OncomiRs-enhanced cells were demonstrated to have oncogenic effects on HCC cells by upregulating the activities of protein kinase B (AKT)/extracellular signal-regulated kinase (ERK) signal pathways. Equivalent results were also found in HCC xenografted tumor models. The findings suggested that the OncomiR secretion and transference by cancer cells-released EVs can mediate the communication between HCC cells and HSCs. HCC cells and caHSCs, as well as their secreted EVs, jointly construct a pro-metastatic TME suitable for invasion and metastasis of cancer cells, all these TME components form a positive feedback loop to promote HCC progression and metastasis.
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Affiliation(s)
- Jiang Li
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Yan Yan
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Lin Ang
- Department of Pathology, The Second People's Hospital of Hefei, Hefei, Anhui Province, China
| | - Xiaoya Li
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Chunying Liu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Xuejing Lin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Zhangxiao Peng
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Xiaofeng Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Qin Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Hongping Wu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Min Zhao
- Department of Pathology, The Second People's Hospital of Hefei, Hefei, Anhui Province, China
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
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31
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Barry AE, Baldeosingh R, Lamm R, Patel K, Zhang K, Dominguez DA, Kirton KJ, Shah AP, Dang H. Hepatic Stellate Cells and Hepatocarcinogenesis. Front Cell Dev Biol 2020; 8:709. [PMID: 32850829 PMCID: PMC7419619 DOI: 10.3389/fcell.2020.00709] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.
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Affiliation(s)
- Anna E Barry
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
| | - Rajkumar Baldeosingh
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
| | - Ryan Lamm
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Keyur Patel
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Kai Zhang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
| | - Dana A Dominguez
- Department of General Surgery, UCSF East Bay, Oakland, CA, United States
| | - Kayla J Kirton
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Ashesh P Shah
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA, United States.,Sidney Kimmel Cancer Center, Philadelphia, PA, United States
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Wan S, Luo F, Huang C, Liu C, Luo Q, Zhu X. Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways. Aging (Albany NY) 2020; 12:10614-10632. [PMID: 32496208 PMCID: PMC7346053 DOI: 10.18632/aging.103282] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is the reversible deposition of extracellular matrix (ECM) and scar formation after liver damage by various stimuli. The interaction between NOX4/ROS and RhoA/ROCK1 in liver fibrosis is not yet clear. Ursolic acid (UA) is a traditional Chinese medicine with anti-fibrotic effects, but the molecular mechanism underlying these effects is still unclear. We investigated the interaction between NOX4/ROS and RhoA/ROCK1 during liver fibrosis and whether these molecules are targets for the anti-fibrotic effects of UA. First, we confirmed that UA reversed CCl4-induced liver fibrosis. In the NOX4 intervention and RhoA intervention groups, related experimental analyses confirmed the decrease in CCl4-induced liver fibrosis. Next, we determined that the expression of NOX4 and RhoA/ROCK1 was decreased in UA-treated liver fibrotic mice. Furthermore, RhoA/ROCK1 expression was decreased in the NOX4 intervention group, but there was no significant change in the expression of NOX4 in the RhoA intervention group. Finally, we found that liver fibrotic mice showed a decline in their microbiota diversity and abundance, a change in their microbiota composition, and a reduction in the number of potential beneficial bacteria. However, in UA-treated liver fibrotic mice, the microbiota dysbiosis was ameliorated. In conclusion, the NOX4/ROS and RhoA/ROCK1 signalling pathways are closely linked to the development of liver fibrosis. UA can reverse liver fibrosis by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, which may interact with each other.
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Affiliation(s)
- Sizhe Wan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fangyun Luo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chenkai Huang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Cong Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qingtian Luo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xuan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Origin and role of hepatic myofibroblasts in hepatocellular carcinoma. Oncotarget 2020; 11:1186-1201. [PMID: 32284794 PMCID: PMC7138168 DOI: 10.18632/oncotarget.27532] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 03/03/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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Abstract
The liver is the largest organ in the human body and is prone for cancer metastasis. Although the metastatic pattern can differ depending on the cancer type, the liver is the organ to which cancer cells most frequently metastasize for the majority of prevalent malignancies. The liver is unique in several aspects: the vascular structure is highly permeable and has unparalleled dual blood connectivity, and the hepatic tissue microenvironment presents a natural soil for the seeding of disseminated tumor cells. Although 70% of the liver is composed of the parenchymal hepatocytes, the remaining 30% is composed of nonparenchymal cells including Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells. Recent discoveries show that both the parenchymal and the nonparenchymal cells can modulate each step of the hepatic metastatic cascade, including the initial seeding and colonization as well as the decision to undergo dormancy versus outgrowth. Thus, a better understanding of the molecular mechanisms orchestrating the formation of a hospitable hepatic metastatic niche and the identification of the drivers supporting this process is critical for the development of better therapies to stop or at least decrease liver metastasis. The focus of this perspective is on the bidirectional interactions between the disseminated cancer cells and the unique hepatic metastatic niche.
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Affiliation(s)
- Ainhoa Mielgo
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Michael C Schmid
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L69 3GE, United Kingdom
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36
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Haaker MW, Vaandrager AB, Helms JB. Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158674. [PMID: 32105672 DOI: 10.1016/j.bbalip.2020.158674] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 12/13/2022]
Abstract
Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs.
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Affiliation(s)
- Maya W Haaker
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Arie B Vaandrager
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - J Bernd Helms
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
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Miyazoe Y, Miuma S, Miyaaki H, Kanda Y, Nakashiki S, Sasaki R, Haraguchi M, Shibata H, Honda T, Taura N, Nakao K. Extracellular vesicles from senescent hepatic stellate cells promote cell viability of hepatoma cells through increasing EGF secretion from differentiated THP-1 cells. Biomed Rep 2020; 12:163-170. [PMID: 32190304 PMCID: PMC7054706 DOI: 10.3892/br.2020.1279] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 01/17/2020] [Indexed: 12/28/2022] Open
Abstract
Since the discovery of the senescence-associated secretory phenotype, the role of senescent hepatic stellate cells (HSCs) in hepatocellular carcinoma (HCC) development has gained increasing attention. Similar to cytokines, extracellular vesicles (EVs) are essential for intercellular communication. However, the function of EVs derived from senescent HSCs in HCC progression has not been extensively studied. The aims of the present study were to characterize the EVs derived from senescent HSCs and determine their role in the tumor microenvironment. Cellular senescence was induced in human hepatic stellate cells (HHSteCs) with various concentrations of etoposide. Induction was confirmed using EdU staining and 53BP1 and p21 immunostaining. EVs were isolated by ultracentrifugation and analyzed by nanoparticle tracking analysis. Multiplex immunoassays were used to compare the levels of growth factors secreted from hepatoma cell lines and macrophage cells pretreated with EVs derived from senescent HHSteCs (senescent EVs) with those pretreated with EVs derived from normal cultured HHSteCs (normal EVs). Treatment with 25 µM etoposide for 3 days was the most effective at inducing senescence in HHSteCs. This finding was confirmed by induction of irreversible cell-cycle arrest, upregulation of 53BP1 and p21 expression, and increased SA-β-gal staining. Senescent HHSteCs released increased quantities of EV particles compared with normally cultured HHSteCs. Multiplex analysis revealed that there was no difference between hepatoma cell lines treated with normal EVs and those treated with senescent EVs in growth factor secretion. In contrast, the secretion of epidermal growth factor (EGF) was increased by macrophage cells treated with senescent EVs compared with those treated with normal EVs. Furthermore, senescent EVs did not affect the viability of hepatoma cells but increased the viability of hepatoma cells co-cultured with macrophage cells. In conclusion, the release of EVs from senescent HSCs was higher compared with normal HSCs. Furthermore, senescent EVs promoted HCC development by upregulating EGF secretion from macrophages.
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Affiliation(s)
- Yuri Miyazoe
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Yasuko Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Suguru Nakashiki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Takuya Honda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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Das D, Fayazzadeh E, Li X, Koirala N, Wadera A, Lang M, Zernic M, Panick C, Nesbitt P, McLennan G. Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase-independent cell death pathway: Central role of apoptosis-inducing factor. J Cell Physiol 2020; 235:6167-6182. [PMID: 31975386 DOI: 10.1002/jcp.29545] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/03/2020] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide and in the United States as its incidence has increased substantially within the past two decades. HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A-HSCs) are the key cell types involved in hepatic fibrosis/cirrhosis. A-HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A-HSCs an important therapeutic target in hepatic fibrosis/cirrhosis as well as in HCC. Although many studies have reported the role of A-HSCs in cancer generation and investigated the therapeutic potential of A-HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q-HSCs) in cancer growth or arrest. Here we report that Q-HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q-HSCs (Q-HSCCM) induces cancer cell death through a caspase-independent mechanism that involves an increase in apoptosis-inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q-HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy.
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Affiliation(s)
- Dola Das
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ehsan Fayazzadeh
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Section of Vascular and Interventional Radiology, Department of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
| | - Xin Li
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nischal Koirala
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, Ohio
| | - Akshay Wadera
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,School of Medicine, New York Medical College, Valhalla, New York
| | - Min Lang
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Maximilian Zernic
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Catherine Panick
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, Oregon
| | - Pete Nesbitt
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania
| | - Gordon McLennan
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Section of Vascular and Interventional Radiology, Department of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
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Zhang R, Gao X, Zuo J, Hu B, Yang J, Zhao J, Chen J. STMN1 upregulation mediates hepatocellular carcinoma and hepatic stellate cell crosstalk to aggravate cancer by triggering the MET pathway. Cancer Sci 2019; 111:406-417. [PMID: 31785057 PMCID: PMC7004522 DOI: 10.1111/cas.14262] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/20/2019] [Accepted: 11/26/2019] [Indexed: 12/12/2022] Open
Abstract
STMN1 has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. However, the detailed functions and underlying mechanisms of STMN1 are still largely unknown in hepatocellular carcinoma (HCC) development. Herein, we analyzed STMN1 expression and the related clinical significance in HCC by using well‐established Protein Atlas, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cancer databases. Analysis indicated that STMN1 was highly expressed in HCC and closely associated with vascular invasion, higher histological grade, advanced clinical grade and shorter survival time in HCC patients. Overexpressing and silencing STMN1 in HCC cell lines showed that STMN1 could regulate cell proliferation, migration, drug resistance, cancer stem cell properties in vitro as well as tumor growth in vivo. Further experiments showed that STMN1 mediated intricate crosstalk between HCC and hepatic stellate cells (HSC) by triggering the hepatocyte growth factor (HGF)/MET signal pathway. When HSC were cocultured with HCC cells, HSC secreted more HGF to stimulate the expression of STMN1 in HCC cells. Mutually, STMN1 upregulation in HCC cells facilitated HSC activation to acquire cancer‐associated fibroblast (CAF) features. The MET inhibitor crizotinib significantly blocked this crosstalk and slowed tumor growth in vivo. In conclusion, our findings shed new insight on STMN1 function, and suggest that STMN1 may be used as a potential marker to identify patients who may benefit from MET inhibitor treatment.
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Affiliation(s)
- Rui Zhang
- Department of General Surgery, Fudan University, Shanghai, China
| | - Xiaomei Gao
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jieliang Zuo
- Department of General Surgery, Fudan University, Shanghai, China
| | - Beiyuan Hu
- Department of General Surgery, Fudan University, Shanghai, China
| | - Jimeng Yang
- Department of General Surgery, Fudan University, Shanghai, China
| | - Jing Zhao
- Department of General Surgery, Fudan University, Shanghai, China
| | - Jinhong Chen
- Department of General Surgery, Fudan University, Shanghai, China
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Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity. Oncogene 2019; 39:2328-2344. [PMID: 31844251 DOI: 10.1038/s41388-019-1140-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 11/24/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022]
Abstract
Myocardin-related transcription factors A and B (MRTFs) are coactivators of Serum Response Factor (SRF) that mediates the expression of genes involved in cell proliferation, migration and differentiation. There is mounting evidence that MRTFs and SRF represent promising targets for hepatocellular carcinoma (HCC) growth. Since MRTF-A nuclear localization is a prerequisite for its transcriptional activity and oncogenic properties, we searched for pharmacologically active compounds able to redistribute MRTF-A to the cytoplasm. We identified NS8593, a negative gating modulator of the transient receptor potential cation channel TRPM7, as a novel inhibitor of MRTF-A nuclear localization and transcriptional activity. Using a pharmacological approach and targeted genome editing, we investigated the functional contribution of TRPM7, a unique ion channel containing a serine-threonine kinase domain, to MRTF transcriptional and tumorigenic activity. We found that TRPM7 function regulates RhoA activity and subsequently actin polymerization, MRTF-A-Filamin A complex formation and MRTF-A/SRF target gene expression. Mechanistically, TRPM7 signaling relies on TRPM7 channel-mediated Mg2+ influx and phosphorylation of RhoA by TRPM7 kinase. Pharmacological blockade of TRPM7 results in oncogene-induced senescence of hepatocellular carcinoma (HCC) cells in vitro and in vivo in HCC xenografts. Hence, inhibition of the TRPM7/MRTF axis emerges as a promising strategy to curb HCC growth.
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41
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Xia YH, Lu Z, Wang SM, Hu LX. Nrf2 activation mediates tumor-specific hepatic stellate cells-induced DIgR2 expression in dendritic cells. Aging (Albany NY) 2019; 11:11565-11575. [PMID: 31831714 PMCID: PMC6932929 DOI: 10.18632/aging.102554] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/20/2019] [Indexed: 01/24/2023]
Abstract
Our previous studies discovered that tumor-specific hepatic stellate cells (tHSCs) induced dendritic cell-derived immunoglobulin receptor 2 (DIgR2) expression in bone marrow-derived dendritic cells (mDCs), inhibiting splenic T cell activation. The current study aims to explore the underlying mechanism of DIgR2 expression by focusing on Nrf2 (nuclear-factor-E2-related factor 2) signaling. We show that tHSCs co-culture induced significant Nrf2 signaling activation in mDCs. The latter was evidenced by Nrf2-Keap1 disassociation, Nrf2 protein stabilization, accumulation and nuclear translocation. Expression of Nrf2-dependent genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), were detected in tHSCs-co-cultured mDCs. Importantly tHSCs-induced DIgR2 expression was blocked by Nrf2 shRNA or knockout (KO, by CRISPR/Cas9 method). Conversely, forced activation of Nrf2, by Keap1 shRNA or the Nrf2 activators (3H-1,2-dithiole-3-thione and MIND4-17), induced significant DIgR2 expression. tHSCs stimulation induced reactive oxygen species (ROS) production in mDCs. Conversely, ROS scavengers inhibited tHSCs-induced ROS production, Nrf2 activation and DIgR2 expression in mDCs. Significantly, tHSCs inhibited production of multiple cytokines (CD80, CD86 and IL-12) in mDCs, reversed by Nrf2 depletion. Moreover, Nrf2 shRNA or KO attenuated splenic T cell inhibition by tHSCs-stimulated mDCs. Together, we conclude that Nrf2 activation mediates tHSCs-induced DIgR2 expression in mDCs.
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Affiliation(s)
- Yun-Hong Xia
- Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Zhen Lu
- Department of General Surgery, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Shou-Min Wang
- Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Li-Xia Hu
- Department of Oncology, Hefei Hospital, Anhui Medical University, Hefei, China
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42
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Kikuchi K, Tsukamoto H. Stearoyl-CoA desaturase and tumorigenesis. Chem Biol Interact 2019; 316:108917. [PMID: 31838050 DOI: 10.1016/j.cbi.2019.108917] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 12/09/2019] [Indexed: 01/07/2023]
Abstract
Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also stimulates canonical Wnt pathway and YAP activation in support of stemness and tumorigenesis. SCD facilitates metabolic reprogramming in cancer which is mediated, at least in part, by regulation of AKT, AMPK, and NF-kB via MUFAs. Our research has revealed the novel positive loop to amplify Wnt signaling through stabilization of LRP5/6 in both hepatic stellate cells and liver tumor-initiating stem cell-like cells. As such, this loop is pivotal in promoting liver fibrosis and liver tumor development. This review summarizes the mechanisms of SCD-mediated tumor promotion described by recent studies and discusses the future prospect for SCD-mediated signaling crosstalk as a potential therapeutic target for cancer.
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Affiliation(s)
- Kohtaro Kikuchi
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
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43
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Liao X, Bu Y, Chang F, Jia F, Song G, Xiao X, Zhang M, Ning P, Jia Q. Remodeling of hepatic stellate cells orchestrated the stroma-derived oxaliplatin-resistance through CCN3 paracrine in hepatocellular carcinoma. BMC Cancer 2019; 19:1192. [PMID: 31805888 PMCID: PMC6896671 DOI: 10.1186/s12885-019-6362-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/14/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. However, the precise role of HSCs trending, infiltration and paracrine in orchestrating the stroma-derived oxaliplatin-resistance in HCC is still vague. METHODS The chemo-resistant models were established to explore the correlation between HSC cells and the condition of chemoresistance. The HCC clinical samples were collected to confirm this phenomenon. Then, the relationship between secretory CCN3 from oxaliplatin-resistant HCC and the infiltration of HSCs in associated HCC microenvironment was evaluated. Finally, the role and mechanism of HSCs remodeling in the orchestration of oxaliplatin-resistant HCC were explored. RESULTS The increased infiltration of HSCs and collagen accumulation were found in the microenvironment of oxaliplatin-resistant HCC. The cDNA profiles of the oxaliplatin-resistant HCC was reanalyzed, and CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then the enhanced abilities of migration and proliferation of HSCs, and elevation of the cytokines paracrine from HSCs relating to HCC malignancy were proved in vitro and in vivo, and which were related to CCN3-ERK signaling pathway activation. CONCLUSIONS HSCs remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.
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Affiliation(s)
- Xia Liao
- Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan, 750001, China
| | - Fan Chang
- Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, 710043, China
| | - Fengan Jia
- Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, 710043, China
| | - Ge Song
- Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xuelian Xiao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China
| | - Mei Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China
| | - Pengbo Ning
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, China
| | - Qingan Jia
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China.
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Wan SZ, Liu C, Huang CK, Luo FY, Zhu X. Ursolic Acid Improves Intestinal Damage and Bacterial Dysbiosis in Liver Fibrosis Mice. Front Pharmacol 2019; 10:1321. [PMID: 31736766 PMCID: PMC6838135 DOI: 10.3389/fphar.2019.01321] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/15/2019] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a reversible process of extracellular matrix deposition or scar formation after liver injury. Intestinal damage and bacterial dysbiosis are important concomitant intestinal changes in liver fibrosis and may in turn accelerate the progression of liver fibrosis through the gut-liver axis. RhoA, an important factor in the regulation of the cytoskeleton, plays an important role in intestinal damage. We investigated the effects of ursolic acid (UA), a traditional Chinese medicine with anti-fibrotic effects, on intestinal damage and bacterial disorder through the RhoA pathway. UA treatment reduced intestinal damage by inhibiting the inflammatory factor TNF-α and increasing the expression of tight junction proteins and antibacterial peptides to protect the intestinal barrier. Moreover, the corrective effect of UA on bacterial dysbiosis was also confirmed by sequencing of the 16S rRNA gene. Potential beneficial bacteria, such as the phylum Firmicutes and the genera Lactobacillus and Bifidobacterium, were increased in the UA group compared to the CCl4 group. In liver fibrosis mice with RhoA inhibition via injection of adeno-associated virus, the liver fibrosis, intestinal damage, and flora disturbances were improved. Moreover, UA inhibited the expression of RhoA pathway components. In conclusion, UA improves intestinal damage and bacterial dysbiosis partly via the RhoA pathway. This may be a potential mechanism by which UA exerts its anti-fibrotic effects and provides effective theoretical support for the future use of UA in clinical practice.
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Affiliation(s)
- Si-Zhe Wan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Cong Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chen-Kai Huang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fang-Yun Luo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xuan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Xu Y, Fang F, Jiao H, Zheng X, Huang L, Yi X, Zhao W. Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma. Cancer Immunol Immunother 2019; 68:1959-1969. [PMID: 31641797 DOI: 10.1007/s00262-019-02414-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 10/10/2019] [Indexed: 12/13/2022]
Abstract
Hepatic stellate cells (HSCs) are important stromal cells and pivotal mediators involved in the pathogenesis and immunosuppression of hepatocellular carcinoma (HCC). The liver has been demonstrated to be a site for accumulation of tumor-induced myeloid-derived suppressor cells (MDSCs). We previously reported that HSCs induced an increase in the number of MDSCs in HCC. However, how MDSCs are recruited in HCC remains largely unclear. In the present study, we found that HSC-conditioned medium (HSC-CM) induced bone marrow-derived cell and splenocyte migration, especially MDSC migration. Using chemokine-neutralizing antibodies and chemokine receptor inhibitors, we found that HSCs promoted MDSC migration through the SDF-1/CXCR4 axis. Subsequently, we used an orthotopic mouse liver tumor model to determine how HSCs mediated MDSC migration to HCC in vivo. The in vivo results indicated that pretreatment of MDSCs with a CXCR4 inhibitor or injection with SDF-1-knocked down HSCs inhibited MDSC migration to the spleen and liver of the tumor-bearing mice. Together, our findings indicate a central role for HSCs in MDSC migration mediated by the SDF-1/CXCR4 axis, thus revealing a potentially effective approach for modulating the tumor microenvironment by targeting HSCs in HCC.
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Affiliation(s)
- Yaping Xu
- Key Laboratory of Functional and Clinical Translational Medicine, Department of Physiology, Xiamen Medical College, Xiamen, 361023, China.,Xiamen Key Laboratory of Respiratory Diseases, Xiamen, 361023, China
| | - Fei Fang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Building 6, No. 209, South Hubin Road, Xiamen, 361004, China
| | - Hui Jiao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Building 6, No. 209, South Hubin Road, Xiamen, 361004, China
| | - Xiaohui Zheng
- Key Laboratory of Functional and Clinical Translational Medicine, Department of Physiology, Xiamen Medical College, Xiamen, 361023, China
| | - Liyue Huang
- Key Laboratory of Functional and Clinical Translational Medicine, Department of Physiology, Xiamen Medical College, Xiamen, 361023, China
| | - Xue Yi
- Key Laboratory of Functional and Clinical Translational Medicine, Department of Physiology, Xiamen Medical College, Xiamen, 361023, China.,Xiamen Key Laboratory of Respiratory Diseases, Xiamen, 361023, China
| | - Wenxiu Zhao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Building 6, No. 209, South Hubin Road, Xiamen, 361004, China.
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46
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Maia-Ceciliano TC, Dutra RR, Aguila MB, Mandarim-De-Lacerda CA. The deficiency and the supplementation of vitamin D and liver: Lessons of chronic fructose-rich diet in mice. J Steroid Biochem Mol Biol 2019; 192:105399. [PMID: 31175967 DOI: 10.1016/j.jsbmb.2019.105399] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/25/2019] [Accepted: 06/05/2019] [Indexed: 01/01/2023]
Abstract
The fructose added to soft drinks and processed food, as well as frequent detection of vitamin D deficiency in the body, are two insults increasingly considered to cause lesions in target organs. We studied the liver after a chronic high-fructose diet deficient and supplemented with vitamin D. Sixty C57BL/6 mature male mice were allocated into six groups (n = 10) for ten weeks: control (C), control deficient in vitamin D (CDD), control supplemented with vitamin D (CDS), fructose (F), fructose deficient in vitamin D (FDD), and fructose supplemented with vitamin D (FDS). The gene expressions of vitamin D receptor and CYP27B1 and 25 hydroxyvitamin D plasma level ensured that the diets caused vitamin D deficiency or supplementation. Body mass did not change, but blood pressure (BP) increased in CDD, F, and FDD, whereas BP was controlled in FDS. Insulinemia, insulin tolerance and resistance were seen in both vitamin D deficiency and fructose groups but improved with vitamin D supplementation. The steatosis and fibrosis were observed in the CDD, F and FDD groups. Also, F and FDD showed activation of stellate cells (HSC). Lipogenesis and inflammation gene expressions were enhanced in the CDD, F and FDD groups, but diminished with vitamin D supplementation. In conclusion, we demonstrated the adverse effects of vitamin D deficiency on metabolism, liver steatosis and, combined with fructose intake, liver interstitial fibrosis with hepatic stellate cell activation, and alteration of the lipogenesis, beta-oxidation, and liver inflammation. All these data improved when vitamin D was supplemented in the animals.
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Affiliation(s)
- Thais C Maia-Ceciliano
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Rafaela R Dutra
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Marcia B Aguila
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Carlos A Mandarim-De-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
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47
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Li J, You S, Zhang S, Hu Q, Wang F, Chi X, Zhao W, Xie C, Zhang C, Yu Y, Liu J, Zhao Y, Liu P, Zhang Y, Wei X, Li Q, Wang X, Yin Z. Elevated N-methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform. Mol Oncol 2019; 13:1993-2009. [PMID: 31294922 PMCID: PMC6717763 DOI: 10.1002/1878-0261.12544] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/17/2019] [Accepted: 07/10/2019] [Indexed: 12/31/2022] Open
Abstract
The cross‐talk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, but the underlying mechanism is largely unknown. We report here that activated HSCs induce upregulation of nicotinamide N‐methyltransferase (NNMT), which is known to regulate multiple metabolic pathways in hepatoma cells of the liver. High levels of NNMT in HCC tissues were positively correlated with vascular invasion, increased serum HBV‐DNA levels, and distant metastasis. In addition, functional assays showed that NNMT promoted HCC cell invasion and metastasis by altering the histone H3 methylation on 27 methylation pattern and transcriptionally activating cluster of differentiation 44 (CD44). NNMT‐mediated N6‐methyladenosine modification of CD44 mRNA resulted in the formation of a CD44v3 splice variant, while its product 1‐methyl‐nicotinamide stabilized CD44 protein by preventing ubiquitin‐mediated degradation. Finally, NNMT was also shown to be a target of statins that inhibited metastasis of hepatoma cells. Taken together, our study shows for the first time that the NNMT/CD44v3 axis regulates HCC metastasis and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Jie Li
- Department of Hepatobiliary Surgery, ZhongShan Hospital of Xiamen University, Fujian, China.,Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Song You
- Graduate College of Fujian Medical University, Fuzhou, Fujian, China
| | - Sheng Zhang
- Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qing Hu
- Medicine Clinical Laboratory, Xiamen Xianyue Hospital, Fujian, China
| | - Fuqiang Wang
- Department of Hepatobiliary Surgery, ZhongShan Hospital of Xiamen University, Fujian, China.,Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Xiaoqin Chi
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Wenxiu Zhao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Chengrong Xie
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Changmao Zhang
- Graduate College of Fujian Medical University, Fuzhou, Fujian, China
| | - Yaqi Yu
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Jianmin Liu
- Department of Hepatobiliary Surgery, ZhongShan Hospital of Xiamen University, Fujian, China.,Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Yue Zhao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Pingguo Liu
- Department of Hepatobiliary Surgery, ZhongShan Hospital of Xiamen University, Fujian, China.,Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Yi Zhang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Xujin Wei
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Qiu Li
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Xiaomin Wang
- Department of Hepatobiliary Surgery, ZhongShan Hospital of Xiamen University, Fujian, China.,Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
| | - Zhenyu Yin
- Department of Hepatobiliary Surgery, ZhongShan Hospital of Xiamen University, Fujian, China.,Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, ZhongShan Hospital of Xiamen University, Fujian, China
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48
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Ressel S, Rosca A, Gordon K, Buck AH. Extracellular RNA in viral-host interactions: Thinking outside the cell. WILEY INTERDISCIPLINARY REVIEWS. RNA 2019; 10:e1535. [PMID: 30963709 PMCID: PMC6617787 DOI: 10.1002/wrna.1535] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/13/2019] [Accepted: 03/14/2019] [Indexed: 12/15/2022]
Abstract
Small RNAs and their associated RNA interference (RNAi) pathways underpin diverse mechanisms of gene regulation and genome defense across all three kingdoms of life and are integral to virus-host interactions. In plants, fungi and many animals, an ancestral RNAi pathway exists as a host defense mechanism whereby viral double-stranded RNA is processed to small RNAs that enable recognition and degradation of the virus. While this antiviral RNAi pathway is not generally thought to be present in mammals, other RNAi mechanisms can influence infection through both viral- and host-derived small RNAs. Furthermore, a burgeoning body of data suggests that small RNAs in mammals can function in a non-cell autonomous manner to play various roles in cell-to-cell communication and disease through their transport in extracellular vesicles. While vesicular small RNAs have not been proposed as an antiviral defense pathway per se, there is increasing evidence that the export of host- or viral-derived RNAs from infected cells can influence various aspects of the infection process. This review discusses the current knowledge of extracellular RNA functions in viral infection and the technical challenges surrounding this field of research. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action.
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Affiliation(s)
- Sarah Ressel
- Institute of Immunology and Infection Research, School of Biological SciencesUniversity of EdinburghEdinburghUK
| | - Adelina Rosca
- Department of VirologyCarol Davila University of Medicine and PharmacyBucharestRomania
| | - Katrina Gordon
- Institute of Immunology and Infection Research, School of Biological SciencesUniversity of EdinburghEdinburghUK
| | - Amy H. Buck
- Institute of Immunology and Infection Research, School of Biological SciencesUniversity of EdinburghEdinburghUK
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49
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Zhang R, Lin XH, Liu HH, Ma M, Chen J, Chen J, Gao DM, Cui JF, Chen RX. Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation. Int J Hyperthermia 2019; 36:253-263. [PMID: 30701994 DOI: 10.1080/02656736.2018.1558459] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Rui Zhang
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Xia-Hui Lin
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Hua-Hua Liu
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Min Ma
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Jie Chen
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Jun Chen
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Dong-Mei Gao
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Jie-Feng Cui
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Rong-Xin Chen
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
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50
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Curcumin Suppresses Hepatic Stellate Cell-Induced Hepatocarcinoma Angiogenesis and Invasion through Downregulating CTGF. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8148510. [PMID: 30800209 PMCID: PMC6360067 DOI: 10.1155/2019/8148510] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 09/16/2018] [Accepted: 10/08/2018] [Indexed: 12/20/2022]
Abstract
Microenvironment plays a vital role in tumor progression; we focused on elucidating the role of hepatic stellate cells (HSCs) in hepatocarcinoma (HCC) aggressiveness and investigated the potential protective effect of curcumin on HSC-driven hepatocarcinoma angiogenesis and invasion. Our data suggest that HSCs increase HCC reactive oxygen species (ROS) production to upregulate hypoxia-inducible factor-1α (HIF-1α) expression to promote angiogenesis, epithelial to mesenchymal transition (EMT) process and invasion. And HSCs could secrete soluble factors, such as interleukin-6 (IL-6), vascular endothelial cell growth factor (VEGF), and stromal-derived factor-1 (SDF-1) to facilitate HCC progression. Curcumin could significantly suppress the above HSC-induced effects in HCC and could abrogate ROS and HIF-1α expression in HCC. HIF-1α or connective tissue growth factor (CTGF) knockdown could abolish the aforementioned curcumin affection. Moreover, CTGF is a downstream gene of HIF-1α. In addition, nuclear factor E2-related factor 2 (Nrf2) and glutathione (GSH) are involved in curcumin protection of HCC. These data indicate that curcumin may induce ROS scavenging by upregulating Nrf2 and GSH, thus inhibiting HIF-1α stabilization to suppress CTGF expression to exhibit its protection on HCC. Curcumin has a promising therapeutic effect on HCC. CTGF is responsible for curcumin-induced protection in HCC.
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