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Wang F, Keating CR, Xu Y, Hou W, Malnassy G, Boedeker K, Perera A, Ham E, Patel D, Ding X, Qiu W. Suppression of Hepatocellular Carcinoma by Deletion of SIRT2 in Hepatocytes via Elevated C/EBPβ/GADD45γ. Cell Mol Gastroenterol Hepatol 2025; 19:101494. [PMID: 40081570 DOI: 10.1016/j.jcmgh.2025.101494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/28/2025] [Accepted: 02/28/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND & AIMS There is a gap in our understanding of mechanisms promoting hepatocellular carcinoma (HCC), and this limits our ability to provide targeted therapy interventions for HCC. In HCC samples, NAD-dependent deacetylase sirtuin 2 (SIRT2) levels are increased and associated with a significantly worse prognosis, but the role of SIRT2 in hepatocarcinogenesis remains controversial. METHODS To assess the role of SIRT2 in hepatocarcinogenesis, we used a hepatocyte-specific knockout of SIRT2 and two plasmid overexpression HCC models: c-MET (MET)/β-catenin (CAT) and protein kinase B (AKT)/Nras. RNA sequencing of mouse liver tissue was performed, and mechanistic findings were confirmed using immunohistochemistry (IHC), quantitative polymerase chain reaction, Western blot, and Cell Counting Kit-8. RESULTS Using the MET/CAT and AKT/Nras models, we found that SIRT2 is a significant mediator of liver tumorigenesis, with the knockout of SIRT2 delaying tumor growth. RNA sequencing of MET/CAT-driven tumor tissue showed an increase in growth arrest and DNA-damage-inducible protein gamma (GADD45γ) in SIRT2 knockout mice compared with wild-type. GADD45γ is a known tumor suppressor, but the regulation of GADD45γ by SIRT2 has not been shown. CCAAT/enhancer-binding protein beta (C/EBPβ) proteins are known to regulate GADD45γ expression, and we found that C/EBPβ expression was increased in SIRT2 knockout livers and HCC cells. Also, C/EBPβ knockdown reversed GADD45γ expression and growth suppression following SIRT2 inhibition. Finally, C/EBPβ or GADD45γ overexpression significantly suppressed MET/CAT-induced HCC development. CONCLUSIONS SIRT2 is a potent tumor promotor in HCC that negatively regulates GADD45γ expression through C/EBPβ. The SIRT2-C/EBPβ-GADD45γ pathway elucidates a novel mechanism in HCC and establishes SIRT2 as a therapeutic target for patients with HCC.
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Affiliation(s)
- Fang Wang
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Claudia Rose Keating
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Yingchen Xu
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Wei Hou
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Greg Malnassy
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Kyle Boedeker
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Aldeb Perera
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Eugene Ham
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Diya Patel
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Xianzhong Ding
- Department of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Wei Qiu
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.
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Li C, Ling Y, Kuang H. Research progress on FSH-FSHR signaling in the pathogenesis of non-reproductive diseases. Front Cell Dev Biol 2024; 12:1506450. [PMID: 39633710 PMCID: PMC11615068 DOI: 10.3389/fcell.2024.1506450] [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: 10/05/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Follicle-stimulating hormone (FSH), a glycoprotein hormone synthesized and secreted by the anterior pituitary gland, plays a critical role in reproductive development and regulation by binding to FSH receptor (FSHR). Beyond reproductive tissue, FSHRs have been identified in various non-reproductive tissues, indicating broader functions. FSH levels chronically rise during menopause and remain elevated in postmenopausal life. This increase in FSH level has been indicated to be associated with heightened risk of several non-reproductive diseases, including osteoporosis, hypercholesterolemia, type 2 diabetes mellitus, obesity, cardiovascular disease, Alzheimer's disease, and certain cancers. In this review, we will examine the role of FSH-FSHR signaling in the pathogenesis of these non-reproductive diseases and explore therapeutic strategies targeting FSH-FSHR signaling pathways.
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Affiliation(s)
- Chenhe Li
- Department of Clinical Medicine, School of Queen Mary, Nanchang University, Nanchang, Jiangxi, China
- Department of Physiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yan Ling
- Department of Obstetrics and Gynecology, Jiangxi provincial People’s Hospital, Nanchang, Jiangxi, China
| | - Haibin Kuang
- Department of Physiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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Van Dender C, Timmermans S, Paakinaho V, Vanderhaeghen T, Vandewalle J, Claes M, Garcia B, Roman B, De Waele J, Croubels S, De Bosscher K, Meuleman P, Herpain A, Palvimo JJ, Libert C. A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death. EMBO Mol Med 2024; 16:2485-2515. [PMID: 39261648 PMCID: PMC11473810 DOI: 10.1038/s44321-024-00130-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/24/2024] [Accepted: 08/13/2024] [Indexed: 09/13/2024] Open
Abstract
In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.
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Affiliation(s)
- Céline Van Dender
- Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Steven Timmermans
- Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Ville Paakinaho
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Tineke Vanderhaeghen
- Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Jolien Vandewalle
- Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Maarten Claes
- Research Group SynBioC, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium
| | - Bruno Garcia
- Experimental Laboratory of Intensive Care, Université Libre de Bruxelles, 1050, Brussels, Belgium
- Department of Intensive Care, Center Hospitalier Universitaire de Lille, 59000, Lille, France
| | - Bart Roman
- Research Group SynBioC, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium
| | - Jan De Waele
- Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Siska Croubels
- Laboratory of Pharmacology and Toxicology, Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Karolien De Bosscher
- Center for Medical Biotechnology, VIB, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Antoine Herpain
- Experimental Laboratory of Intensive Care, Université Libre de Bruxelles, 1050, Brussels, Belgium
- Department of Intensive Care, St.-Pierre University Hospital, Université Libre de Bruxelles, 1050, Brussels, Belgium
| | - Jorma J Palvimo
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Claude Libert
- Center for Inflammation Research, VIB, Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
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Martucci NJ, Stoops J, Bowen W, Orr A, Cotner MC, Michalopoulos GK, Bhushan B, Mars WM. A Novel Role for the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Delta Isoform in Hepatocellular Proliferation. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1511-1527. [PMID: 38705383 PMCID: PMC11393825 DOI: 10.1016/j.ajpath.2024.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 02/09/2024] [Accepted: 03/22/2024] [Indexed: 05/07/2024]
Abstract
The phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform (Pik3cd), usually considered immune-specific, was unexpectedly identified as a gene potentially related to either regeneration and/or differentiation in animals lacking hepatocellular Integrin Linked Kinase (ILK). Since a specific inhibitor (Idelalisib, or CAL101) for the catalytic subunit encoded by Pik3cd (p110δ) has reported hepatotoxicity when used for treating chronic lymphocytic leukemia and other lymphomas, the authors aimed to elucidate whether there is a role for p110δ in normal liver function. To determine the effect on normal liver regeneration, partial hepatectomy (PHx) was performed using mice in which p110δ was first inhibited using CAL101. Inhibition led to over a 50% decrease in proliferating hepatocytes in the first 2 days after PHx. This difference correlated with phosphorylation changes in the HGF and EGF receptors (MET and EGFR, respectively) and NF-κB signaling. Ingenuity Pathway Analyses implicated C/EBPβ, HGF, and the EGFR heterodimeric partner, ERBB2, as three of the top 20 regulators downstream of p110δ signaling because their pathways were suppressed in the presence of CAL101 at 1 day post-PHx. A regulatory role for p110δ signaling in mouse and rat hepatocytes through MET and EGFR was further verified using hepatocyte primary cultures, in the presence or absence of CAL101. Combined, these data support a role for p110δ as a downstream regulator of normal hepatocytes when stimulated to proliferate.
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Affiliation(s)
- Nicole J Martucci
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - John Stoops
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - William Bowen
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anne Orr
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mary-Claire Cotner
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Bharat Bhushan
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Wendy M Mars
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Ren Q, Liu Z, Wu L, Yin G, Xie X, Kong W, Zhou J, Liu S. C/EBPβ: The structure, regulation, and its roles in inflammation-related diseases. Biomed Pharmacother 2023; 169:115938. [PMID: 38000353 DOI: 10.1016/j.biopha.2023.115938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 11/26/2023] Open
Abstract
Inflammation, a mechanism of the human body, has been implicated in many diseases. Inflammatory responses include the release of inflammatory mediators by activating various signaling pathways. CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor in the C/EBP family, contains the leucine zipper (bZIP) domain. The expression of C/EBPβ is mediated at the transcriptional and post-translational levels, such as phosphorylation, acetylation, methylation, and SUMOylation. C/EBPβ has been involved in inflammatory responses by mediating several signaling pathways, such as MAPK/NF-κB and IL-6/JAK/STAT3 pathways. C/EBPβ plays an important role in the pathological development of inflammation-related diseases, such as osteoarthritis, pneumonia, hepatitis, inflammatory bowel diseases, and rheumatoid arthritis. Here, we comprehensively discuss the structure and biological effects of C/EBPβ and its role in inflammatory diseases.
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Affiliation(s)
- Qun Ren
- Department of Pharmacy, Gannan Medical University, Ganzhou 341000, China
| | - Zhaowen Liu
- Department of Pharmacy, Gannan Medical University, Ganzhou 341000, China
| | - Longhuo Wu
- Department of Pharmacy, Gannan Medical University, Ganzhou 341000, China
| | - Guoqiang Yin
- Ganzhou People's Hospital Affiliated to Nanchang University, Ganzhou 341000, China
| | - Xunlu Xie
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Weihao Kong
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Jianguo Zhou
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China
| | - Shiwei Liu
- Department of Joint Surgery, Ganzhou People's Hospital, Ganzhou 341000, China.
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Li G, Zhu L, Guo M, Wang D, Meng M, Zhong Y, Zhang Z, Lin Y, Liu C, Wang J, Zhang Y, Gao Y, Cao Y, Xia Z, Qiu J, Li Y, Liu S, Chen H, Liu W, Han Y, Zheng M, Ma X, Xu L. Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration. JHEP Rep 2023; 5:100906. [PMID: 38023606 PMCID: PMC10679869 DOI: 10.1016/j.jhepr.2023.100906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 08/07/2023] [Accepted: 08/24/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND & AIMS Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. METHODS Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3-Cebpb axis in human liver samples. RESULTS Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. CONCLUSIONS These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. IMPACT AND IMPLICATIONS Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.
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Affiliation(s)
- Guoqiang Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Lijun Zhu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Mingwei Guo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Dongmei Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Meiyao Meng
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yinzhao Zhong
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Zhijian Zhang
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Yi Lin
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Caizhi Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiawen Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yahui Zhang
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Yining Gao
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuxiang Cao
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Zhirui Xia
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jin Qiu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yu Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shuang Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Haibing Chen
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wenyue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu Han
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, China
- Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, China
| | - Lingyan Xu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
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Xiong J, Kang SS, Wang M, Wang Z, Xia Y, Liao J, Liu X, Yu SP, Zhang Z, Ryu V, Yuen T, Zaidi M, Ye K. FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPβ/δ-secretase in female mice. Nat Commun 2023; 14:6577. [PMID: 37852961 PMCID: PMC10584868 DOI: 10.1038/s41467-023-42282-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Alzheimer's disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR in the hippocampus, to drive AD-like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPβ/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPβ/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aβ and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPβ/δ-secretase signalling.
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Affiliation(s)
- Jing Xiong
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Seong Su Kang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Mengmeng Wang
- Faculty of Life and Health Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China
| | - Zhihao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Yiyuan Xia
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Jianming Liao
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Shan-Ping Yu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Vitaly Ryu
- Mount Sinai Bone Program, Department of Medicine and Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, 10029, USA
| | - Tony Yuen
- Mount Sinai Bone Program, Department of Medicine and Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, 10029, USA
| | - Mone Zaidi
- Mount Sinai Bone Program, Department of Medicine and Department of Orthopedics, Mount Sinai School of Medicine, New York, NY, 10029, USA
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Faculty of Life and Health Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
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8
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Baird L, Taguchi K, Zhang A, Takahashi Y, Suzuki T, Kensler TW, Yamamoto M. A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells. Redox Biol 2023; 66:102845. [PMID: 37597423 PMCID: PMC10458321 DOI: 10.1016/j.redox.2023.102845] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/02/2023] [Accepted: 08/07/2023] [Indexed: 08/21/2023] Open
Abstract
While it is well established that the KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative stress, this cytoprotective function of NRF2 could become deleterious to the host if it confers survival onto irreparably damaged cells. In this regard, we have found that in diseased states, NRF2 promotes the transcriptional activation of a specific subset of the senescence-associated secretory phenotype (SASP) gene program, which we have named the NRF2-induced secretory phenotype (NISP). In two models of hepatic disease using Pten::Keap1 and Keap1::Atg7 double knockout mice, we found that the NISP functions in the liver to recruit CCR2 expressing monocytes, which function as immune system effector cells to directly remove the damaged cells. Through activation of this immune surveillance pathway, in non-transformed cells, NRF2 functions as a tumour suppressor to mitigate the long-term survival of damaged cells which otherwise would be detrimental for host survival. This pathway represents the final stage of the oxidative stress response, as it allows cells to be safely removed if the macromolecular damage caused by the original stressor is so extensive that it is beyond the repair capacity of the cell.
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Affiliation(s)
- Liam Baird
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, 980-8575, Japan.
| | - Keiko Taguchi
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan
| | - Anqi Zhang
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan
| | - Yushi Takahashi
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan
| | - Takafumi Suzuki
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan
| | - Thomas W Kensler
- Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, United States
| | - Masayuki Yamamoto
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, 980-8575, Japan.
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9
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Elias G, Schonfeld M, Saleh S, Parrish M, Barmanova M, Weinman SA, Tikhanovich I. Sepsis-induced endothelial dysfunction drives acute-on-chronic liver failure through Angiopoietin-2-HGF-C/EBPβ pathway. Hepatology 2023; 78:803-819. [PMID: 36943063 PMCID: PMC10440279 DOI: 10.1097/hep.0000000000000354] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/13/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AND AIMS Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis. A common cause of ACLF is sepsis secondary to bacterial infection. Sepsis-associated ACLF involves a loss of differentiated liver function in the absence of direct liver injury, and its mechanism is unknown. We aimed to study the mechanism of sepsis-associated ACLF using a novel mouse model. APPROACH AND RESULTS Sepsis-associated ACLF was induced by cecal ligation and puncture procedure (CLP) in mice treated with thioacetamide (TAA). The combination of TAA and CLP resulted in a significant decrease in liver synthetic function and high mortality. These changes were associated with reduced metabolic gene expression and increased CCAAT enhancer binding protein beta (C/EBPβ) transcriptional activity. We found that C/EBPβ binding to its target gene promoters was increased. In humans, C/EBPβ chromatin binding was similarly increased in the ACLF group compared with control cirrhosis. Hepatocyte-specific Cebpb knockout mice had reduced mortality and increased gene expression of hepatocyte differentiation markers in TAA/CLP mice, suggesting that C/EBPβ promotes liver failure in these mice. C/EBPβ activation was associated with endothelial dysfunction, characterized by reduced Angiopoietin-1/Angiopoietin-2 ratio and increased endothelial production of HGF. Angiopoietin-1 supplementation or Hgf knockdown reduced hepatocyte C/EBPβ accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives ACLF through HGF-C/EBPβ pathway. CONCLUSIONS The transcription factor C/EBPβ is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis.
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Affiliation(s)
- Grant Elias
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Michael Schonfeld
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Sara Saleh
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Mark Parrish
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Marina Barmanova
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
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10
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Wang C, Zhang H, Zhu J, Liu H, Yang Y, Sun B, Wu T, Zhang Y, Yao D. The transcription factor CEBP homolog of Penaeus vannamei contributes to WSSV replication. FISH & SHELLFISH IMMUNOLOGY 2023; 134:108571. [PMID: 36736844 DOI: 10.1016/j.fsi.2023.108571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/19/2023] [Accepted: 01/26/2023] [Indexed: 06/18/2023]
Abstract
The cellular transcription factors are known to play important roles in virus infection. The present study cloned and characterized a transcription factor CCAAT/Enhancer-binding protein homolog from the shrimp Penaeus vannamei (designates as PvCEBP), and explored its potential functions in white spot syndrome virus (WSSV) infection. PvCEBP has an open reading frame (ORF) of 864 bp encoding a putative protein of 287 amino acids, which contained a highly C-terminal conserved bZIP domain. Phylogenetic tree analysis showed that PvCEBP was evolutionarily clustered with invertebrate CEBPs and closely related to the CEBP of Homarus americanus. Quantitative real-time PCR (qPCR) analysis revealed that PvCEBP was expressed in all examined shrimp tissues, with transcript levels increased in shrimp hemocytes and gill upon WSSV challenge. Furthermore, knockdown of PvCEBP mediated by RNA interference significantly decreased the expression of WSSV genes and viral loads, while enhanced the shrimp survival rate under WSSV challenge. In silico prediction and reporter gene assays demonstrated that PvCEBP could activate the promoter activity of the viral immediate-early gene ie1. Collectively, our findings suggest that PvCEBP is annexed by WSSV to promote its propagation by enhancing the expression of viral immediate-early genes.
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Affiliation(s)
- Chuanqi Wang
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Huimin Zhang
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Jinghua Zhu
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Haiping Liu
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Yiqing Yang
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Bingbing Sun
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Tingchu Wu
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Yueling Zhang
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Defu Yao
- Institute of Marine Sciences and Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China.
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11
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Yu Q, Liu X, Fang J, Wu H, Guo C, Zhang W, Liu N, Jiang C, Sha Q, Yuan X, Wang Z, Qu K. Dynamics and regulation of mitotic chromatin accessibility bookmarking at single-cell resolution. SCIENCE ADVANCES 2023; 9:eadd2175. [PMID: 36696508 PMCID: PMC9876548 DOI: 10.1126/sciadv.add2175] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 12/29/2022] [Indexed: 06/17/2023]
Abstract
Although mitotic chromosomes are highly compacted and transcriptionally inert, some active chromatin features are retained during mitosis to ensure the proper postmitotic reestablishment of maternal transcriptional programs, a phenomenon termed "mitotic bookmarking." However, the dynamics and regulation of mitotic bookmarking have not been systemically surveyed. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we examined 6538 mitotic L02 human liver cells of variable stages and found that chromatin accessibility remained changing throughout cell division, with a constant decrease until metaphase and a gradual increase as chromosomes segregated. In particular, a subset of chromatin regions were identified to remain open throughout mitosis, and genes associated with these bookmarked regions are primarily linked to rapid reactivation upon mitotic exit. We also demonstrated that nuclear transcription factor Y subunit α (NF-YA) preferentially occupied bookmarked regions and contributed to transcriptional reactivation after mitosis. Our study uncovers the dynamic and regulatory blueprint of mitotic bookmarking.
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Affiliation(s)
- Qiaoni Yu
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230021, China
| | - Xu Liu
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA
| | - Jingwen Fang
- Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
- HanGene Biotech, Xiaoshan Innovation Polis, Hangzhou, Zhejiang 311200, China
| | - Huihui Wu
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA
| | - Chuang Guo
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Wen Zhang
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Nianping Liu
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Chen Jiang
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Qing Sha
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Xiao Yuan
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA
| | - Zhikai Wang
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA
- Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Kun Qu
- MOE Key Laboratory for Cellular Dynamics, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230021, China
- Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
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12
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Wang H, Chen G, Ahn EH, Xia Y, Kang SS, Liu X, Liu C, Han MH, Chen S, Ye K. C/EBPβ/AEP is age-dependently activated in Parkinson's disease and mediates α-synuclein in the gut and brain. NPJ Parkinsons Dis 2023; 9:1. [PMID: 36609384 PMCID: PMC9822984 DOI: 10.1038/s41531-022-00430-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 11/11/2022] [Indexed: 01/09/2023] Open
Abstract
Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPβ from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPβ/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPβ or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPβ/AEP-dependent manner. Hence, our studies demonstrate that C/EBPβ/AEP pathway is critical for mediating Lewy body pathology progression in PD.
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Affiliation(s)
- Hualong Wang
- grid.16821.3c0000 0004 0368 8293Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China ,grid.452458.aDepartment of Neurology, The First Hospital of Hebei Medical University (Department of Neurology, Hebei Hospital of Xuanwu Hospital Capital Medical University), Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, 050031 Hebei P. R. China ,grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA
| | - Guiqin Chen
- grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA ,grid.412632.00000 0004 1758 2270Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060 China
| | - Eun Hee Ahn
- grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA ,grid.256753.00000 0004 0470 5964Department of Physiology, College of Medicine, Hallym University, Hallymdaehak-gil, Chuncheon-si, Gangwon-Do, 24252, South Korea
| | - Yiyuan Xia
- grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA
| | - Seong Su Kang
- grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA
| | - Xia Liu
- grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA
| | - Chang Liu
- grid.458489.c0000 0001 0483 7922CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055 China ,grid.458489.c0000 0001 0483 7922Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518000, China
| | - Ming-Hu Han
- grid.458489.c0000 0001 0483 7922Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055 China
| | - Shengdi Chen
- grid.16821.3c0000 0004 0368 8293Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
| | - Keqiang Ye
- grid.189967.80000 0001 0941 6502Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 USA ,grid.458489.c0000 0001 0483 7922Department of Biology, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055 China
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13
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House JS, Gray S, Owen JR, Jima DD, Smart RC, Hall JR. C/EBPβ deficiency enhances the keratinocyte innate immune response to direct activators of cytosolic pattern recognition receptors. Innate Immun 2023; 29:14-24. [PMID: 37094088 PMCID: PMC10164275 DOI: 10.1177/17534259231162192] [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: 10/27/2022] [Revised: 01/10/2023] [Accepted: 02/08/2023] [Indexed: 04/26/2023] Open
Abstract
The skin is the first line of defense to cutaneous microbes and viruses, and epidermal keratinocytes play a critical role in preventing infection by viruses and pathogens through activation of the type I interferon (IFN) response. Using RNAseq analysis, here we report that the conditional deletion of C/EBPβ transcription factor in mouse epidermis (CKOβ mice) resulted in the upregulation of IFNβ and numerous keratinocyte interferon-stimulated genes (ISGs). The expression of cytosolic pattern recognition receptors (cPRRs), that recognize viral RNA and DNA, were significantly increased, and enriched in the RNAseq data set. cPRRs stimulate a type I IFN response that can trigger cell death to eliminate infected cells. To determine if the observed increases in cPRRs had functional consequences, we transfected CKOβ primary keratinocytes with the pathogen and viral mimics poly(I:C) (dsRNA) or poly(dA:dT) (synthetic B-DNA) that directly activate PRRs. Transfected CKOβ primary keratinocytes displayed an amplified type I IFN response which was accompanied by increased activation of IRF3, enhanced ISG expression, enhanced activation of caspase-8, caspase-3 and increased apoptosis. Our results identify C/EBPβ as a critical repressor of the keratinocyte type I IFN response, and demonstrates that the loss of C/EBPβ primes keratinocytes to the activation of cytosolic PRRs by pathogen RNA and DNA to induce cell death mediated by caspase-8 and caspase-3.
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Affiliation(s)
- John S. House
- Center of Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
- Toxicology Graduate Program, North Carolina State University, Raleigh, NC, 27695, USA
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC 27709, USA
| | - Sophia Gray
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
| | - Jennifer R. Owen
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
| | - Dereje D. Jima
- Center of Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, 27695, USA
| | - Robert C. Smart
- Center of Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
- Toxicology Graduate Program, North Carolina State University, Raleigh, NC, 27695, USA
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
| | - Jonathan R. Hall
- Center of Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
- Toxicology Graduate Program, North Carolina State University, Raleigh, NC, 27695, USA
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
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14
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Pibiri M, Simbula G. Role of the Hippo pathway in liver regeneration and repair: recent advances. Inflamm Regen 2022; 42:59. [PMID: 36471376 PMCID: PMC9720992 DOI: 10.1186/s41232-022-00235-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.
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Affiliation(s)
- Monica Pibiri
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
| | - Gabriella Simbula
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
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15
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Mir KB, Faheem MM, Ahmad SM, Rasool JU, Amin T, Chakraborty S, Bhagat M, Ahmed Z, Ali A, Goswami A. β-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPβ mediates the transition of breast cancer cells from autophagy to senescence. Front Oncol 2022; 12:1013500. [PMID: 36465376 PMCID: PMC9713483 DOI: 10.3389/fonc.2022.1013500] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 10/17/2022] [Indexed: 08/06/2023] Open
Abstract
ATF-4 is a master regulator of transcription of genes essential for cellular-adaptive function. In response to the quantum and duration of stress, ATF-4 diligently responds to both pro-apoptotic and pro-survival signals converging into either autophagy or apoptosis/senescence. Despite emerging cues implying a relationship between autophagy and senescence, how these two processes are controlled remains unknown. Herein, we demonstrate β-(4-fluorobenzyl) Arteannuin B (here after Arteannuin 09), a novel semisynthetic derivative of Arteannuin B, as a potent ER stress inducer leading to the consistent activation of ATF-4. Persistent ATF-4 expression at early time-points facilitates the autophagy program and consequently by upregulating p21 at later time-points, the signaling is shifted towards G2/M cell cycle arrest. As bZIP transcription factors including ATF-4 are obligate dimers, and because ATF-4 homodimers are not highly stable, we hypothesized that ATF-4 may induce p21 expression by physically interacting with another bZIP family member i.e., C/EBPβ. Our co-immunoprecipitation and co-localization studies demonstrated that ATF-4 is principally responsible for the autophagic potential of Arteannuin 09, while as, induction of both ATF-4 and C/EBPβ is indispensable for the p21 regulated-cell cycle arrest. Interestingly, inhibition of autophagy signaling switches the fate of Arteannuin 09 treated cells from senescence to apoptosis. Lastly, our data accomplished that Arteannuin 09 is a potent inhibitor of tumor growth and inducer of premature senescence in vivo.
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Affiliation(s)
- Khalid Bashir Mir
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Pharmacology Division, Council of Scientific & Industrial Research (CSIR)-Indian Indian Institute of Integrative Medicine, Jammu, India
| | - Mir Mohd Faheem
- Pharmacology Division, Council of Scientific & Industrial Research (CSIR)-Indian Indian Institute of Integrative Medicine, Jammu, India
- School of Biotechnology, University of Jammu, Jammu, India
| | - Syed Mudabir Ahmad
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Pharmacology Division, Council of Scientific & Industrial Research (CSIR)-Indian Indian Institute of Integrative Medicine, Jammu, India
| | - Javeed Ur Rasool
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Natural Product and Medicinal Chemistry Division, Council of Scientific & Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu, India
| | - Tanzeeba Amin
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Pharmacology Division, Council of Scientific & Industrial Research (CSIR)-Indian Indian Institute of Integrative Medicine, Jammu, India
| | | | | | - Zabeer Ahmed
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Pharmacology Division, Council of Scientific & Industrial Research (CSIR)-Indian Indian Institute of Integrative Medicine, Jammu, India
| | - Asif Ali
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Natural Product and Medicinal Chemistry Division, Council of Scientific & Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu, India
- Division of Medicinal and Process Chemistry, Council of Scientific & Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Anindya Goswami
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
- Pharmacology Division, Council of Scientific & Industrial Research (CSIR)-Indian Indian Institute of Integrative Medicine, Jammu, India
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16
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Moshkovits I, Kaminitz A, Reuveni D, Pasmanik‐Chor M, Brazowski E, Mildner A, Leutz A, Zigmond E. Immune cell C/EBPβ deficiency is associated with hepatic mononuclear defects and spontaneous hepatitis but not steatohepatitis induced liver fibrosis. Immun Inflamm Dis 2022; 10:e728. [PMID: 36301029 PMCID: PMC9609438 DOI: 10.1002/iid3.728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/20/2022] [Accepted: 10/12/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor known to be involved in macrophage differentiation and function, steatohepatitis and liver fibrosis. METHODS Immune restricted C/EBPβ deficient and control mice were investigated in steady-state and in the CDA-HFD steatohepatitis model. Mice were assessed for weight change, liver biochemical profile, histology and hepatic phagocytes composition. RESULTS Flow cytometry analysis of hepatic nonparenchymal cells revealed reduced numbers of hepatic monocytes and Kupffer cells and an increase in hepatic MHC class II positive myeloid cells in immune cells restricted C/EBPβ deficient mice. Immune-restricted C/EBPβ deficiency resulted in decreased weight gain and appearance of mild spontaneous liver inflammation. Nevertheless, In the CDA-HFD steatohepatitis model, immune restricted C/EBPβ deficient and proficient mice exhibit similar grade of hepatic steatosis, liver enzymes levels and fibrosis stage. CONCLUSIONS Immune-restricted C/EBPβ deficiency leads to significant alteration in hepatic mononuclear phagocytes composition associated with spontaneous mild hepatitis. Steatohepatitis associated fibrosis is not dependent on C/EBPβ expression by immune cells.
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Affiliation(s)
- Itay Moshkovits
- Research Center for Digestive DiseasesTel Aviv Sourasky Medical CenterTel AvivIsrael,Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
| | - Ayelet Kaminitz
- Research Center for Digestive DiseasesTel Aviv Sourasky Medical CenterTel AvivIsrael,Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
| | - Debby Reuveni
- Research Center for Digestive DiseasesTel Aviv Sourasky Medical CenterTel AvivIsrael,Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael,Center for Autoimmune Liver DiseasesTel Aviv Sourasky Medical CenterTel AvivIsrael
| | - Metsada Pasmanik‐Chor
- Bioinformatics Unit, George‐S. Wise Faculty of Life ScienceTel Aviv UniversityTel AvivIsrael
| | - Eli Brazowski
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael,Department of PathologyTel Aviv Sourasky Medical CenterTel AvivIsrael
| | | | - Achim Leutz
- Max Delbrück Center for Molecular MedicineBerlinGermany
| | - Ehud Zigmond
- Research Center for Digestive DiseasesTel Aviv Sourasky Medical CenterTel AvivIsrael,Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael,Center for Autoimmune Liver DiseasesTel Aviv Sourasky Medical CenterTel AvivIsrael
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17
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Liver Regeneration: Changes in Oxidative Stress, Immune System, Cytokines, and Epigenetic Modifications Associated with Aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9018811. [PMID: 35936214 PMCID: PMC9352489 DOI: 10.1155/2022/9018811] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/25/2022] [Accepted: 06/29/2022] [Indexed: 01/10/2023]
Abstract
The regenerative capacity of the liver decreases with increase in age. In recent years, studies in mice have found that the regenerative capacity of the liver is associated with changes in the immune system of the liver, cytokines in the body, aging-related epigenetic modifications in the cell, and intracellular signaling pathways. In the immune system of the aging liver, monocytes and macrophages play an important role in tissue repair. During tissue repair, monocytes and macrophages undergo a series of functional and phenotypic changes to initiate and maintain tissue repair. Studies have discovered that knocking out macrophages in the liver during the repair phase results in significant impairment of liver regeneration. Furthermore, as the body ages, the secretion and function of cytokines undergo a series of changes. For example, the levels of interleukin-6, transforming growth factor-alpha, hepatocyte growth factor, and vascular endothelial growth factor undergo changes that alter hepatocyte regulation, thereby affecting its proliferation. In addition, body aging is accompanied by cellular aging, which leads to changes in gene expression and epigenetic modifications. Additionally, this in turn causes alterations in cell function, morphology, and division and affects the regenerative capacity of the liver. As the body ages, the activity of associated functional proteins, such as CCAAT-enhancer-binding proteins, p53, and switch/sucrose nonfermentable complex, changes in the liver, leading to alterations in several signaling pathways, such as the Hippo, PI3K-Akt, mTOR, and STAT3 pathways. Therefore, in recent years, research on aging and liver regeneration has primarily focused on the immune system, signaling pathways, epigenetic changes of senescent cells, and cytokine secretion in the liver. Hence, this review details the roles of these influencing factors in liver regeneration and impact of aging-related factors.
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18
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Jiang M, Huang Y, Hu L, Wu H, Liu Y, Ni K, Zhang X, Sun Y, Gu X. The transcription factor CCAAT/enhancer-binding protein β in spinal microglia contributes to pre-operative stress-induced prolongation of postsurgical pain. Mol Pain 2022; 18:17448069221099360. [PMID: 35451875 PMCID: PMC9257637 DOI: 10.1177/17448069221099360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Prolongation of postsurgical pain caused by pre-operative stress is a clinically significant problem, although the mechanisms are not fully understood. Stress can promote the pro-inflammatory activation of microglia, and the transcription factor CCAAT/enhancer-binding protein (C/EBP) β regulates pro-inflammatory gene expression in microglia. Therefore, we speculated that C/EBPβ in spinal microglia may have critical roles in the development of chronic postsurgical pain. Accordingly, in this study, we used a single prolonged stress (SPS) procedure and plantar incisions to evaluate the roles of C/EBPβ in postsurgical pain. Our experiments showed that SPS exposure prolonged mechanical allodynia, increased the expression of C/EBPβ and pro-inflammatory cytokines, and potentiated the activation of spinal microglia. Subsequently, microinjection of C/EBPβ siRNA attenuated the duration of SPS-prolonged postoperative mechanical allodynia and inhibited microglial activation in the spinal cord. Conversely, mimicking this increase in C/EBPβ promoted microglial activation via pretreatment with a pre-injection of AAV5-C/EBPβ, leading to prolongation of postsurgical pain. Overall, these results suggested that spinal microglia may play key roles in prolongation of postsurgical pain induced by pre-operative stress and that C/EBPβ may be a potential target for disease treatment.
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Affiliation(s)
- Ming Jiang
- Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Yulin Huang
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Lijun Hu
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Hao Wu
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Yue Liu
- Department of Anesthesiology66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Kun Ni
- Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Xiaokun Zhang
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Yu'e Sun
- 66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
| | - Xiaoping Gu
- Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School66506Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
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19
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Nachiyappan A, Soon JLJ, Lim HJ, Lee VK, Taneja R. EHMT1 promotes tumor progression and maintains stemness by regulating ALDH1A1 expression in alveolar rhabdomyosarcoma. J Pathol 2022; 256:349-362. [PMID: 34897678 DOI: 10.1002/path.5848] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/16/2021] [Accepted: 12/09/2021] [Indexed: 11/06/2022]
Abstract
Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. Cancer stem cells (CSCs) are seeds for tumor relapse and metastasis. However, pathways that maintain stemness genes are not fully understood. Here, we report that the enzyme euchromatic histone lysine methyltransferase 1 (EHMT1) is expressed in primary and relapse ARMS tumors. EHMT1 suppression impaired motility and induced differentiation in ARMS cell lines and reduced tumor progression in a mouse xenograft model in vivo. RNA sequencing of EHMT1-depleted cells revealed downregulation of ALDH1A1 that is associated with CSCs. Consistent with this, inhibition of ALDH1A1 expression and activity mimicked EHMT1 depletion phenotypes and reduced tumorsphere formation. Mechanistically, we demonstrate that EHMT1 does not bind to the ALDH1A1 promoter but activates it by stabilizing C/EBPβ, a known regulator of ALDH1A1 expression. Our findings identify a role for EHMT1 in maintenance of stemness by regulating ALDH1A1 expression and suggest that targeting ALDH+ cells is a promising strategy in ARMS. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Alamelu Nachiyappan
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Joshua Ling Jun Soon
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Huey Jin Lim
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Victor Km Lee
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Reshma Taneja
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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20
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Neuronal ApoE4 stimulates C/EBPβ activation, promoting Alzheimer’s disease pathology in a mouse model. Prog Neurobiol 2022; 209:102212. [DOI: 10.1016/j.pneurobio.2021.102212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 12/05/2021] [Accepted: 12/22/2021] [Indexed: 12/15/2022]
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21
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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22
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AlSudais H, Wiper-Bergeron N. From quiescence to repair: C/EBPβ as a regulator of muscle stem cell function in health and disease. FEBS J 2021; 289:6518-6530. [PMID: 34854237 DOI: 10.1111/febs.16307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/21/2021] [Accepted: 11/30/2021] [Indexed: 11/26/2022]
Abstract
CCAAT/Enhancer Binding protein beta (C/EBPβ) is a transcriptional regulator involved in numerous physiological processes. Herein, we describe a role for C/EBPβ as a regulator of skeletal muscle stem cell function. In particular, C/EBPβ is expressed in muscle stem cells in healthy muscle where it inhibits myogenic differentiation. Downregulation of C/EBPβ expression at the protein and transcriptional level allows for differentiation. Persistence of C/EBPβ promotes stem cell self-renewal and C/EBPβ expression is required for mitotic quiescence in this cell population. As a critical regulator of skeletal muscle homeostasis, C/EBPβ expression is stimulated in pathological conditions such as cancer cachexia, which perturbs muscle regeneration and promotes myofiber atrophy in the context of systemic inflammation. C/EBPβ is also an important regulator of cytokine expression and immune response genes, a mechanism by which it can influence muscle stem cell function. In this viewpoint, we describe a role for C/EBPβ in muscle stem cells and propose a functional intersection between C/EBPβ and NF-kB action in the regulation of cancer cachexia.
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Affiliation(s)
- Hamood AlSudais
- Graduate Program in Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Canada.,Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Saudi Arabia
| | - Nadine Wiper-Bergeron
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Canada
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23
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Lei K, Kang SS, Ahn EH, Chen C, Liao J, Liu X, Li H, Edgington-Mitchell LE, Jin L, Ye K. C/EBPβ/AEP Signaling Regulates the Oxidative Stress in Malignant Cancers, Stimulating the Metastasis. Mol Cancer Ther 2021; 20:1640-1652. [PMID: 34158346 DOI: 10.1158/1535-7163.mct-21-0019] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/07/2021] [Accepted: 06/14/2021] [Indexed: 11/16/2022]
Abstract
Solid tumors start as a local disease, but some are capable of metastasizing to the lymph nodes and distant organs. The hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating cancer progression and metastasis. However, the molecular mechanisms mediating the disseminated cancer cell metastasis remain incompletely understood. Here, we show that C/EBPβ/AEP signaling that is upregulated in breast cancers mediates oxidative stress and lung metastasis, and inactivation of asparagine endopeptidase (AEP, also known as legumain) robustly regulates breast cancer reactive oxygen species (ROS) and metastasis. AEP, a protease activated in acidic conditions, is overexpressed in numerous types of cancer and promotes metastasis. Employing a breast cancer cell line MDA-MD-231, we show that C/EBPβ, an oxidative stress or inflammation-activated transcription factor, and its downstream target AEP mediate ROS production as well as migration and invasion in cancer cells. Deficiency of AEP in the MMTV-PyMT transgenic breast cancer mouse model significantly regulates oxidative stress and suppresses lung metastasis. Administration of an innovative AEP inhibitor substantially mitigates ROS production and cancer metastasis. Hence, our study demonstrates that pharmacologic inhibition of AEP activity might provide a disease-modifying strategy to suppress cancer metastasis.
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Affiliation(s)
- Kecheng Lei
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.,Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Seong Su Kang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Eun Hee Ahn
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Chun Chen
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Jianming Liao
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Hua Li
- School of Pharmacy, Tongji Medical College, Huazhong Science & Technology University, Wuhan, China
| | - Laura E Edgington-Mitchell
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.,Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, Bluestone Center for Clinical Research, New York, New York
| | - Lingjing Jin
- Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, P.R. China.,Neurorehabilitation Center of Yangzhi Rehabilitation Hospital, Tongji University School of Medicine, Songjiang Disc, Shanghai, China
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
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24
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Chembazhi UV, Bangru S, Hernaez M, Kalsotra A. Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver. Genome Res 2021; 31:576-591. [PMID: 33649154 DOI: 10.1101/2020.05.29.124263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 02/02/2021] [Indexed: 05/24/2023]
Abstract
The adult liver has an exceptional ability to regenerate, but how it maintains its specialized functions during regeneration is unclear. Here, we used partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ∼22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results uncovered that, following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Cumulative EdU labeling and immunostaining of metabolic, portal, and central vein-specific markers revealed that hepatocyte proliferation after PHx initiates in the midlobular region before proceeding toward the periportal and pericentral areas. We further demonstrate that portal and central vein proximal hepatocytes retain their metabolically active state to preserve essential liver functions while midlobular cells proliferate nearby. Through combined analysis of gene regulatory networks and cell-cell interaction maps, we found that regenerating hepatocytes redeploy key developmental regulons, which are guided by extensive ligand-receptor-mediated signaling events between hepatocytes and nonparenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferative requirements of a regenerating liver.
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Affiliation(s)
- Ullas V Chembazhi
- Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA
| | - Sushant Bangru
- Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA
- Cancer Center@Illinois, University of Illinois, Urbana, Illinois 61801, USA
| | - Mikel Hernaez
- Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, Illinois 61801, USA
- Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, 31008 Navarra, Spain
| | - Auinash Kalsotra
- Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA
- Cancer Center@Illinois, University of Illinois, Urbana, Illinois 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, Illinois 61801, USA
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25
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Wang ZH, Xia Y, Liu P, Liu X, Edgington-Mitchell L, Lei K, Yu SP, Wang XC, Ye K. ApoE4 activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer's disease. Prog Neurobiol 2021; 202:102032. [PMID: 33716161 DOI: 10.1016/j.pneurobio.2021.102032] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 01/17/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-β (Aβ) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aβ-dependent and -independent pathways. C/EBPβ, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPβ/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aβ and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPβ/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPβ depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPβ/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.
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Affiliation(s)
- Zhi-Hao Wang
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA; Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yiyuan Xia
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA; Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pai Liu
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA; Neuroscience Graduate Program, Laney Graduate School, Emory University, Atlanta, GA, 30322, USA
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Laura Edgington-Mitchell
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne Victoria, 3010, Australia
| | - Kecheng Lei
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Shan Ping Yu
- Department of Anesthesiology, Emory University School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Xiao-Chuan Wang
- Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, 226001, China.
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA.
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26
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Nie X, Qian L, Sun R, Huang B, Dong X, Xiao Q, Zhang Q, Lu T, Yue L, Chen S, Li X, Sun Y, Li L, Xu L, Li Y, Yang M, Xue Z, Liang S, Ding X, Yuan C, Peng L, Liu W, Yi X, Lyu M, Xiao G, Xu X, Ge W, He J, Fan J, Wu J, Luo M, Chang X, Pan H, Cai X, Zhou J, Yu J, Gao H, Xie M, Wang S, Ruan G, Chen H, Su H, Mei H, Luo D, Zhao D, Xu F, Li Y, Zhu Y, Xia J, Hu Y, Guo T. Multi-organ proteomic landscape of COVID-19 autopsies. Cell 2021; 184:775-791.e14. [PMID: 33503446 PMCID: PMC7794601 DOI: 10.1016/j.cell.2021.01.004] [Citation(s) in RCA: 301] [Impact Index Per Article: 75.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/22/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.
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Affiliation(s)
- Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Liujia Qian
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Rui Sun
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Bo Huang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaochuan Dong
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qi Xiao
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Qiushi Zhang
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China; Westlake Omics (Hangzhou) Biotechnology Co., Ltd., Hangzhou 310024, China
| | - Tian Lu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Liang Yue
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Shuo Chen
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiang Li
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yaoting Sun
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Lu Li
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Luang Xu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Yan Li
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ming Yang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhangzhi Xue
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Shuang Liang
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Xuan Ding
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Chunhui Yuan
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Li Peng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Liu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Xiao Yi
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Mengge Lyu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Guixiang Xiao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xia Xu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weigang Ge
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China; Westlake Omics (Hangzhou) Biotechnology Co., Ltd., Hangzhou 310024, China
| | - Jiale He
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Junhua Wu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Meng Luo
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China; Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Xiaona Chang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huaxiong Pan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xue Cai
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Junjie Zhou
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Yu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Huanhuan Gao
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Mingxing Xie
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Sihua Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Guan Ruan
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Hao Chen
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China; Westlake Omics (Hangzhou) Biotechnology Co., Ltd., Hangzhou 310024, China
| | - Hua Su
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Heng Mei
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Danju Luo
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dashi Zhao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Fei Xu
- Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Yan Li
- Department of Anatomy and Physiology, College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Yi Zhu
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China.
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Tiannan Guo
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China.
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C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease. Mol Psychiatry 2021; 26:6002-6022. [PMID: 33339957 PMCID: PMC8758498 DOI: 10.1038/s41380-020-00956-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023]
Abstract
The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-β (Aβ) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPβ acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPβ binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPβ in AD mouse models diminishes ApoE expression and Aβ pathologies, whereas overexpression of C/EBPβ accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPβ selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPβ in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPβ is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.
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Park SH, Lee JE, Lee SM, Lee J, Seo CS, Hwang GS, Jung J. An unbiased lipidomics approach identifies key lipid molecules as potential therapeutic targets of Dohongsamul-tang against non-alcoholic fatty liver diseases in a mouse model of obesity. JOURNAL OF ETHNOPHARMACOLOGY 2020; 260:112999. [PMID: 32454173 DOI: 10.1016/j.jep.2020.112999] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dohongsamul-tang (DST) is a traditional herbal formula used to promote the blood circulation and inhibit inflammation, and also widely has been used in the treatment of patients with chronic liver diseases in Korea and China. AIM OF THE STUDY This study aimed to investigate the effect of DST on regulation of lipid metabolism of chronic liver diseases in mouse model of non-alcoholic fatty liver diseases (NAFLD). MATERIALS AND METHODS In this study, we evaluated the effect of DST on high-fat and high-cholesterol diet (HFHC, 40% fat and 1% cholesterol)-induced NAFLD, and applied unbiased lipidomics using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS) coupled with multivariate analysis. RESULTS DST improved hepatic morphology and reduced levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In addition, DST inhibited hepatic lipid accumulation through the downregulation of C/EBPα, PPARγ, and pAMPK. To further elucidate the effect of DST on hepatic lipid metabolism, we applied UPLC/Q-TOF MS-based lipidomics. The score plots of partial least squares-discriminant analysis (PLS-DA) showed that DST changed the lipid metabolic pattern of high-fat and high-cholesterol diet (HFHC) mice. Twenty-two lipid metabolites were selected as biomarkers regulated by DST and pathway analysis revealed that sphingolipid metabolism and glycerophospholipid metabolism were associated with the effect of DST on NAFLD. Among the 22 selected biomarkers, 14 were phospholipids, and DST significantly reversed the increased expression of lysophospholipase 3 (LYPLA3) and neuropathy target esterase (NTE), which are key enzymes in glycerophospholipid metabolism. Given that alterations in sphingolipids and phospholipids can have effects on apoptosis and insulin resistance (IR), we subsequently investigated changes in the expression of apoptosis-related proteins, including Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl2), and IR-related markers after DST treatment. We accordingly found that the ratio of Bax to Bcl-2 expression, a maker of apoptosis, was also elevated in HFHC mice and reduced by DST treatment. In addition, DST enhanced hepatic insulin signaling by upregulating the expression of insulin receptor substrate 1 (IRS-1) and phospho-protein kinase B (pAKT), and oral glucose tolerance test (OGTT) analysis indicated that this herbal preparation also ameliorated systemic IR. CONCLUSIONS This study suggested that DST might have an effect on NAFLD by regulating the metabolism of lipids such as phospholipids and sphingolipids and demonstrated that lipidomic profiling is useful to investigate the therapeutic effects of herbal decoctions from traditional Korean and Chinese medicine.
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Affiliation(s)
- Seong-Hwan Park
- Clinical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, 34054, Daejeon, Republic of Korea.
| | - Jung-Eun Lee
- Clinical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, 34054, Daejeon, Republic of Korea.
| | - So Min Lee
- Nonclinical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, 34054, Daejeon, Republic of Korea.
| | - Jueun Lee
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, 03760, Seoul, Republic of Korea.
| | - Chang-Seob Seo
- Nonclinical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, 34054, Daejeon, Republic of Korea.
| | - Geum-Sook Hwang
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, 03760, Seoul, Republic of Korea.
| | - Jeeyoun Jung
- Clinical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, 34054, Daejeon, Republic of Korea.
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Dawood RM, Salum GM, Abd El-Meguid M, Shemis M, Abdel Aziz AO, El Awady MK. Recipient interleukin 6 gene polymorphism and expression predict HCV recurrence post liver transplantation. Gene 2020; 754:144887. [PMID: 32534059 DOI: 10.1016/j.gene.2020.144887] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver transplantation (LTX)is a lifesaving- effective protocol for patients suffering end stage liver disease (ESLD) and its complications post HCV infection. Recurrence of disease is a frequent clinical complication that is observed in patients undergoing LTX. Cytokines play a central role in the immunological events occurring after the surgery. METHODS Using Allelic Discrimination PCR, the allelic variation G174C of IL-6 gene was investigated. The abundance of IL6- mRNA and plasma IL6 cytokine levels were evaluated by using qRT-PCR in peripheral blood mononuclear cells (PBMCs) and enzyme-linked immunosorbent assay (ELISA) respectively in 76 liver transplant recipients recruited from Al Sahel teaching hospital, Ministry of Health and Population Cairo Egypt within the period between June 2015 and October 2017. RESULTS The frequencies of IL-6 GG genotype and the G allele were significantly detected more in LTX recipients who experienced HCV recurrence versus those who did not suffer recurrence when compared to healthy controls (P = 0.001) and (P = 0.006), respectively. On the contrary, levels of IL-6 related transcripts in PBMC's of recurrent patients were indifferent from non-recurrent patients and healthy controls (P ≥ 0.124). Interestingly, the circulating IL-6 protein in plasma was significantly elevated in recurrent as compared to the non-recurrent recipients (P = 0.002). CONCLUSION HCV recurrence post liver transplantation occur more frequently in patients with -174 G/G IL-6 genotype and elevated plasma IL-6 levels.
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Affiliation(s)
- Reham M Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt.
| | - Ghada M Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt
| | - Mohamed Shemis
- Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Egypt
| | - Ashraf O Abdel Aziz
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt
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Hu Z, Han Y, Liu Y, Zhao Z, Ma F, Cui A, Zhang F, Liu Z, Xue Y, Bai J, Wu H, Bian H, Chin YE, Yu Y, Meng Z, Wang H, Liu Y, Fan J, Gao X, Chen Y, Li Y. CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice. Hepatology 2020; 71:1421-1436. [PMID: 31469186 DOI: 10.1002/hep.30919] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 08/25/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS STAT3, a member of the signal transducer and activator of transcription (STAT) family, is strongly associated with liver injury, inflammation, regeneration, and hepatocellular carcinoma development. However, the signals that regulate STAT3 activity are not completely understood. APPROACH AND RESULTS Here we characterize CREB/ATF bZIP transcription factor CREBZF as a critical regulator of STAT3 in the hepatocyte to repress liver regeneration. We show that CREBZF deficiency stimulates the expression of the cyclin gene family and enhances liver regeneration after partial hepatectomy. Flow cytometry analysis reveals that CREBZF regulates cell cycle progression during liver regeneration in a hepatocyte-autonomous manner. Similar results were observed in another model of liver regeneration induced by intraperitoneal injection of carbon tetrachloride (CCl4 ). Mechanistically, CREBZF potently associates with the linker domain of STAT3 and represses its dimerization and transcriptional activity in vivo and in vitro. Importantly, hepatectomy-induced hyperactivation of cyclin D1 and liver regeneration in CREBZF liver-specific knockout mice was reversed by selective STAT3 inhibitor cucurbitacin I. In contrast, adeno-associated virus-mediated overexpression of CREBZF in the liver inhibits the expression of the cyclin gene family and attenuates liver regeneration in CCl4 -treated mice. CONCLUSIONS These results characterize CREBZF as a coregulator of STAT3 to inhibit regenerative capacity, which may represent an essential cellular signal to maintain liver mass homeostasis. Therapeutic approaches to inhibit CREBZF may benefit the compromised liver during liver transplantation.
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Affiliation(s)
- Zhimin Hu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yamei Han
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuxiao Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Zehua Zhao
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fengguang Ma
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Aoyuan Cui
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feifei Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Zhengshuai Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yaqian Xue
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jinyun Bai
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Haifu Wu
- Metabolic and Bariatric Surgery of Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Y Eugene Chin
- Institute of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu, China
| | - Ying Yu
- Department of Pharmacology, Key Laboratory of Immune Microenvironment and Disease, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zhuoxian Meng
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yong Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, Wuhan, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Yan Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yu Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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Lin H, Liu S, Gao W, Liu H. DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ. J Pharm Pharmacol 2020; 72:807-815. [PMID: 32189359 DOI: 10.1111/jphp.13243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 02/09/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Cancer stem cells (CSCs) have been identified to correlate with the initiation and metastasis of tumours, and DNA damage-inducible transcript 3 (DDIT3) is associated with the poor prognosis in gastric cancer (GC). However, whether DDIT3 mediates CSCs stemness in GC is still unclear. METHODS Microarray analysis and Gene Ontology (GO) were conducted to identify the differentially expressed genes in GC tissues from GC patients. The interaction between DDIT3 and CEBPβ was determined using immunoprecipitation (IP) analysis. KEY FINDINGS Herein, microarray analysis showed that DDIT3 expression is increased in GC tissues. qRT-PCR confirmed that DDIT3 is significantly increased in GC tissues and cancer cell lines compared with healthy tissues and normal cell lines, individually. Genetic overexpression of DDIT3 enhanced GC cell proliferation, colony-forming ability, sphere formation and CSCs stemness. Mechanistically, DDIT3 directly up-regulated the expression of transcription factor CEBPβ, leading to the increased expression of CSCs markers SOX2, NANOG, OCT4 and CD133 in gastric CSCs. Genetic downregulation of CEBPβ significantly abolishes DDIT3-mediated increased cell proliferation, colony-forming ability, sphere formation and CSCs stemness. CONCLUSION Our results demonstrated that DDIT3 promotes CSCs stemness by up-regulating CEBPβ in GC that provides novel targets for the further GC therapy.
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Affiliation(s)
- Hai Lin
- Department of digestive medicine, Linyi Central Hospital, Linyi, Shandong, China
| | - Shufang Liu
- Department of Laboratory, Linyi Central Hospital, Linyi, Shandong, China
| | - Weidong Gao
- Department of Gastroenterology, Lianshui County People's Hospital, The Affiliated Lianshui County People's Hospital of Kangda College of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Hongyu Liu
- Department of Pathology, The First Hospital of Qiqihar, The Affiliated Qiqihar Hospital of Southern Medical University, Qiqihar, Heilongjiang, China
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Banerjee D, Datta Chaudhuri R, Niyogi S, Roy Chowdhuri S, Poddar Sarkar M, Chatterjee R, Chakrabarti P, Sarkar S. Metabolic impairment in response to early induction of C/EBPβ leads to compromised cardiac function during pathological hypertrophy. J Mol Cell Cardiol 2020; 139:148-163. [PMID: 31958467 DOI: 10.1016/j.yjmcc.2020.01.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/06/2019] [Accepted: 01/08/2020] [Indexed: 11/16/2022]
Abstract
Chronic pressure overload-induced left ventricular hypertrophy in heart is preceded by a metabolic perturbation that prefers glucose over lipid as substrate for energy requirement. Here, we establish C/EBPβ (CCAAT/enhancer-binding protein β) as an early marker of the metabolic derangement that triggers the imbalance in fatty acid (FA) oxidation and glucose uptake with increased lipid accumulation in cardiomyocytes during pathological hypertrophy, leading to contractile dysfunction and endoplasmic reticulum (ER) stress. This is the first study that shows that myocardium-targeted C/EBPβ knockdown prevents the impaired cardiac function during cardiac hypertrophy led by maladaptive metabolic response with persistent hypertrophic stimuli, whereas its targeted overexpression in control increases lipid accumulation significantly compared to control hearts. A new observation from this study was the dual and opposite transcriptional regulation of the alpha and gamma isoforms of Peroxisomal proliferator activated receptors (PPARα and PPARγ) by C/EBPβ in hypertrophied cardiomyocytes. Before the functional and structural remodeling sets in the diseased myocardium, C/EBPβ aggravates lipid accumulation with the aid of the increased FA uptake involving induced PPARγ expression and decreased fatty acid oxidation (FAO) by suppressing PPARα expression. Glucose uptake into cardiomyocytes was greatly increased by C/EBPβ via PPARα suppression. The activation of mammalian target of rapamycin complex-1 (mTORC1) during increased workload in presence of glucose as the only substrate was prevented by C/EBPβ knockdown, thereby abating contractile dysfunction in cardiomyocytes. Our study thus suggests that C/EBPβ may be considered as a novel cellular marker for deranged metabolic milieu before the heart pathologically remodels itself during hypertrophy.
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Affiliation(s)
- Durba Banerjee
- Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, West Bengal, India
| | - Ratul Datta Chaudhuri
- Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, West Bengal, India
| | - Sougata Niyogi
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sumedha Roy Chowdhuri
- Department of Botany, Centre of Advanced Study, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India
| | - Mousumi Poddar Sarkar
- Department of Botany, Centre of Advanced Study, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India
| | - Raghunath Chatterjee
- Human Genetics Unit, Indian Statistical Institute, 203 B T Road, Kolkata 700108, India
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sagartirtha Sarkar
- Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, West Bengal, India.
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Pibiri M. Liver regeneration in aged mice: new insights. Aging (Albany NY) 2019; 10:1801-1824. [PMID: 30157472 PMCID: PMC6128415 DOI: 10.18632/aging.101524] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023]
Abstract
The regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are involved in the impairment of liver mass recovery during aging. Among the intracellular factors, age-dependent decrease of BubR1 (budding uninhibited by benzimidazole-related 1), YAP (Yes-associated protein) and SIRT1 (Sirtuin-1) have been associated to dampening of tissue reconstitution and inhibition of cell cycle genes following partial hepatectomy. Extra-cellular factors, such as age-dependent changes in hepatic stellate cells affect liver regeneration through inhibition of progenitor cells and reduction of liver perfusion. Furthermore, chronic release of pro-inflammatory proteins by senescent cells (SASP) affects cell proliferation suggesting that senescent cell clearance might improve tissue regeneration. Accordingly, young plasma restores liver regeneration in aged animals through autophagy re-establishment. This review will discuss how intracellular and extracellular factors cooperate to guarantee a proper liver regeneration and the possible causes of its impairment during aging. The possibility that an improvement of the liver regenerative capacity in elderly might be achieved through elimination of senescent cells via autophagy or by administration of direct mitogenic agents devoid of cytotoxicity will also be entertained.
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Affiliation(s)
- Monica Pibiri
- Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cagliari 09124, Italy
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C/EBPβ Is a Transcriptional Regulator of Wee1 at the G₂/M Phase of the Cell Cycle. Cells 2019; 8:cells8020145. [PMID: 30754676 PMCID: PMC6407104 DOI: 10.3390/cells8020145] [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: 01/18/2019] [Revised: 02/06/2019] [Accepted: 02/09/2019] [Indexed: 12/25/2022] Open
Abstract
The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein were expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying the G2/M transition in the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with simultaneously increased Wee1 and decreased Cdc25B expression. Chromatin immunoprecipitation (ChIP) analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through its interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G2/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G2/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.
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A Pre-Clinical Large Animal Model of Sustained Liver Injury and Regeneration Stimulus. Sci Rep 2018; 8:14987. [PMID: 30301901 PMCID: PMC6177392 DOI: 10.1038/s41598-018-32889-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 09/17/2018] [Indexed: 01/15/2023] Open
Abstract
A feasible large animal model to evaluate regenerative medicine techniques is vital for developing clinical applications. One such appropriate model could be to use retrorsine (RS) together with partial hepatectomy (PH). Here, we have developed the first porcine model using RS and PH. RS or saline control was administered intraperitoneally to Göttingen miniature pigs twice, two weeks apart. Four weeks after the second dose, animals underwent PH. Initially, we tested different doses of RS and resection of different amounts of liver, and selected 50 mg/kg RS with 60% hepatectomy as our model for further testing. Treated animals were sacrificed 3, 10, 17 or 28 days after PH. Blood samples and resected liver were collected. Serum and liver RS content was determined by Liquid Chromatograph-tandem Mass Spectrometer. Blood analyses demonstrated liver dysfunction after PH. Liver regeneration was significantly inhibited 10 and 17 days after PH in RS-treated animals, to the extent of 20%. Histological examination indicated hepatic injury and regenerative responses after PH. Immunohistochemical staining demonstrated accumulation of Cyclin D1 and suppression of Ki-67 and PCNA in RS-treated animals. We report the development of the first large animal model of sustained liver injury with suppression of hepatic regeneration.
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Yang M, Tao J, Wu H, Zhang L, Yao Y, Liu L, Zhu T, Fan H, Cui X, Dou H, Liu G. Responses of Transgenic Melatonin-Enriched Goats on LPS Stimulation and the Proteogenomic Profiles of Their PBMCs. Int J Mol Sci 2018; 19:ijms19082406. [PMID: 30111707 PMCID: PMC6121286 DOI: 10.3390/ijms19082406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/04/2018] [Accepted: 08/10/2018] [Indexed: 01/13/2023] Open
Abstract
The anti-inflammatory activity of melatonin (MT) has been well documented; however, little is known regarding endogenously occurring MT in this respect, especially for large animals. In the current study, we created a MT-enriched animal model (goats) overexpressing the MT synthetase gene Aanat. The responses of these animals to lipopolysaccharide (LPS) stimulation were systematically studied. It was found that LPS treatment exacerbated the inflammatory response in wild-type (WT) goats and increased their temperature to 40 °C. In addition, their granulocyte counts were also significantly elevated. In contrast, these symptoms were not observed in transgenic goats with LPS treatment. The rescue study with MT injection into WT goats who were treated with LPS confirmed that the protective effects in transgenic goats against LPS were attributed to a high level of endogenously produced MT. The proteomic analysis in the peripheral blood mononuclear cells (PBMCs) isolated from the transgenic animals uncovered several potential mechanisms. MT suppressed the lysosome formation as well as its function by downregulation of the lysosome-associated genes Lysosome-associated membrane protein 2 (LAMP2), Insulin-like growth factor 2 receptor (IGF2R), and Arylsulfatase B (ARSB). A high level of MT enhanced the antioxidant capacity of these cells to reduce the cell apoptosis induced by the LPS. In addition, the results also uncovered previously unknown information that showed that MT may have protective effects on some human diseases, including tuberculosis, bladder cancer, and rheumatoid arthritis, by downregulation of these disease-associated genes. All these observations warranted further investigations.
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Affiliation(s)
- Minghui Yang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Jingli Tao
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Hao Wu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Lu Zhang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Yujun Yao
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Lixi Liu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Tianqi Zhu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Hao Fan
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
| | - Xudai Cui
- Qingdao Sanuels Industrial & Commercial Co., Ltd., Qingdao 266000, China.
| | - Haoran Dou
- Qingdao Sanuels Industrial & Commercial Co., Ltd., Qingdao 266000, China.
| | - Guoshi Liu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100000, China.
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C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease. Nat Commun 2018; 9:1784. [PMID: 29725016 PMCID: PMC5934399 DOI: 10.1038/s41467-018-04120-z] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 04/05/2018] [Indexed: 01/21/2023] Open
Abstract
Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer’s disease (AD). However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression. Delta-secretase cleaves both APP and Tau, and contributes to Alzheimer’s disease-like pathology. Here the authors show that C/EBPβ, a regulator of inflammation, also regulates transcription of delta-secretase in an age-dependent manner and contributes to Alzheimer’s disease-like pathology in mouse models.
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Chae MS, Moon KU, Chung HS, Park CS, Lee J, Choi JH, Hong SH. Serum interleukin-6 and tumor necrosis factor-α are associated with early graft regeneration after living donor liver transplantation. PLoS One 2018; 13:e0195262. [PMID: 29649247 PMCID: PMC5896938 DOI: 10.1371/journal.pone.0195262] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 03/19/2018] [Indexed: 02/07/2023] Open
Abstract
Background Liver graft regeneration is orchestrated by specific and sequential stimuli, including hepatocyte growth factors, cytokines, and catecholamines. We evaluated the association between preoperative serum cytokines and early liver graft regeneration in human living donor liver transplantation (LDLT). Patients and methods We retrospectively reviewed the data of adult patients who underwent LDLT from January 2010 to December 2014. Serum cytokines, including interleukin (IL)-2, 6, 10, 12, 17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured in the recipients 1 day before surgery and on postoperative day (POD) 7. Liver graft volume was estimated using abdominal computed tomography images of the donors and recipients. Results In total, 226 patients were analyzed in this study. Median preoperative levels of serum cytokines were as follows: IL-2, 0.1 (0.1–1.6) pg/mL; IL-6, 7.3 (0.1–30.2) pg/mL; IL-10, 0.5 (0.1–11.0) pg/mL; IL-12, 0.1 (0.1–0.1) pg/mL; IL-17, 2.0 (0.1–16.4) pg/mL; IFN-γ, 3.2 (0.1–16.0) pg/mL; and TNF-α, 9.8 (5.4–17.9) pg/mL. Higher preoperative serum levels of IL-6, IL-10, and TNF-α, dichotomized at the median, were associated with increased relative liver volumes by POD 7. Multivariate analysis revealed that higher levels of serum IL-6 and TNF-α were independently associated with increased graft volume during the first 1 week after LDLT, based on the lower levels of those cytokines. Conclusions IL-6 and TNF-α were important mediators of the success of early graft regeneration in patients who underwent LDLT.
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Affiliation(s)
- Min Suk Chae
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kwang Uck Moon
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun Sik Chung
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chul Soo Park
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jaemin Lee
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Ho Choi
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Hyun Hong
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- * E-mail:
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Gardiner JD, Abegglen LM, Huang X, Carter BE, Schackmann EA, Stucki M, Paxton CN, Lor Randall R, Amatruda JF, Putnam AR, Kovar H, Lessnick SL, Schiffman JD. C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells. Oncotarget 2018; 8:26013-26026. [PMID: 28148901 PMCID: PMC5432234 DOI: 10.18632/oncotarget.14847] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 01/16/2017] [Indexed: 12/26/2022] Open
Abstract
CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPβ isoforms while re-expression of EWS-FLI1 rescued C/EBPβ expression. Overexpression of C/EBPβ-1, the largest of the three C/EBPβ isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPβ decreased colony formation, and re-expression of either C/EBPβ-1 or C/EBPβ-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPβ in Ewing sarcoma. Furthermore, increased expression of C/EBPβ led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPβ-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance.
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Affiliation(s)
- Jamie D Gardiner
- Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Lisa M Abegglen
- Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Xiaomeng Huang
- Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Bryce E Carter
- School of Medicine, University of Utah, Salt Lake City, UT, USA
| | | | - Marcus Stucki
- Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Christian N Paxton
- ARUP Institute for Clinical and Experimental Pathology®, Salt Lake City, UT, USA
| | - R Lor Randall
- Department of Orthopaedic Surgery, Sarcoma Services, University of Utah, Salt Lake City, UT, USA
| | - James F Amatruda
- Department of Pediatrics, Internal Medicine and Molecular Biology, University of Texas Southwestern, Dallas, TX, USA
| | - Angelica R Putnam
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - Heinrich Kovar
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
| | - Stephen L Lessnick
- Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital, and the Division of Pediatric Heme/Onc/BMT, The Ohio State University, Columbus, OH, USA
| | - Joshua D Schiffman
- Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Abstract
The liver is an essential organ for nutrient and drug metabolism - possessing the remarkable ability to sense environmental and metabolic stimuli and provide an optimally adaptive response. Early growth response 1 (Egr1), an immediate early transcriptional factor which acts as a coordinator of the complex response to stress, is induced during liver injury and controls the expression of a wide range of genes involved in metabolism, cell proliferation, and role of Egr1 in liver injury and repair, deficiency of Egr1 delays liver regeneration process. The known upstream regulators of Egr1 include, but are not limited to, growth factors (e.g. transforming growth factor β1, platelet-derived growth factor, epidermal growth factor, hepatocyte growth factor), nuclear receptors (e.g. hepatocyte nuclear factor 4α, small heterodimer partner, peroxisome proliferator-activated receptor-γ), and other transcription factors (e.g. Sp1, E2F transcription factor 1). Research efforts using various animal models such as fatty liver, liver injury, and liver fibrosis contribute greatly to the elucidation of Egr1 function in the liver. Hepatocellular carcinoma (HCC) represents the second leading cause of cancer mortality worldwide due to the heterogeneity and the late stage at which cancer is generally diagnosed. Recent studies highlight the involvement of Egr1 in HCC development. The purpose of this review is to summarize current studies pertaining to the role of Egr1 in liver metabolism and liver diseases including liver cancer.
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Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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EMMPRIN (CD147) is induced by C/EBPβ and is differentially expressed in ALK+ and ALK- anaplastic large-cell lymphoma. J Transl Med 2017; 97:1095-1102. [PMID: 28581487 DOI: 10.1038/labinvest.2017.54] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 04/12/2017] [Accepted: 04/14/2017] [Indexed: 01/11/2023] Open
Abstract
Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPβ, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPβ for the unusual phenotype of ALK+ ALCL cells, C/EBPβ was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK- cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPβ knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK- ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPβ knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK- ALCL, suggesting an additional role of C/EBPβ in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPβ plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL.
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Identification of a new liver-specific c-type mRNA transcriptional variant for mouse ST3GAL5 (GM3/GM4 synthase). Glycoconj J 2017; 34:651-659. [DOI: 10.1007/s10719-017-9788-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 07/26/2017] [Indexed: 10/19/2022]
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Ding S, Gan T, Song M, Dai Q, Huang H, Xu Y, Zhong C. C/EBPB-CITED4 in Exercised Heart. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1000:247-259. [PMID: 29098625 DOI: 10.1007/978-981-10-4304-8_14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
C/EBPB is a crucial transcription factor, participating in a variety of biological processes including cell proliferation, differentiation and development. In the cardiovascular system, C/EBPB-CITED4 signaling is known as a signaling pathway mediating exercise-induced cardiac growth. After its exact role in exercised heart firstly reported in 2010, more and more evidence confirmed that. MicroRNA (e.g. miR-222) and many molecules (e.g. Alpha-lipoic acid) can regulate this pathway and then involve in the cardiac protection effect induced by endurance exercise training. In addition, in cardiac growth during pregnancy, C/EBPB is also a required regulator. This chapter will give an introduction of the C/EBPB-CITED4 signaling and the regulatory network based on this signaling pathway in exercised heart.
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Affiliation(s)
- Shengguang Ding
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Tianyi Gan
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Meiyi Song
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun Road, Shanghai, 200065, China
| | - Qiying Dai
- Metrowest Medical Center, Framingham, 01702, MA, USA.,Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Haitao Huang
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yiming Xu
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Chongjun Zhong
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
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Kuttippurathu L, Patra B, Cook D, Hoek JB, Vadigepalli R. Pattern analysis uncovers a chronic ethanol-induced disruption of the switch-like dynamics of C/EBP-β and C/EBP-α genome-wide binding during liver regeneration. Physiol Genomics 2016; 49:11-26. [PMID: 27815535 DOI: 10.1152/physiolgenomics.00097.2016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 09/23/2016] [Accepted: 10/26/2016] [Indexed: 01/19/2023] Open
Abstract
Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3rd partial hepatectomy (PHx) to investigate how adaptation to chronic ethanol intake affects the genome-wide binding profiles of the transcription factors C/EBP-β and C/EBP-α. These factors participate in complementary and often opposing functions for maintaining cellular differentiation, regulating metabolism, and governing cell growth during liver regeneration. We analyzed ChIP-seq data with a comparative pattern count (COMPACT) analysis, which exhaustively enumerates temporal patterns of discretized binding profiles to identify dominant as well as subtle patterns that may not be apparent from conventional clustering analyses. We found that adaptation to chronic ethanol intake significantly alters the genome-wide binding profile of C/EBP-β and C/EBP-α before and following PHx. A subset of these ethanol-induced changes include C/EBP-β binding to promoters of genes involved in the profibrogenic transforming growth factor-β pathway, and both C/EBP-β and C/EBP-α binding to promoters of genes involved in the cell cycle, apoptosis, homeostasis, and metabolic processes. The shift in C/EBP binding loci, coupled with an ethanol-induced increase in C/EBP-β binding at 6 h post-resection, indicates that ethanol adaptation may change both the amount and nature of C/EBP binding postresection. Taken together, our results suggest that chronic ethanol consumption leads to a spatially and temporally reorganized activity at many genomic loci, resulting in a shift in the dynamic balance and coordination of cellular processes underlying regenerative response.
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Affiliation(s)
- Lakshmi Kuttippurathu
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Biswanath Patra
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Daniel Cook
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware; and
| | - Jan B Hoek
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; .,MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
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45
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Kuttippurathu L, Juskeviciute E, Dippold RP, Hoek JB, Vadigepalli R. A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration. BMC Genomics 2016; 17:260. [PMID: 27012785 PMCID: PMC4807561 DOI: 10.1186/s12864-016-2492-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 02/17/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Liver regeneration is inhibited by chronic ethanol consumption and this impaired repair response may contribute to the risk for alcoholic liver disease. We developed and applied a novel data analysis approach to assess the effect of chronic ethanol intake in the mechanisms responsible for liver regeneration. We performed a time series transcriptomic profiling study of the regeneration response after 2/3rd partial hepatectomy (PHx) in ethanol-fed and isocaloric control rats. RESULTS We developed a novel data analysis approach focusing on comparative pattern counts (COMPACT) to exhaustively identify the dominant and subtle differential expression patterns. Approximately 6500 genes were differentially regulated in Ethanol or Control groups within 24 h after PHx. Adaptation to chronic ethanol intake significantly altered the immediate early gene expression patterns and nearly completely abrogated the cell cycle induction in hepatocytes post PHx. The patterns highlighted by COMPACT analysis contained several non-parenchymal cell specific markers indicating their aberrant transcriptional response as a novel mechanism through which chronic ethanol intake deregulates the integrated liver tissue response. CONCLUSIONS Our novel comparative pattern analysis revealed new insights into ethanol-mediated molecular changes in non-parenchymal liver cells as a possible contribution to the defective liver regeneration phenotype. The results revealed for the first time an ethanol-induced shift of hepatic stellate cells from a pro-regenerative phenotype to that of an anti-regenerative state after PHx. Our results can form the basis for novel interventions targeting the non-parenchymal cells in normalizing the dysfunctional repair response process in alcoholic liver disease. Our approach is illustrated online at http://compact.jefferson.edu .
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Affiliation(s)
- Lakshmi Kuttippurathu
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Egle Juskeviciute
- MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Rachael P Dippold
- MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Jan B Hoek
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.,MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. .,MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
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Huang J, Schriefer AE, Cliften PF, Dietzen D, Kulkarni S, Sing S, Monga SPS, Rudnick DA. Postponing the Hypoglycemic Response to Partial Hepatectomy Delays Mouse Liver Regeneration. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:587-99. [PMID: 26772417 DOI: 10.1016/j.ajpath.2015.10.027] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 10/19/2015] [Accepted: 10/27/2015] [Indexed: 12/13/2022]
Abstract
All serious liver injuries alter metabolism and initiate hepatic regeneration. Recent studies using partial hepatectomy (PH) and other experimental models of liver regeneration implicate the metabolic response to hepatic insufficiency as an important source of signals that promote regeneration. Based on these considerations, the analyses reported here were undertaken to assess the impact of interrupting the hypoglycemic response to PH on liver regeneration in mice. A regimen of parenteral dextrose infusion that delays PH-induced hypoglycemia for 14 hours after surgery was identified, and the hepatic regenerative response to PH was compared between dextrose-treated and control mice. The results showed that regenerative recovery of the liver was postponed in dextrose-infused mice (versus vehicle control) by an interval of time comparable to the delay in onset of PH-induced hypoglycemia. The regulation of specific liver regeneration-promoting signals, including hepatic induction of cyclin D1 and S-phase kinase-associated protein 2 expression and suppression of peroxisome proliferator-activated receptor γ and p27 expression, was also disrupted by dextrose infusion. These data support the hypothesis that alterations in metabolism that occur in response to hepatic insufficiency promote liver regeneration, and they define specific pro- and antiregenerative molecular targets whose regenerative regulation is postponed when PH-induced hypoglycemia is delayed.
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Affiliation(s)
- Jiansheng Huang
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Andrew E Schriefer
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
| | - Paul F Cliften
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
| | - Dennis Dietzen
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Sakil Kulkarni
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Sucha Sing
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Satdarshan P S Monga
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David A Rudnick
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
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Berasain C, Avila MA. Regulation of hepatocyte identity and quiescence. Cell Mol Life Sci 2015; 72:3831-51. [PMID: 26089250 PMCID: PMC11114060 DOI: 10.1007/s00018-015-1970-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 05/23/2015] [Accepted: 06/12/2015] [Indexed: 12/11/2022]
Abstract
The liver is a highly differentiated organ with a central role in metabolism, detoxification and systemic homeostasis. To perform its multiple tasks, liver parenchymal cells, the hepatocytes, express a large complement of enabling genes defining their complex phenotype. This phenotype is progressively acquired during fetal development and needs to be maintained in adulthood to guarantee the individual's survival. Upon injury or loss of functional mass, the liver displays an extraordinary regenerative response, mainly based on the proliferation of hepatocytes which otherwise are long-lived quiescent cells. Increasing observations suggest that loss of hepatocellular differentiation and quiescence underlie liver malfunction in chronic liver disease and pave the way for hepatocellular carcinoma development. Here, we briefly review the essential mechanisms leading to the acquisition of liver maturity. We also identify the key molecular factors involved in the preservation of hepatocellular homeostasis and finally discuss potential strategies to preserve liver identity and function.
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Affiliation(s)
- Carmen Berasain
- Division of Hepatology, CIMA, University of Navarra, CIBEREHD, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Avda. Pio XII, n55, 31008, Pamplona, Spain.
| | - Matías A Avila
- Division of Hepatology, CIMA, University of Navarra, CIBEREHD, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Avda. Pio XII, n55, 31008, Pamplona, Spain.
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Tamura A, Hirai H, Yokota A, Sato A, Shoji T, Kashiwagi T, Iwasa M, Fujishiro A, Miura Y, Maekawa T. Accelerated apoptosis of peripheral blood monocytes in Cebpb-deficient mice. Biochem Biophys Res Commun 2015; 464:654-8. [PMID: 26168729 DOI: 10.1016/j.bbrc.2015.07.045] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 07/08/2015] [Indexed: 12/20/2022]
Abstract
The CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor is required for granulopoiesis under stress conditions. However, little is known about its roles in steady state hematopoiesis. Here, we analyzed the peripheral blood and bone marrow of Cebpb(-/-) mice at steady state by flow cytometry and unexpectedly found that the number of peripheral blood monocytes was severely reduced, while the number of bone marrow monocytes was maintained. The ability of Cebpb(-/-) bone marrow cells to give rise to macrophages/monocytes in vitro was comparable to that of wild-type bone marrow cells. Apoptosis of monocytes was enhanced in the peripheral blood, but not in the bone marrow of Cebpb(-/-) mice. These results indicate that C/EBPβ is required for the survival of monocytes in peripheral blood.
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Affiliation(s)
- Akihiro Tamura
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Hideyo Hirai
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
| | - Asumi Yokota
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Atsushi Sato
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Tsukimi Shoji
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Takahiro Kashiwagi
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Masaki Iwasa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; Division of Gastroenterology and Hematology, Shiga University of Medical Science, Otsu, Japan
| | - Aya Fujishiro
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; Division of Gastroenterology and Hematology, Shiga University of Medical Science, Otsu, Japan
| | - Yasuo Miura
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
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Lai S, Yuan J, Zhao D, Shen N, Chen W, Ding Y, Yu D, Li J, Pan F, Zhu M, Li C, Xue B. Regulation of mice liver regeneration by early growth response-1 through the GGPPS/RAS/MAPK pathway. Int J Biochem Cell Biol 2015; 64:147-154. [PMID: 25882493 DOI: 10.1016/j.biocel.2015.04.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 02/14/2015] [Accepted: 04/03/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND & AIMS Liver regeneration (LR) consists of a series of complicated processes in which several transcription factors play important roles. Among them, the early growth response 1 gene (EGR-1) is rapidly induced in response to liver resection. Previous studies have shown that EGR-1-/- mice exhibit delayed hepatocellular mitotic progression after partial hepatectomy (PH). The mechanism underlying the EGR-1 regulated LR is still unknown. Our aim is to elucidate the underlying mechanism. METHODS Mice infected with adenoviral vectors expressing GFP, EGR-1 or dominant negative EGR-1 (dnEGR-1) were subjected to 2/3 PH. The serum starvation recovery cell model was chosen to mimic the regeneration process for the in vitro studies. Cell proliferation and signaling pathways downstream of geranylgeranyl diphosphate synthase (GGPPS) were examined in the regenerating liver and serum starvation recovery cell model. RESULTS Loss of function of EGR-1 significantly inhibited liver recovery and the expression of cyclin D1, cyclin E, and proliferating cell nuclear antigen (PCNA). The expression of GGPPS and the activity of the downstream RAS/MAPK pathway were inhibited in dnEGR-1-infected liver, which was consistent with the serum-induced cell model. In addition, loss of function of EGR-1 aggravated liver damage with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. CONCLUSIONS EGR-1-induced GGPPS plays a vital role in the LR after PH through the RAS/MAPK signaling.
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Affiliation(s)
- Shanshan Lai
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China
| | - Jun Yuan
- Biochemical and Environmental Engineering School of Xiaozhuang Collage, Nanjing 211171, China
| | - Dandan Zhao
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China
| | - Ning Shen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China
| | - Weibo Chen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210093, China
| | - Yao Ding
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210097, China
| | - Decai Yu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210093, China
| | - Jing Li
- Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
| | - Feiyan Pan
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210097, China
| | - Minsheng Zhu
- MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing 210093, China
| | - Chaojun Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China.
| | - Bin Xue
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China.
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50
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Cai Y, Hirata A, Nakayama S, VanderLaan PA, Levantini E, Yamamoto M, Hirai H, Wong KK, Costa DB, Watanabe H, Kobayashi SS. CCAAT/enhancer binding protein β is dispensable for development of lung adenocarcinoma. PLoS One 2015; 10:e0120647. [PMID: 25767874 PMCID: PMC4358974 DOI: 10.1371/journal.pone.0120647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 01/25/2015] [Indexed: 11/18/2022] Open
Abstract
Lung cancer is the leading cause of cancer death worldwide. Although disruption of normal proliferation and differentiation is a vital component of tumorigenesis, the mechanisms of this process in lung cancer are still unclear. A transcription factor, C/EBPβ is a critical regulator of proliferation and/or differentiation in multiple tissues. In lung, C/EBPβ is expressed in alveolar pneumocytes and bronchial epithelial cells; however, its roles on normal lung homeostasis and lung cancer development have not been well described. Here we investigated whether C/EBPβ is required for normal lung development and whether its aberrant expression and/or activity contribute to lung tumorigenesis. We showed that C/EBPβ was expressed in both human normal pneumocytes and lung adenocarcinoma cell lines. We found that overall lung architecture was maintained in Cebpb knockout mice. Neither overexpression of nuclear C/EBPβ nor suppression of CEBPB expression had significant effects on cell proliferation. C/EBPβ expression and activity remained unchanged upon EGF stimulation. Furthermore, deletion of Cebpb had no impact on lung tumor burden in a lung specific, conditional mutant EGFR lung cancer mouse model. Analyses of data from The Cancer Genome Atlas (TCGA) revealed that expression, promoter methylation, or copy number of CEBPB was not significantly altered in human lung adenocarcinoma. Taken together, our data suggest that C/EBPβ is dispensable for development of lung adenocarcinoma.
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Affiliation(s)
- Yi Cai
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Ayako Hirata
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Sohei Nakayama
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Paul A. VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Elena Levantini
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy
| | - Mihoko Yamamoto
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hideyo Hirai
- Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Kwok-Kin Wong
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Daniel B. Costa
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hideo Watanabe
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
- * E-mail: (HW); (SSK)
| | - Susumu S. Kobayashi
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- Harvard Stem Cell Institute, Cambridge, Massachusetts, United States of America
- * E-mail: (HW); (SSK)
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