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Yang JY, Luo CH, Wang KB, Tu XY, Xiao YY, Ou YT, Xie YX, Guan CX, Zhong WJ. Unraveling the mechanisms of NINJ1-mediated plasma membrane rupture in lytic cell death and related diseases. Int J Biol Macromol 2025; 309:143165. [PMID: 40239793 DOI: 10.1016/j.ijbiomac.2025.143165] [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: 01/29/2025] [Revised: 04/03/2025] [Accepted: 04/13/2025] [Indexed: 04/18/2025]
Abstract
Plasma membrane rupture (PMR), the ultimate event during lytic cell death, releases damage-associated molecular patterns (DAMPs) that trigger inflammation and immune responses in the development of various diseases. Recent years have witnessed significant advances in understanding the PMR mediated by ninjurin1 (NINJ1) in different lytic cell death processes. NINJ1 oligomerizes and ruptures the membrane in pyroptosis and other lytic cell death, participating in the pathogenesis of multiple diseases. Although the membrane-permeabilizing function of NINJ1 is well recognized, the role of NINJ1 in different types of lytic cell death and its impact on multiple disease processes have yet to be fully elucidated. This review summarizes the latest advances in the mechanisms of NINJ1-mediated PMR, discusses the membrane-inducing activity of NINJ1 in different lytic cell death, explains the implications of NINJ1 in lytic cell death-related diseases, and lists the inhibitory strategies for NINJ1. We expect to provide new insights into targeting NINJ1 to suppress lytic cell death for therapeutic benefit, which may become a new strategy to control inflammatory cell lysis-related diseases.
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Affiliation(s)
- Ji-Yan Yang
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of the General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, Hunan 410078, China; National Experimental Teaching Demonstration Center for Medical Function, Changsha, Hunan 410078, China
| | - Chen-Hua Luo
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Kun-Bo Wang
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Xin-Yu Tu
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Yun-Ying Xiao
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Ye-Tong Ou
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Yan-Xin Xie
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Cha-Xiang Guan
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of the General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, Hunan 410078, China; National Experimental Teaching Demonstration Center for Medical Function, Changsha, Hunan 410078, China
| | - Wen-Jing Zhong
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of the General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, Hunan 410078, China; National Experimental Teaching Demonstration Center for Medical Function, Changsha, Hunan 410078, China.
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Zhang J, Kong X, Chen X. Development of Novel Peptides That Target the Ninjurin 1 and 2 Pathways to Inhibit Cell Growth and Survival via p53. Cells 2025; 14:401. [PMID: 40136650 PMCID: PMC11941050 DOI: 10.3390/cells14060401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/01/2025] [Accepted: 03/05/2025] [Indexed: 03/27/2025] Open
Abstract
Ninjurin 1 and 2 (NINJ1, NINJ2) belong to the homophilic cell adhesion family and play significant roles in cellular communication and tissue development. While both NINJ1 and NINJ2 are found to be over-expressed in several types of cancers, it remains unclear whether they can be targeted for cancer treatment. In this study, we aimed to develop NINJ1/2 peptides derived from the N-terminal extracellular domain that can elicit growth suppression and thus possess therapeutic potentials. We found that peptide NINJ1-A, which is derived from the N-terminal adhesion motif of NINJ1, was able to inhibit cell growth in a NINJ1- or p53-dependent manner. Similarly, peptide NINJ2-A, which is derived from the N-terminal adhesion motif of NINJ2, was able to inhibit cell growth in a NINJ2- or p53-dependent manner. We also found that NINJ1 and NINJ2 physically interact via their respective N-terminal domains. Interestingly, NINJ1-B and NINJ2-B peptides, which were derived from the N-terminal amphipathic helix domains of NINJ1 and NINJ2, respectively, were able to disrupt NINJ1-NINJ2 interaction and inhibit cell growth in a NINJ1/NINJ2-dependent manner. Notably, NINJ1-B and NINJ2-B peptides demonstrated greater potency in growth suppression than NINJ1-A and NINJ2-A peptides, respectively. Mechanistically, we found that NINJ1-B and NINJ2-B peptides were able to induce p53 expression and suppress cell growth in a p53-dependent manner. Together, our findings provide valuable insights into the development of NINJ1/NINJ2 peptides as potential cancer therapeutics, particularly for cancers harboring wild-type p53.
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Affiliation(s)
- Jin Zhang
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, CA 95616, USA;
| | | | - Xinbin Chen
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, CA 95616, USA;
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Chen SY, Shyu IL, Chi JT. NINJ1 in Cell Death and Ferroptosis: Implications for Tumor Invasion and Metastasis. Cancers (Basel) 2025; 17:800. [PMID: 40075648 PMCID: PMC11898531 DOI: 10.3390/cancers17050800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/19/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
NINJ1 was initially recognized for its role in nerve regeneration and cellular adhesion. Subsequent studies have uncovered its participation in cancer progression, where NINJ1 regulates critical steps in tumor metastasis, such as cell migration and invasion. More recently, NINJ1 has emerged as a multifunctional protein mediating plasma membrane rupture (PMR) in several lytic cell death processes, including apoptosis, necroptosis, and pyroptosis. However, its role in ferroptosis-an iron-dependent form of lytic cell death characterized by lipid peroxidation-remained unclear until 2024. Ferroptosis is a tumor suppression mechanism that may be particularly relevant to detached and metastatic cancer cells. This review explores the role of NINJ1 in tumor invasion and metastasis, focusing on its regulation of ferroptosis via a non-canonical mechanism distinct from other cell deaths. We discuss the process of ferroptosis and its implications for cancer invasion and metastasis. Furthermore, we review recent studies highlighting the diverse roles of NINJ1 in ferroptosis regulation, including its canonical function in PMR and its non-canonical function of modulating intracellular levels of glutathione (GSH) and coenzyme A (CoA) via interaction with xCT anti-porter. Given that ferroptosis has been associated with tumor suppression, metastasis, the elimination of treatment-resistant cancer cells, and tumor dormancy, NINJ1's modulation of ferroptosis presents a promising therapeutic target for inhibiting metastasis. Understanding the dual role of NINJ1 in promoting or restraining ferroptosis depending on cellular context could open avenues for novel anti-cancer strategies to enhance ferroptotic vulnerability in metastatic tumors.
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Affiliation(s)
- Ssu-Yu Chen
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA;
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ing-Luen Shyu
- Department of Obstetrics and Gynecology, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
- Center for Advanced Genomic Technologies, Duke University School of Medicine, Durham, NC 27710, USA
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Zheng XB, Wang X, Gao SQ, Gao CC, Li T, Han YL, Zhao R, Sun Y, Miao SH, Qiu JY, Jin WX, Zhou ML. NINJ1-mediated plasma membrane rupture of pyroptotic endothelial cells exacerbates blood-brain barrier destruction caused by neutrophil extracellular traps in traumatic brain injury. Cell Death Discov 2025; 11:69. [PMID: 39979243 PMCID: PMC11842820 DOI: 10.1038/s41420-025-02350-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/23/2025] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
Brain endothelial cell (bEC) dysfunction is the main factor of blood-brain barrier (BBB) breakdown, which triggers a vicious cycle of aggravating traumatic brain injury (TBI) pathogenesis. Previous studies have revealed that neutrophil extracellular traps (NETs) released by neutrophils can lead to BBB disruption, but there is a lack of research on the underlying mechanisms after TBI. Here, excessive NETs were found in both contused brain tissue and circulation following TBI. We found that NETs could activate the TLR4/NF-κB pathway to induce bEC pyroptosis, which led to BBB disruption after TBI. During this process, ninjurin-1 (NINJ1) was activated in pyroptotic bECs, and it mediated the release of high mobility group box 1 protein (HMGB1) via plasma membrane rupture (PMR) to promote NET formation. NINJ1-mediated release of HMGB1 aggravated NET accumulation by forming a vicious circle following TBI. Knockdown of NINJ1 rescued NET formation, attenuated BBB leakage, and improved neurological outcomes after TBI. NINJ1 may represent a promising target for alleviating NET-induced BBB destruction and other related injuries after TBI.
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Affiliation(s)
- Xiao-Bo Zheng
- Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xue Wang
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Sheng-Qing Gao
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Chao-Chao Gao
- Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Tao Li
- Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yan-Ling Han
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ran Zhao
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yan Sun
- Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Shu-Hao Miao
- Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Jia-Yin Qiu
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Wang-Xuan Jin
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Meng-Liang Zhou
- Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Song CH, Kim N, Nam RH, Choi SI, Jang JY, Kim EH, Ha S, Shin E, Choi H, Kim KW, Jeon S, Oh GT, Seok YJ. Ninjurin1 deficiency differentially mitigates colorectal cancer induced by azoxymethane and dextran sulfate sodium in male and female mice. Int J Cancer 2025; 156:826-839. [PMID: 39417611 DOI: 10.1002/ijc.35225] [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: 09/22/2023] [Revised: 06/07/2024] [Accepted: 06/14/2024] [Indexed: 10/19/2024]
Abstract
This study investigated the role of Ninjurin1 (Ninj1), encoding a small transmembrane protein, in colitis-associated colon tumorigenesis in relation to sex hormones. Male and female wild-type (WT) and Ninj1 knockout (KO) mice were treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), with or without testosterone propionate (TP). At week 2 (acute colitis stage), Ninj1 KO exhibited an alleviation in the colitis symptoms in both male and female mice. The M2 macrophage population increased and CD8+ T cell population decreased only in the female Ninj1 KO than in the female WT AOM/DSS group. In the female AOM/DSS group, TP treatment exacerbated colon shortening in the Ninj1 KO than in the WT. At week 13 (tumorigenesis stage), male Ninj1 KO mice had fewer tumors, but females showed similar tumors. In the WT AOM/DSS group, females had more M2 macrophages and fewer M1 macrophages than males, but this difference was absent in Ninj1 KO mice. In the Ninj1 KO versus WT group, the expression of pro-inflammatory mediators and Ho-1 and CD8+ T cell populations decreased in both female and male Ninj1 KO mice. In the WT group, M2 macrophage populations were increased by AOM/DSS treatment and decreased by TP treatment. However, neither treatment changed the cell populations in the Ninj1 KO group. These results suggest that Ninj1 is involved in colorectal cancer development in a testosterone-dependent manner, which was different in male and female. This highlights the importance of considering sex disparities in understanding Ninj1's role in cancer pathogenesis.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Nayoung Kim
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Soo In Choi
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Jae Young Jang
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Eun Hye Kim
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Sungchan Ha
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Eun Shin
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi-do, South Korea
| | - Hoon Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Kyu-Won Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Sejin Jeon
- Department of Vaccine Biothechnology, Andong National University, Andong, South Korea
| | - Goo Taeg Oh
- Department of Life Sciences, Heart-Immune-Brain Network Research Center, Ewha Womans University, Seoul, South Korea
| | - Yeong-Jae Seok
- Department of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul, South Korea
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Zhu L, Xu Y. Multifaceted roles of ninjurin1 in immunity, cell death, and disease. Front Immunol 2025; 16:1519519. [PMID: 39958360 PMCID: PMC11825492 DOI: 10.3389/fimmu.2025.1519519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
Ninjurin1 (NINJ1) is initially identified as a nerve injury-induced adhesion molecule that facilitates axon growth. It is initially characterized to promote nerve regeneration and mediate the transendothelial transport of monocytes/macrophages associated with neuroinflammation. Recent evidence indicates that NINJ1 mediates plasma membrane rupture (PMR) in lytic cell death. The absence or inhibition of NINJ1 can delay PMR, thereby mitigating the spread of inflammation resulting from cell lysis and preventing the progression of various cell death-related pathologies, suggesting a conserved regulatory mechanism across these processes. Further research elucidated the structural basis and mechanism of NINJ1-mediated PMR. Although the role of NINJ1 in PMR is established, the identity of its activating factors and its implications in diseases remain to be fully explored. This review synthesizes current knowledge regarding the structural basis and mechanism of NINJ1-mediated PMR and discusses its significance and therapeutic targeting potential in inflammatory diseases, neurological disorders, cancer, and vascular injuries.
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Affiliation(s)
- Lili Zhu
- Department of Pathology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
| | - Yunfei Xu
- Department of Pathophysiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
- Postdoctoral Research Station of Biology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
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Xu Y, Zhang E, Wei L, Dai Z, Chen S, Zhou S, Huang Y. NINJ1: A new player in multiple sclerosis pathogenesis and potential therapeutic target. Int Immunopharmacol 2024; 141:113021. [PMID: 39197295 DOI: 10.1016/j.intimp.2024.113021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 08/07/2024] [Accepted: 08/23/2024] [Indexed: 09/01/2024]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination. Current treatment options for MS focus on immunosuppression, but their efficacy can be limited. Recent studies suggest a potential role for nerve injury-induced protein 1 (NINJ1) in MS pathogenesis. NINJ1, a protein involved in cell death and inflammation, may contribute to the infiltration and activation of inflammatory cells in the CNS, potentially through enhanced blood-brain barrier crossing; enhancing plasma membrane rupture during cell death, leading to the release of inflammatory mediators and further tissue damage. This review explores the emerging evidence for NINJ1's involvement in MS. It discusses how NINJ1 might mediate the migration of immune cells across the blood-brain barrier, exacerbate neuroinflammation, and participate in plasma membrane rupture-related damage. Finally, the review examines potential therapeutic strategies targeting NINJ1 for improved MS management. Abbreviations: MS, Multiple sclerosis; CNS, Central nervous system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma membrane rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated molecular patterns; PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis factor; APCs, Antigen-presenting cells; ECs, Endothelial cells; TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear cells; FACS, Fluorescence-activated cell sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T cell receptor; ROS, Reactive oxygen species; AP-1, Activator protein-1; ANG1, Angiopoietin 1; BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related protein 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase 1; PAK1, p21-activated kinases 1; Rac1, Ras-related C3 botulinum toxin substrate 1; β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor domain-containing adapter protein; TLR4, Toll-like receptor 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF receptor associated factor 6; TAB2/3, TAK1 binding protein 2/3; TAK1, transforming growth factor-β-activated kinase 1; JNK, c-Jun N-terminal kinase; ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa-B; AP-1, activator protein-1; ASC, Apoptosis-associated Speck-like protein containing a CARD; NEK7, NIMA-related kinase 7; NLRP3, Pyrin domain-containing 3; CREB, cAMP response element-binding protein.
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Affiliation(s)
- Yinbin Xu
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China
| | - Enhao Zhang
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China
| | - Liangzhe Wei
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China
| | - Zifeng Dai
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China
| | - Siqi Chen
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China
| | - Shengjun Zhou
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China.
| | - Yi Huang
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, Zhejiang 315010, China.
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Skerget S, Penaherrera D, Chari A, Jagannath S, Siegel DS, Vij R, Orloff G, Jakubowiak A, Niesvizky R, Liles D, Berdeja J, Levy M, Wolf J, Usmani SZ, Christofferson AW, Nasser S, Aldrich JL, Legendre C, Benard B, Miller C, Turner B, Kurdoglu A, Washington M, Yellapantula V, Adkins JR, Cuyugan L, Boateng M, Helland A, Kyman S, McDonald J, Reiman R, Stephenson K, Tassone E, Blanski A, Livermore B, Kirchhoff M, Rohrer DC, D'Agostino M, Gamella M, Collison K, Stumph J, Kidd P, Donnelly A, Zaugg B, Toone M, McBride K, DeRome M, Rogers J, Craig D, Liang WS, Gutierrez NC, Jewell SD, Carpten J, Anderson KC, Cho HJ, Auclair D, Lonial S, Keats JJ. Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes. Nat Genet 2024; 56:1878-1889. [PMID: 39160255 PMCID: PMC11387199 DOI: 10.1038/s41588-024-01853-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 06/28/2024] [Indexed: 08/21/2024]
Abstract
Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.
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Affiliation(s)
- Sheri Skerget
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Daniel Penaherrera
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Ajai Chari
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Sundar Jagannath
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - David S Siegel
- Hackensack University Medical Center, Hackensack, NJ, USA
| | - Ravi Vij
- Division of Oncology, Washington University, St. Louis, MO, USA
| | | | | | | | - Darla Liles
- Division of Hematology/Oncology, East Carolina University, Greenville, NC, USA
| | | | - Moshe Levy
- Baylor Scott and White Research Institute, Dallas, TX, USA
| | - Jeffrey Wolf
- Department of Medicine, UCSF Medical Center, San Francisco, CA, USA
| | | | - Austin W Christofferson
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Sara Nasser
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Jessica L Aldrich
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Christophe Legendre
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Brooks Benard
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Chase Miller
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Bryce Turner
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Ahmet Kurdoglu
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Megan Washington
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Venkata Yellapantula
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Jonathan R Adkins
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Lori Cuyugan
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Martin Boateng
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Adrienne Helland
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Shari Kyman
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Jackie McDonald
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Rebecca Reiman
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Kristi Stephenson
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Erica Tassone
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | | | | | | | - Mattia D'Agostino
- Division of Hematology, AOU Città della Salute e della Scienza di Torino, University of Torino and Department of Molecular Biotechnology and Health Sciences, Torino, Italy
| | - Manuela Gamella
- Division of Hematology, AOU Città della Salute e della Scienza di Torino, University of Torino and Department of Molecular Biotechnology and Health Sciences, Torino, Italy
| | | | | | - Pam Kidd
- Spectrum Health, Grand Rapids, MI, USA
| | | | | | | | | | - Mary DeRome
- Multiple Myeloma Research Foundation, Norwalk, CT, USA
| | | | - David Craig
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Winnie S Liang
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Norma C Gutierrez
- Department of Hematology, University Hospital of Salamanca, IBSAL, Cancer Research Center-IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
| | | | - John Carpten
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Hearn Jay Cho
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
- Multiple Myeloma Research Foundation, Norwalk, CT, USA
| | | | - Sagar Lonial
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
| | - Jonathan J Keats
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
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9
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Park SY, Kim MW, Kang JH, Hwang JH, Choi H, Park J, Seong JK, Yoon YS, Oh SH. Loss of Ninjurin1 alleviates acetaminophen-induced liver injury via enhancing AMPKα-NRF2 pathway. Life Sci 2024; 350:122782. [PMID: 38848941 DOI: 10.1016/j.lfs.2024.122782] [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: 04/15/2024] [Revised: 05/20/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.
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Affiliation(s)
- Se Yong Park
- College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Min Woo Kim
- College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Ju-Hee Kang
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea
| | - Jung Ho Hwang
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea
| | - Hoon Choi
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea
| | - Jiwon Park
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Yeo Sung Yoon
- College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Seung Hyun Oh
- College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.
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10
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Zhang J, Kong X, Yang HJ, Zhang W, Chen M, Chen X. Ninjurin 2 Modulates Tumorigenesis, Inflammation, and Metabolism via Pyroptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:849-860. [PMID: 38325550 PMCID: PMC11074982 DOI: 10.1016/j.ajpath.2024.01.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/08/2024] [Accepted: 01/19/2024] [Indexed: 02/09/2024]
Abstract
The nerve injury-induced protein 2 (NINJ2) belongs to a family of homophilic adhesion molecules and was initially found to be involved in nerve regeneration. However, the role of NINJ2 in other cellular processes is not well studied. The Ninj2-deficient mice generated in the current study had a short lifespan and were prone to spontaneous tumors, systemic inflammation, and metabolic defects. Comprehensive carbohydrate and lipid metabolic analyses were performed to better understand the metabolic traits that contribute to these phenotypes. Carbohydrate metabolic analyses showed that NINJ2 deficiency led to defects in monosaccharide metabolism along with accumulation of multiple disaccharides and sugar alcohols. Lipidomic analyses showed that Ninj2 deficiency altered patterns of several lipids, including triglycerides, phospholipids, and ceramides. To identify a cellular process that associated with these metabolic defects, the role of NINJ2 in pyroptosis, a programmed cell death that links cancer, inflammation, and metabolic disorders, was examined. Loss of NINJ2 promoted pyroptosis by activating the NOD-like receptor protein 3 (NLRP3) inflammasome. Taken together, these data reveal a critical role of NINJ2 in tumorigenesis, inflammatory response, and metabolism via pyroptosis.
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Affiliation(s)
- Jin Zhang
- Comparative Oncology Laboratory, University of California, Davis, Davis, California.
| | - Xiangmudong Kong
- Comparative Oncology Laboratory, University of California, Davis, Davis, California
| | - Hee Jung Yang
- Comparative Oncology Laboratory, University of California, Davis, Davis, California
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, California
| | - Mingyi Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xinbin Chen
- Comparative Oncology Laboratory, University of California, Davis, Davis, California.
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11
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Zhang J, Kong X, Yang HJ, Mohibi S, Lucchesi CA, Zhang W, Chen X. Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion. Cancers (Basel) 2024; 16:229. [PMID: 38201656 PMCID: PMC10778559 DOI: 10.3390/cancers16010229] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/12/2024] Open
Abstract
The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion.
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Affiliation(s)
- Jin Zhang
- Comparative Oncology Laboratory, The University of California, Davis, CA 95616, USA; (X.K.); (H.J.Y.); (S.M.); (C.A.L.)
| | - Xiangmudong Kong
- Comparative Oncology Laboratory, The University of California, Davis, CA 95616, USA; (X.K.); (H.J.Y.); (S.M.); (C.A.L.)
| | - Hee Jung Yang
- Comparative Oncology Laboratory, The University of California, Davis, CA 95616, USA; (X.K.); (H.J.Y.); (S.M.); (C.A.L.)
| | - Shakur Mohibi
- Comparative Oncology Laboratory, The University of California, Davis, CA 95616, USA; (X.K.); (H.J.Y.); (S.M.); (C.A.L.)
| | - Christopher August Lucchesi
- Comparative Oncology Laboratory, The University of California, Davis, CA 95616, USA; (X.K.); (H.J.Y.); (S.M.); (C.A.L.)
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, The University of California, Davis, CA 95616, USA;
| | - Xinbin Chen
- Comparative Oncology Laboratory, The University of California, Davis, CA 95616, USA; (X.K.); (H.J.Y.); (S.M.); (C.A.L.)
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12
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Lee C, Xin G, Li F, Wan C, Yu X, Feng L, Wen A, Cao Y, Huang W. Calcium/P53/Ninjurin 1 Signaling Mediates Plasma Membrane Rupture of Acinar Cells in Severe Acute Pancreatitis. Int J Mol Sci 2023; 24:11554. [PMID: 37511311 PMCID: PMC10380776 DOI: 10.3390/ijms241411554] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Ninjurin 1 (NINJ1) is a double-transmembrane cell-surface protein that might mediate plasma membrane rupture (PMR) and the diffusion of inflammatory factors. PMR is a characteristic of acinar cell injury in severe acute pancreatitis (SAP). However, the involvement of NINJ1 in mediating the PMR of acinar cells in SAP is currently unclear. Our study has shown that NINJ1 is expressed in acinar cells, and the expression is significantly upregulated in sodium-taurocholate-induced SAP. The knockout of NINJ1 delays PMR in acinar cells and alleviates SAP. Moreover, we observed that NINJ1 expression is mediated by Ca2+ concentration in acinar cells. Importantly, we found that Ca2+ overload drives mitochondrial stress to upregulate the P53/NINJ1 pathway, inducing PMR in acinar cells, and amlodipine, a Ca2+ channel inhibitor, can reduce the occurrence of PMR by decreasing the concentration of Ca2+. Our results demonstrate the mechanism by which NINJ1 induces PMR in SAP acinar cells and provide a potential new target for treatment of SAP.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Wen Huang
- Department of Emergency Medicine and Laboratory of Ethnopharmacology, Tissue-Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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Hu S, Guo W, Shen Y. Potential link between the nerve injury-induced protein (Ninjurin) and the pathogenesis of endometriosis. Int Immunopharmacol 2023; 114:109452. [PMID: 36446236 DOI: 10.1016/j.intimp.2022.109452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/29/2022] [Accepted: 11/10/2022] [Indexed: 11/27/2022]
Abstract
Endometriosis remains a widespread but severe gynecological disease in women of reproductive age, with an unknown etiology and few treatment choices. The menstrual reflux theory is largely accepted as the underlying etiology but does not explain the morbidity or unpleasant pain sensations of endometriosis. The neurological and immune systems are both involved in pain mechanisms of endometriosis, and interlinked through a complex combination of cytokines and neurotransmitters. Numerous pieces of evidence suggest that the nerve injury-inducible protein, Ninjurin, is actively expressed in endometriosis lesions, which contributes to the etiology and development of endometriosis. It may be explored in the future as a novel therapeutic target. The aim of the present review was to elucidate the multifaceted role of Ninjurin. Furthermore, we summarize the association of Ninjurin with the pain mechanism of endometriosis and outline the future research directions. A novel therapeutic pathway can be discovered based on the potential pathogenic variables.
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Affiliation(s)
- Sijian Hu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weina Guo
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yi Shen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Role of p53 in Regulating Radiation Responses. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071099. [PMID: 35888186 PMCID: PMC9319710 DOI: 10.3390/life12071099] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/15/2022] [Accepted: 07/16/2022] [Indexed: 12/12/2022]
Abstract
p53 is known as the guardian of the genome and plays various roles in DNA damage and cancer suppression. The p53 gene was found to express multiple p53 splice variants (isoforms) in a physiological, tissue-dependent manner. The various genes that up- and down-regulated p53 are involved in cell viability, senescence, inflammation, and carcinogenesis. Moreover, p53 affects the radioadaptive response. Given that several studies have already been published on p53, this review presents its role in the response to gamma irradiation by interacting with MDM2, NF-κB, and miRNA, as well as in the inflammation processes, senescence, carcinogenesis, and radiation adaptive responses. Finally, the potential of p53 as a biomarker is discussed.
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15
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Hyun SY, Min HY, Lee HJ, Cho J, Boo HJ, Noh M, Jang HJ, Lee HJ, Park CS, Park JS, Shin YK, Lee HY. Ninjurin1 drives lung tumor formation and progression by potentiating Wnt/β-Catenin signaling through Frizzled2-LRP6 assembly. J Exp Clin Cancer Res 2022; 41:133. [PMID: 35395804 PMCID: PMC8991582 DOI: 10.1186/s13046-022-02323-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 03/10/2022] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Cancer stem-like cells (CSCs) play a pivotal role in lung tumor formation and progression. Nerve injury-induced protein 1 (Ninjurin1, Ninj1) has been implicated in lung cancer; however, the pathological role of Ninj1 in the context of lung tumorigenesis remains largely unknown. METHODS The role of Ninj1 in the survival of non-small cell lung cancer (NSCLC) CSCs within microenvironments exhibiting hazardous conditions was assessed by utilizing patient tissues and transgenic mouse models where Ninj1 repression and oncogenic KrasG12D/+ or carcinogen-induced genetic changes were induced in putative pulmonary stem cells (SCs). Additionally, NSCLC cell lines and primary cultures of patient-derived tumors, particularly Ninj1high and Ninj1low subpopulations and those with gain- or loss-of-Ninj1 expression, and also publicly available data were all used to assess the role of Ninj1 in lung tumorigenesis. RESULTS Ninj1 expression is elevated in various human NSCLC cell lines and tumors, and elevated expression of this protein can serve as a biomarker for poor prognosis in patients with NSCLC. Elevated Ninj1 expression in pulmonary SCs with oncogenic changes promotes lung tumor growth in mice. Ninj1high subpopulations within NSCLC cell lines, patient-derived tumors, and NSCLC cells with gain-of-Ninj1 expression exhibited CSC-associated phenotypes and significantly enhanced survival capacities in vitro and in vivo in the presence of various cell death inducers. Mechanistically, Ninj1 forms an assembly with lipoprotein receptor-related protein 6 (LRP6) through its extracellular N-terminal domain and recruits Frizzled2 (FZD2) and various downstream signaling mediators, ultimately resulting in transcriptional upregulation of target genes of the LRP6/β-catenin signaling pathway. CONCLUSIONS Ninj1 may act as a driver of lung tumor formation and progression by protecting NSCLC CSCs from hostile microenvironments through ligand-independent activation of LRP6/β-catenin signaling.
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Affiliation(s)
- Seung Yeob Hyun
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hye-Young Min
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ho Jin Lee
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jaebeom Cho
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hye-Jin Boo
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Myungkyung Noh
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hyun-Ji Jang
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hyo-Jong Lee
- School of Pharmacy, Sungkyunkwan University, Suwon-Si, Gyeonggi-do, 16419, Republic of Korea
| | - Choon-Sik Park
- Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, 14584, Republic of Korea
| | - Jong-Sook Park
- Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, 14584, Republic of Korea
| | - Young Kee Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ho-Young Lee
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
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Xu P, Wang M, Song WM, Wang Q, Yuan GC, Sudmant PH, Zare H, Tu Z, Orr ME, Zhang B. The landscape of human tissue and cell type specific expression and co-regulation of senescence genes. Mol Neurodegener 2022; 17:5. [PMID: 35000600 PMCID: PMC8744330 DOI: 10.1186/s13024-021-00507-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood. METHODS This study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity. RESULTS Through a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A (p21)-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis. CONCLUSIONS This study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.
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Affiliation(s)
- Peng Xu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
| | - Won-min Song
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
| | - Qian Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
| | - Guo-Cheng Yuan
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Institute for Precision Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
| | - Peter H. Sudmant
- Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720 USA
- Center for Computational Biology, University of California Berkeley, Berkeley, CA 94720 USA
| | - Habil Zare
- Department of Cell Systems & Anatomy, The University of Texas Health Science Center, San Antonio, TX 78229 USA
- Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX 78229 USA
| | - Zhidong Tu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
| | - Miranda E. Orr
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Salisbury VA Medical Center, Salisbury, NC 28144 USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
- Department of Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 USA
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Bourdonnay E, Henry T. Transcriptional and Epigenetic Regulation of Gasdermins. J Mol Biol 2021; 434:167253. [PMID: 34537234 DOI: 10.1016/j.jmb.2021.167253] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/26/2021] [Accepted: 09/09/2021] [Indexed: 12/29/2022]
Abstract
Gasdermins (GSDM) are a family of six homologous proteins (GSDMA to E and Pejvakin) in humans. GSDMA-E are pore-forming proteins targeting the plasma membrane to trigger a rapid cell death termed pyroptosis or bacterial membranes to promote antibacterial immune defenses. Activation of GSDM relies on a proteolytic cleavage but is highly dependent on GSDM expression levels. The different GSDM genes have tissue-specific expression pattern although metabolic, environmental signals, cell stress and numerous cytokines modulate their expression levels in tissues. Furthermore, expression of GSDM genes can be modulated by polymorphisms and have been associated with susceptibility to asthma, inflammatory bowel diseases and rhinovirus wheezing illness. Finally, the expression level of GSDMs controls the balance between apoptosis and pyroptosis affecting both the response and the toxicity to chemotactic drugs and antitumoral treatments. Numerous cancer demonstrate positive or negative modulation of GSDM expression levels correlating with distinct tumor-specific prognosis. In this review, we present the transcriptional and epigenetic mechanisms controlling GSDM levels and their functional consequences in asthma, infection, cancers and inflammatory bowel disease to highlight how this first layer of regulations has key consequences on disease susceptibility and response to treatment.
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Affiliation(s)
- Emilie Bourdonnay
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Univ Lyon, F-69007 Lyon, France
| | - Thomas Henry
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Univ Lyon, F-69007 Lyon, France.
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Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation. Cells 2021; 10:cells10092287. [PMID: 34571936 PMCID: PMC8465636 DOI: 10.3390/cells10092287] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/26/2021] [Accepted: 08/31/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.
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Wu Z, Zhang W, Yang J. Letter by Wu et al Regarding Article, "Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis". Circulation 2021; 143:e919-e920. [PMID: 33970674 DOI: 10.1161/circulationaha.120.053212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Zhenguo Wu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan
| | - Wencheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan
| | - Jianmin Yang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan
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20
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Measuring Translation Efficiency by RNA Immunoprecipitation of Translation Initiation Factors. Methods Mol Biol 2021. [PMID: 33786785 DOI: 10.1007/978-1-0716-1217-0_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Eukaryotic mRNAs are bound by a multitude of RNA binding proteins (RBPs) that control their localization, transport, and translation. Measuring the rate of translation of mRNAs is critical for understanding the factors and pathways involved in gene expression. In this chapter, we present a method to compare the rate of translation of individual mRNA species based on the fraction of mRNA bound by a specific ribonucleoprotein involved in the general translation machinery. The ribonucleoprotein complex is immunoprecipitated using an antibody for the RBP, followed by RT-PCR to semi-quantitatively determine the amount of an individual mRNA fraction bound by a translation regulating protein such as eIF4E.
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21
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Liu K, Wang Y, Li H. The Role of Ninjurin1 and Its Impact beyond the Nervous System. Dev Neurosci 2021; 42:159-169. [PMID: 33657559 DOI: 10.1159/000512222] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/09/2020] [Indexed: 11/19/2022] Open
Abstract
Ninjurin1 (Ninj1) is a double-transmembrane cell surface protein that could promote nerve regeneration in the process of the peripheral nervous system injury and repairment. Nonetheless, the accurate function of Ninj1 in the central nervous system and outside the nervous system is not completely clear. According to the recent studies, we found that Ninj1 is also aberrantly expressed in various pathophysiological processes in vivo, including inflammation, tumorigenesis, and vascular, bone, and muscle homeostasis. These findings suggest that Ninj1 may play an influential role during these pathophysiological processes. Our review summarizes the diverse roles of Ninj1 in multiple pathophysiological processes inside and outside the nervous system. Ninj1 should be considered as an important and novel therapeutic target in certain diseases, such as inflammatory diseases and ischemic diseases. Our study provided a better understanding of Ninj1 in different pathophysiological processes and thereby provided the theoretical support for further research.
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Affiliation(s)
- Ke Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongge Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,
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22
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Choe EK, Lee S, Kim SY, Shivakumar M, Park KJ, Chai YJ, Kim D. Prognostic Effect of Inflammatory Genes on Stage I-III Colorectal Cancer-Integrative Analysis of TCGA Data. Cancers (Basel) 2021; 13:cancers13040751. [PMID: 33670198 PMCID: PMC7916934 DOI: 10.3390/cancers13040751] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/05/2021] [Accepted: 02/07/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Research interest in the role of inflammation in the progression and prognosis of colorectal cancer (CRC) is growing. In this study, we evaluated the expression and DNA methylation levels of inflammation-related genes in CRC tissues using the TCGA-COREAD dataset by integratively combining multi-omics features using machine learning. Statistical analysis was additionally performed to allow for interpretable, understandable, and clinically practical results. An integrative model combining expression, methylation, and clinical features had the highest performance. In multivariate analysis, the methylation levels of CEP250, RAB21, and TNPO3 were significantly associated with overall survival. Our study results implicate the importance of integrating expression and methylation information along with clinical information in the prediction of survival. CEP250, RAB21, and TNPO3 in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reactions and CRC progression. Abstract Background inflammatory status indicators have been reported as prognostic biomarkers of colorectal cancer (CRC). However, since inflammatory interactions with the colon involve various modes of action, the biological mechanism linking inflammation and CRC prognosis has not been fully elucidated. We comprehensively evaluated the predictive roles of the expression and methylation levels of inflammation-related genes for CRC prognosis and their pathophysiological associations. Method. An integrative analysis of 247 patients with stage I-III CRC from The Cancer Genome Atlas was conducted. Lasso-penalized Cox proportional hazards regression (Lasso-Cox) and statistical Cox proportional hazard regression (CPH) were used for the analysis. Results. Models to predict overall survival were designed with respective combinations of clinical variables, including age, sex, stage, gene expression, and methylation. An integrative model combining expression, methylation, and clinical features performed better (median C-index = 0.756) than the model with clinical features alone (median C-index = 0.726). Based on multivariate CPH with features from the best model, the methylation levels of CEP250, RAB21, and TNPO3 were significantly associated with overall survival. They did not share any biological process in functional networks. The 5-year survival rate was 29.8% in the low methylation group of CEP250 and 79.1% in the high methylation group (p < 0.001). Conclusion. Our study results implicate the importance of integrating expression and methylation information along with clinical information in the prediction of survival. CEP250, RAB21, and TNPO3 in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reactions and CRC progression.
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Affiliation(s)
- Eun Kyung Choe
- Department of Surgery, Seoul National University Hospital Healthcare System Gangnam Center, Seoul 06236, Korea;
- Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6116, USA; (S.Y.K.); (M.S.)
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Sangwoo Lee
- Department of Future Convergence, Cyber University of Korea, Seoul 03051, Korea;
| | - So Yeon Kim
- Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6116, USA; (S.Y.K.); (M.S.)
- Department of Software and Computer Engineering, Ajou University, Suwon 16499, Korea
| | - Manu Shivakumar
- Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6116, USA; (S.Y.K.); (M.S.)
| | - Kyu Joo Park
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Young Jun Chai
- Department of Surgery, Seoul Metropolitan Government—Seoul National University Boramae Medical Center, Seoul 07061, Korea;
| | - Dokyoon Kim
- Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6116, USA; (S.Y.K.); (M.S.)
- Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA 19104-6116, USA
- Correspondence: ; Tel.: +1-215-573-5336
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23
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Li P, Mao WW, Zhang S, Zhang L, Chen ZR, Lu ZD. Sodium hydrosulfide alleviates dexamethasone-induced cell senescence and dysfunction through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells. Exp Ther Med 2021; 21:238. [PMID: 33603846 PMCID: PMC7851607 DOI: 10.3892/etm.2021.9669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 09/15/2020] [Indexed: 01/30/2023] Open
Abstract
Glucocorticoid-induced osteoporosis is characterized by osteoblastic cell and microarchitecture dysfunction, as well as a loss of bone mass. Cell senescence contributes to the pathological process of osteoporosis and sodium hydrosulfide (NaHS) regulates the potent protective effects through delaying cell senescence. The aim of the present study was to investigate whether senescence could contribute to dexamethasone (Dex)-induced osteoblast impairment and to examine the effect of NaHS on Dex-induced cell senescence and damage. It was found that the levels of the senescence-associated markers, p53 and p21, were markedly increased in osteoblasts exposed to Dex. A p53 inhibitor reversed Dex-induced osteoblast injury, a process that was mitigated by NaHS administration through alleviating osteoblastic cell senescence. MicroRNA (miR)-22 blocked the impact of NaHS on Dex-induced osteoblast damage and senescence through targeting the regulation of Sirtuin 1 (sirt1) expression, as shown by the decreased cell viability and alkaline phosphatase activity, as well as an increased expression of p53 and p21. It was revealed that the sirt1 gene was the target of miR-22 in osteoblastic MC3T3-E1 cells through combining the results of dual luciferase reporter assays and reverse transcription-quantitative PCR, as well as western blot analyses. Silencing of sirt1 abolished the protective effect of NaHS against Dex-associated osteoblast senescence and injury. Taken together, the present study showed that NaHS prevents Dex-induced cell senescence and damage through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells.
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Affiliation(s)
- Peng Li
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Wei-Wei Mao
- Clinical Skill Center of Yinchuan First People's Hospital, Yinchuan, Ningxia 750001, P.R. China
| | - Shuai Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Liang Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Zhi-Rong Chen
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Zhi-Dong Lu
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
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24
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Bosi E, Marselli L, De Luca C, Suleiman M, Tesi M, Ibberson M, Eizirik DL, Cnop M, Marchetti P. Integration of single-cell datasets reveals novel transcriptomic signatures of β-cells in human type 2 diabetes. NAR Genom Bioinform 2020; 2:lqaa097. [PMID: 33575641 PMCID: PMC7679065 DOI: 10.1093/nargab/lqaa097] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic islet β-cell failure is key to the onset and progression of type 2 diabetes (T2D). The advent of single-cell RNA sequencing (scRNA-seq) has opened the possibility to determine transcriptional signatures specifically relevant for T2D at the β-cell level. Yet, applications of this technique have been underwhelming, as three independent studies failed to show shared differentially expressed genes in T2D β-cells. We performed an integrative analysis of the available datasets from these studies to overcome confounding sources of variability and better highlight common T2D β-cell transcriptomic signatures. After removing low-quality transcriptomes, we retained 3046 single cells expressing 27 931 genes. Cells were integrated to attenuate dataset-specific biases, and clustered into cell type groups. In T2D β-cells (n = 801), we found 210 upregulated and 16 downregulated genes, identifying key pathways for T2D pathogenesis, including defective insulin secretion, SREBP signaling and oxidative stress. We also compared these results with previous data of human T2D β-cells from laser capture microdissection and diabetic rat islets, revealing shared β-cell genes. Overall, the present study encourages the pursuit of single β-cell RNA-seq analysis, preventing presently identified sources of variability, to identify transcriptomic changes associated with human T2D and underscores specific traits of dysfunctional β-cells across different models and techniques.
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Affiliation(s)
- Emanuele Bosi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Lorella Marselli
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Carmela De Luca
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mara Suleiman
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Marta Tesi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, University of Lausanne, Quartier Sorge, CH-1015 Lausanne, Switzerland
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Piero Marchetti
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
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25
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Choi H, Bae SJ, Choi G, Lee H, Son T, Kim JG, An S, Lee HS, Seo JH, Kwon HB, Jeon S, Oh GT, Surh YJ, Kim KW. Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance. FASEB J 2020; 34:8702-8720. [PMID: 32385864 DOI: 10.1096/fj.201902753r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/07/2020] [Accepted: 04/19/2020] [Indexed: 12/20/2022]
Abstract
Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization and dysbiosis contributes to inflammatory bowel disease (IBD) pathogenesis. However, the molecular factors mediating colonic homeostasis are not well characterized. Here, we found that Ninjurin1 (Ninj1) limits colon inflammation by regulating macrophage polarization and microbiota composition under homeostatic conditions and during colitis development. Ninj1 deletion in mice induced hypersusceptibility to colitis, with increased prevalence of colitogenic Prevotellaceae strains and decreased immunoregulatory Lachnospiraceae strains. Upon co-housing (CoH) with WT mice, Ninj1-/- mice showed increased Lachnospiraceae and decreased Prevotellaceae abundance, with subsequent improvement of colitis. Under homeostatic conditions, M1 macrophage frequency was higher in the Ninj1-/- mouse colons than wild-type (WT) mouse colons, which may contribute to increased basal colonic inflammation and microbial imbalance. Following colitis induction, Ninj1 expression was increased in macrophages; meanwhile Ninj1-/- mice showed severe colitis development and impaired recovery, associated with decreased M2 macrophages and escalated microbial imbalance. In vitro, Ninj1 knockdown in mouse and human macrophages activated M1 polarization and restricted M2 polarization. Finally, the transfer of WT macrophages ameliorated severe colitis in Ninj1-/- mice. These findings suggest that Ninj1 mediates colonic homeostasis by modulating M1/M2 macrophage balance and preventing extensive dysbiosis, with implications for IBD prevention and therapy.
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Affiliation(s)
- Hoon Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Sung-Jin Bae
- Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, Korea
| | - Garam Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Hyunseung Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Taekwon Son
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Jeong-Gyun Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Sunho An
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Hye Shin Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Ji Hae Seo
- Department of Biochemistry, School of Medicine, Keimyung University, Daegu, Korea
| | - Hyouk-Bum Kwon
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - Sejin Jeon
- Department of Life Sciences, Ewha Womans University, Seoul, Korea
| | - Goo Taeg Oh
- Department of Life Sciences, Ewha Womans University, Seoul, Korea
| | - Young-Joon Surh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Kyu-Won Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.,Crop Biotechnology Institute, GreenBio Science and Technology, Seoul National University, Pyeongchang, Korea
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Radiation Potentiates Monocyte Infiltration into Tumors by Ninjurin1 Expression in Endothelial Cells. Cells 2020; 9:cells9051086. [PMID: 32353975 PMCID: PMC7291157 DOI: 10.3390/cells9051086] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 04/25/2020] [Accepted: 04/26/2020] [Indexed: 12/12/2022] Open
Abstract
Radiation is a widely used treatment for cancer patients, with over half the cancer patients receiving radiation therapy during their course of treatment. Considerable evidence from both preclinical and clinical studies show that tumor recurrence gets restored following radiotherapy, due to the influx of circulating cells consisting primarily of monocytes. The attachment of monocyte to endothelial cell is the first step of the extravasation process. However, the exact molecules that direct the transmigration of monocyte from the blood vessels to the tumors remain largely unknown. The nerve injury-induced protein 1 (Ninjurin1 or Ninj1) gene, which encodes a homophilic adhesion molecule and cell surface protein, was found to be upregulated in inflammatory lesions, particularly in macrophages/monocytes, neutrophils, and endothelial cells. More recently Ninj1 was reported to be regulated following p53 activation. Considering p53 has been known to be activated by radiation, we wondered whether Ninj1 could be increased in the endothelial cells by radiation and it might contribute to the recruiting of monocytes in the tumor. Here we demonstrate that radiation-mediated up-regulation of Ninj1 in endothelial cell lines such as human umbilical vein endothelial cells (HUVECs), EA.hy926, and immortalized HUVECs. Consistent with this, we found over-expressed Ninj1 in irradiated xenograft tumors, and increased monocyte infiltration into tumors. Radiation-induced Ninj1 was transcriptionally regulated by p53, as confirmed by transfection of p53 siRNA. In addition, Ninj1 over-expression in endothelial cells accelerated monocyte adhesion. Irradiation-induced endothelial cells and monocyte interaction was inhibited by knock-down of Ninj1. Furthermore, over-expressed Ninj1 stimulated MMP-2 and MMP-9 expression in monocyte cell lines, whereas the MMP-2 and MMP-9 expression were attenuated by Ninj1 knock-down in monocytes. Taken together, we provide evidence that Ninj1 is a key molecule that generates an interaction between endothelial cells and monocytes. This result suggests that radiation-mediated Ninj1 expression in endothelial cells could be involved in the post-radiotherapy recurrence mechanism.
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Jung HJ, Kang JH, Pak S, Lee K, Seong JK, Oh SH. Detrimental Role of Nerve Injury-Induced Protein 1 in Myeloid Cells under Intestinal Inflammatory Conditions. Int J Mol Sci 2020; 21:ijms21020614. [PMID: 31963519 PMCID: PMC7013940 DOI: 10.3390/ijms21020614] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/24/2022] Open
Abstract
Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell-surface adhesion molecule that regulates cell migration and attachment. This study demonstrates the increase in Ninj1 protein expression during development of intestinal inflammation. Ninj1-deficient mice exhibited significantly attenuated bodyweight loss, shortening of colon length, intestinal inflammation, and lesser pathological lesions than wild-type mice. Although more severe inflammation and serious lesions are observed in wild-type mice than Ninj1-deficient mice, there were no changes in the numbers of infiltrating macrophages in the inflamed tissues obtained from WT and Ninj1-deficient mice. Ninj1 expression results in activation of macrophages, and these activated macrophages secrete more cytokines and chemokines than Ninj1-deficient macrophages. Moreover, mice with conditional deletion of Ninj1 in myeloid cells (Ninj1fl/fl; Lyz-Cre+) alleviated experimental colitis compared with wild-type mice. In summary, we propose that the Ninj1 in myeloid cells play a pivotal function in intestinal inflammatory conditions.
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Affiliation(s)
- Hyun Jin Jung
- Interdisciplinary Program in Cancer Biology, College of Medicine, Seoul National University, Seoul 03080, Korea;
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Ju-Hee Kang
- College of Pharmacy, Gachon University, Incheon 21936, Korea
| | - Seongwon Pak
- Department of Biomedical Science, Hallym University, Chuncheon 24252, Korea
| | - Keunwook Lee
- Department of Biomedical Science, Hallym University, Chuncheon 24252, Korea
| | - Je Kyung Seong
- Interdisciplinary Program in Cancer Biology, College of Medicine, Seoul National University, Seoul 03080, Korea;
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Laboratory of Developmental Biology and Genomics, Research Institute of Veterinary Science, BK21 Plus Program for Veterinary Science, Seoul National University, Seoul 08826, Korea
- Correspondence: (J.K.S.); (S.H.O.)
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon 21936, Korea
- Correspondence: (J.K.S.); (S.H.O.)
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Ninjurin1 regulates striated muscle growth and differentiation. PLoS One 2019; 14:e0216987. [PMID: 31091274 PMCID: PMC6519837 DOI: 10.1371/journal.pone.0216987] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 05/02/2019] [Indexed: 12/19/2022] Open
Abstract
Chronic pressure overload due to aortic valve stenosis leads to pathological cardiac hypertrophy and heart failure. Hypertrophy is accompanied by an increase in myocyte surface area, which requires a proportional increase in the number of cell-cell and cell-matrix contacts to withstand enhanced workload. In a proteomic analysis we identified nerve injury-induced protein 1 (Ninjurin1), a 16kDa transmembrane cell-surface protein involved in cell adhesion and nerve repair, to be increased in hypertrophic hearts from patients with aortic stenosis. We hypothesised that Ninjurin1 is involved in myocyte hypertrophy. We analyzed cardiac biopsies from aortic-stenosis patients and control patients undergoing elective heart surgery. We studied cardiac hypertrophy in mice after transverse aortic constriction and angiotensin II infusions, and performed mechanistic analyses in cultured myocytes. We assessed the physiological role of ninjurin1 in zebrafish during heart and skeletal muscle development. Ninjurin1 was increased in hearts of aortic stenosis patients, compared to controls, as well as in hearts from mice with cardiac hypertrophy. Besides the 16kDa Ninjurin1 (Ninjurin1-16) we detected a 24kDa variant of Ninjurin1 (Ninjurin1-24), which was predominantly expressed during myocyte hypertrophy. We disclosed that the higher molecular weight of Ninjurin1-24 was caused by N-glycosylation. Ninjurin1-16 was contained in the cytoplasm of myocytes where it colocalized with stress-fibers. In contrast, Ninjurin1-24 was localized at myocyte membranes. Gain and loss-of-function experiments showed that Ninjurin1-24 plays a role in myocyte hypertrophy and myogenic differentiation in vitro. Reduced levels of ninjurin1 impaired cardiac and skeletal muscle development in zebrafish. We conclude that Ninjurin1 contributes to myocyte growth and differentiation, and that these effects are mainly mediated by N-glycosylated Ninjurin1-24.
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Bae SJ, Shin MW, Son T, Lee HS, Chae JS, Jeon S, Oh GT, Kim KW. Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusion osteoclasts. Exp Mol Med 2019; 51:1-16. [PMID: 30700695 PMCID: PMC6353902 DOI: 10.1038/s12276-018-0201-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 08/27/2018] [Accepted: 08/29/2018] [Indexed: 01/20/2023] Open
Abstract
Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1-/- mice exhibit increased trabecular bone volume owing to impaired OC development. Ninj1 deficiency did not alter OC differentiation, transmigration, fusion, or actin ring formation but increased Caspase-9-dependent intrinsic apoptosis in prefusion OCs (preOCs). Overexpression of Ninj1 enhanced the survival of mouse macrophage/preOC RAW264.7 cells in osteoclastogenic culture, suggesting that Ninj1 is important for the survival of preOCs. Finally, analysis of publicly available microarray data sets revealed a potent correlation between high NINJ1 expression and destructive bone disorders in humans. Our data indicate that Ninj1 plays an important role in bone homeostasis by enhancing the survival of preOCs.
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Affiliation(s)
- Sung-Jin Bae
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.,Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, 50612, Korea
| | - Min Wook Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.,RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Taekwon Son
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Hye Shin Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Ji Soo Chae
- Department of Life Sciences and Technology, PerkinElmer, Seoul, 06702, Korea
| | - Sejin Jeon
- Department of Life Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Goo Taeg Oh
- Department of Life Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Kyu-Won Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea. .,Crop Biotechnology Institute, GreenBio Science and Technology, Seoul National University, Pyeongchang, 25354, Korea.
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30
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Miyashita M, Koga K, Takeuchi A, Makabe T, Taguchi A, Urata Y, Izumi G, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Yoshino O, Fujii T, Osuga Y. Expression of Nerve Injury-Induced Protein1 (Ninj1) in Endometriosis. Reprod Sci 2018; 26:1105-1110. [PMID: 30326781 DOI: 10.1177/1933719118806395] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The aim of this study was to clarify the expression of Ninj1 in endometriosis and adenomyosis lesions, and its inductive factor in human endometriotic stromal cells (ESCs). BACKGROUND Nerve injury-induced protein 1 (Ninj1) is a molecule originally identified in dorsal root ganglion neurons and Schwann cells after nerve injury and promotes neurite outgrowth. The aim of this study was to clarify the expression of Ninj1 in endometriosis and adenomyosis lesions, and its inductive factor in human endometriotic stromal cells (ESCs). MATERIALS AND METHODS Tissues were obtained with consent from patients diagnosed with ovarian endometrioma (n = 15 in total), peritoneal endometriosis (n = 5), adenomyosis (n = 5), and other gynecological disorders (n = 5, control) during surgery. Immunohistochemistry was conducted in order to detect Ninj1 protein expression in the lesion of endometriosis, adenomyosis, and eutopic endometrium. Nerve fibers in the ovarian endometrioma were detected by positive staining of PGP-9.5. To evaluate the effects of IL-1β on Ninj1 gene expression in endometriosis, ESCs isolated from ovarian endometrioma (n = 5) were treated with IL-1β (5 ng/mL) for 3 or 6 hours. Messenger RNA (mRNA) expression for Ninj1 was examined using quantitative RT-PCR. RESULTS The Ninj1 protein was expressed by ovarian endometrioma, peritoneal endometriotic, and adenomyotic tissue. Nerve fibers were found in the areas of positive staining for Ninj1 in ovarian endometrioma. IL-1β, an indicator of inflammation in endometriosis, significantly increased Ninj1 mRNA expression by ESC. CONCLUSION Our study demonstrates that Ninj1 is expressed in endometriosis and adenomyosis and is induced by the inflammatory stimuli. Given the neurogenetic property of Ninj1, our results imply that Ninj1, induced by inflammation in endometriosis lesion, may contribute to the pathogenesis of pain symptoms characteristic of endometriosis.
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Affiliation(s)
- Mariko Miyashita
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Kaori Koga
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Arisa Takeuchi
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Tomoko Makabe
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Ayumi Taguchi
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Yoko Urata
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Gentaro Izumi
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Masashi Takamura
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Miyuki Harada
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Tetsuya Hirata
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Yasushi Hirota
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Osamu Wada-Hiraike
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Osamu Yoshino
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Tomoyuki Fujii
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Yutaka Osuga
- 1 Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
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31
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p53 mediated transcriptional regulation of long non-coding RNA by 1-hydroxy-1-norresistomycin triggers intrinsic apoptosis in adenocarcinoma lung cancer. Chem Biol Interact 2018; 287:1-12. [DOI: 10.1016/j.cbi.2018.03.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 03/06/2018] [Accepted: 03/25/2018] [Indexed: 12/20/2022]
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32
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Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner. Proc Natl Acad Sci U S A 2017; 114:11500-11505. [PMID: 29073078 DOI: 10.1073/pnas.1711814114] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer.
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33
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Wu Q, Allouch A, Martins I, Brenner C, Modjtahedi N, Deutsch E, Perfettini JL. Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness. Front Immunol 2017; 8:613. [PMID: 28603525 PMCID: PMC5445662 DOI: 10.3389/fimmu.2017.00613] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 05/09/2017] [Indexed: 12/17/2022] Open
Abstract
Radiation therapy is one of the cornerstones of cancer treatment. In tumor cells, exposure to ionizing radiation (IR) provokes DNA damages that trigger various forms of cell death such as apoptosis, necrosis, autophagic cell death, and mitotic catastrophe. IR can also induce cellular senescence that could serve as an additional antitumor barrier in a context-dependent manner. Moreover, accumulating evidence has demonstrated that IR interacts profoundly with tumor-infiltrating immune cells, which cooperatively drive treatment outcomes. Recent preclinical and clinical successes due to the combination of radiation therapy and immune checkpoint blockade have underscored the need for a better understanding of the interplay between radiation therapy and the immune system. In this review, we will present an overview of cell death modalities induced by IR, summarize the immunogenic properties of irradiated cancer cells, and discuss the biological consequences of IR on innate immune cell functions, with a particular attention on dendritic cells, macrophages, and NK cells. Finally, we will discuss their potential applications in cancer treatment.
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Affiliation(s)
- Qiuji Wu
- Cell Death and Aging Team, Gustave Roussy Cancer Campus, Villejuif, France.,Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Université Paris Saclay, Villejuif, France.,Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Awatef Allouch
- Cell Death and Aging Team, Gustave Roussy Cancer Campus, Villejuif, France.,Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Université Paris Saclay, Villejuif, France
| | - Isabelle Martins
- Cell Death and Aging Team, Gustave Roussy Cancer Campus, Villejuif, France.,Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Université Paris Saclay, Villejuif, France
| | - Catherine Brenner
- Laboratory of Signaling and Cardiovascular Pathophysiology, INSERM UMR-S 1180, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Nazanine Modjtahedi
- Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Université Paris Saclay, Villejuif, France
| | - Eric Deutsch
- Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Université Paris Saclay, Villejuif, France
| | - Jean-Luc Perfettini
- Cell Death and Aging Team, Gustave Roussy Cancer Campus, Villejuif, France.,Laboratory of Molecular Radiotherapy, INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Université Paris Saclay, Villejuif, France
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34
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Sharma NK, Sajuthi SP, Chou JW, Calles-Escandon J, Demons J, Rogers S, Ma L, Palmer ND, McWilliams DR, Beal J, Comeau ME, Cherry K, Hawkins GA, Menon L, Kouba E, Davis D, Burris M, Byerly SJ, Easter L, Bowden DW, Freedman BI, Langefeld CD, Das SK. Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans. J Clin Endocrinol Metab 2016; 101:1455-68. [PMID: 26789776 PMCID: PMC4880154 DOI: 10.1210/jc.2015-3336] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans.
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Affiliation(s)
- Neeraj K Sharma
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Satria P Sajuthi
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Jeff W Chou
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Jorge Calles-Escandon
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Jamehl Demons
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Samantha Rogers
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Lijun Ma
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Nicholette D Palmer
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - David R McWilliams
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - John Beal
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Mary E Comeau
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Kristina Cherry
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Gregory A Hawkins
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Lata Menon
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Ethel Kouba
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Donna Davis
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Marcie Burris
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Sara J Byerly
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Linda Easter
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Donald W Bowden
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Barry I Freedman
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Carl D Langefeld
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Swapan K Das
- Department of Internal Medicine (N.K.S., J.C.-E., J.D., S.R., L.Ma., K.C., L.Me., E.K., D.D., B.I.F., S.K.D.), Center for Public Health Genomics (N.K.S., S.P.S., J.W.C., L.Ma., N.D.P., D.R.M., M.C., G.A.H., B.I.F., C.D.L., S.K.D.), Department of Biostatistical Sciences, Division of Public Health Sciences (S.P.S., J.W.C., D.R.M., J.B., M.C., C.D.L.), Department of Biochemistry (N.D.P., D.W.B.), Center for Diabetes Research and Center for Genomics and Personalized Medicine Research (N.D.P., G.A.H., D.W.B., B.I.F.), and Clinical Research Unit, Biomedical Research Services and Administration (M.B., S.J.B., L.E.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
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Leung AWY, Hung SS, Backstrom I, Ricaurte D, Kwok B, Poon S, McKinney S, Segovia R, Rawji J, Qadir MA, Aparicio S, Stirling PC, Steidl C, Bally MB. Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro. PLoS One 2016; 11:e0150675. [PMID: 26938915 PMCID: PMC4777418 DOI: 10.1371/journal.pone.0150675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 02/16/2016] [Indexed: 01/22/2023] Open
Abstract
Platinum-based combination chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). While cisplatin is effective, its use is not curative and resistance often emerges. As a consequence of microenvironmental heterogeneity, many tumour cells are exposed to sub-lethal doses of cisplatin. Further, genomic heterogeneity and unique tumor cell sub-populations with reduced sensitivities to cisplatin play a role in its effectiveness within a site of tumor growth. Being exposed to sub-lethal doses will induce changes in gene expression that contribute to the tumour cell’s ability to survive and eventually contribute to the selective pressures leading to cisplatin resistance. Such changes in gene expression, therefore, may contribute to cytoprotective mechanisms. Here, we report on studies designed to uncover how tumour cells respond to sub-lethal doses of cisplatin. A microarray study revealed changes in gene expressions that occurred when A549 cells were exposed to a no-observed-effect level (NOEL) of cisplatin (e.g. the IC10). These data were integrated with results from a genome-wide siRNA screen looking for novel therapeutic targets that when inhibited transformed a NOEL of cisplatin into one that induced significant increases in lethality. Pathway analyses were performed to identify pathways that could be targeted to enhance cisplatin activity. We found that over 100 genes were differentially expressed when A549 cells were exposed to a NOEL of cisplatin. Pathways associated with apoptosis and DNA repair were activated. The siRNA screen revealed the importance of the hedgehog, cell cycle regulation, and insulin action pathways in A549 cell survival and response to cisplatin treatment. Results from both datasets suggest that RRM2B, CABYR, ALDH3A1, and FHL2 could be further explored as cisplatin-enhancing gene targets. Finally, pathways involved in repairing double-strand DNA breaks and INO80 chromatin remodeling were enriched in both datasets, warranting further research into combinations of cisplatin and therapeutics targeting these pathways.
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Affiliation(s)
- Ada W. Y. Leung
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- * E-mail:
| | - Stacy S. Hung
- Centre for Lymphoid Cancers, BC Cancer Agency, Vancouver, BC, Canada
| | - Ian Backstrom
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Daniel Ricaurte
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Brian Kwok
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Steven Poon
- Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Steven McKinney
- Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Romulo Segovia
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
| | - Jenna Rawji
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Mohammed A. Qadir
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Samuel Aparicio
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada
| | | | - Christian Steidl
- Centre for Lymphoid Cancers, BC Cancer Agency, Vancouver, BC, Canada
| | - Marcel B. Bally
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
- Centre for Drug Research and Development, Vancouver, BC, Canada
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Jang YS, Kang JH, Woo JK, Kim HM, Hwang JI, Lee SJ, Lee HY, Oh SH. Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway. Int J Cancer 2016; 139:383-95. [DOI: 10.1002/ijc.30021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 12/15/2015] [Accepted: 12/16/2015] [Indexed: 12/13/2022]
Affiliation(s)
- Yeong-Su Jang
- Gachon Institute of Pharmaceutical Sciences, Gachon University; Incheon Republic of Korea
| | - Ju-Hee Kang
- Gachon Institute of Pharmaceutical Sciences, Gachon University; Incheon Republic of Korea
- National Cancer Center; Goyang-Si Gyeonggi-Do Republic of Korea
| | - Jong Kyu Woo
- Gachon Institute of Pharmaceutical Sciences, Gachon University; Incheon Republic of Korea
| | - Hwan Mook Kim
- Gachon Institute of Pharmaceutical Sciences, Gachon University; Incheon Republic of Korea
| | - Jong-Ik Hwang
- Graduate School of Medicine, Korea University; Seoul Republic of Korea
| | - Sang-Jin Lee
- National Cancer Center; Goyang-Si Gyeonggi-Do Republic of Korea
| | - Ho-Young Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University; Seoul Republic of Korea
| | - Seung Hyun Oh
- Gachon Institute of Pharmaceutical Sciences, Gachon University; Incheon Republic of Korea
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37
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Qiao Y, He H, Jonsson P, Sinha I, Zhao C, Dahlman-Wright K. AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression. J Biol Chem 2016; 291:5068-79. [PMID: 26792858 DOI: 10.1074/jbc.m115.702571] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Indexed: 12/21/2022] Open
Abstract
Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFα can facilitate tumor progression and metastasis. However, the mechanistic aspects of inflammation mediated TNBC progression remain unclear. Using ChIP-seq, we demonstrate that the cistrome for the AP-1 transcription factor c-Jun is comprised of 13,800 binding regions in TNFα-stimulated TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFα-regulated transcriptome. Interestingly, high expression level of the c-Jun-regulated pro-invasion gene program is associated with poor clinical outcome in TNBCs. We further demonstrate that c-Jun drives TNFα-mediated increase of malignant characteristics of TNBC cells by transcriptional regulation of Ninj1. As exemplified by the CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-κB might be a pioneer factor required for the regulation of TNFα-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.
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Affiliation(s)
- Yichun Qiao
- From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden
| | - Huan He
- From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden
| | - Philip Jonsson
- Department of Radiation Oncology, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, and
| | - Indranil Sinha
- From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden
| | - Chunyan Zhao
- From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden,
| | - Karin Dahlman-Wright
- From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Solna, Sweden
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38
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SHIN MINWOOK, BAE SUNGJIN, WEE HEEJUN, LEE HYOJONG, AHN BUMJU, LE HOANG, LEE EUNJI, KIM RANHEE, LEE HYESHIN, SEO JIHAE, PARK JIHYEON, KIM KYUWON. Ninjurin1 regulates lipopolysaccharide-induced inflammation through direct binding. Int J Oncol 2015; 48:821-8. [DOI: 10.3892/ijo.2015.3296] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/23/2015] [Indexed: 11/06/2022] Open
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Dynamics of P53 in response to DNA damage: Mathematical modeling and perspective. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2015; 119:175-82. [DOI: 10.1016/j.pbiomolbio.2015.08.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 08/12/2015] [Indexed: 12/21/2022]
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40
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Weng YH, Chen CY, Lin KJ, Chen YL, Yeh TH, Hsiao IT, Chen IJ, Lu CS, Wang HL. (R1441C) LRRK2 induces the degeneration of SN dopaminergic neurons and alters the expression of genes regulating neuronal survival in a transgenic mouse model. Exp Neurol 2015; 275 Pt 1:104-15. [PMID: 26363496 DOI: 10.1016/j.expneurol.2015.09.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 08/13/2015] [Accepted: 09/03/2015] [Indexed: 01/11/2023]
Abstract
Mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Several mutations in LRRK2 gene were reported in PD patients. R1441 is the second most frequent site of LRRK2 mutation. We generated (R1441C) LRRK2 transgenic mice that displayed motor deficits at the age of 16 months. Compared with wild-type mice, 16-month-old (R1441C) LRRK2 mice exhibited a significant reduction in the number of substantia nigra (SN) dopaminergic neurons. To elucidate molecular pathogenic pathways involved in (R1441C) LRRK2-induced death of SN dopaminergic neurons, we performed microarray analysis to visualize altered mRNA expressions in the SN of (R1441C) LRRK2 mouse. In the SN of (R1441C) LRRK2 transgenic mouse, the mRNA expression of three genes that promote cell death was upregulated, while the mRNA expression of seven genes that contribute to neurogenesis/neuroprotection was significantly downregulated. Our results suggest that altered expression of these genes involved in regulating neuronal survival may contribute to the pathogenesis of (R1441C) LRRK2-induced PD.
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Affiliation(s)
- Yi-Hsin Weng
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Chu-Yu Chen
- Department of Physiology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Kun-Jun Lin
- Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Nuclear Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Ying-Ling Chen
- Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC
| | - Tu-Hsueh Yeh
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Ing-Tsung Hsiao
- Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Ing-Jou Chen
- Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Chin-Song Lu
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Hung-Li Wang
- Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Physiology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC.
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Zhang L, Nemzow L, Chen H, Hu JJ, Gong F. Whole genome expression profiling shows that BRG1 transcriptionally regulates UV inducible genes and other novel targets in human cells. PLoS One 2014; 9:e105764. [PMID: 25157878 PMCID: PMC4144907 DOI: 10.1371/journal.pone.0105764] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 07/19/2014] [Indexed: 12/16/2022] Open
Abstract
UV irradiation is known to cause cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6–4) pyrimidone photoproducts (6-4PPs), and plays a large role in the development of cancer. Tumor suppression, through DNA repair and proper cell cycle regulation, is an integral factor in maintaining healthy cells and preventing development of cancer. Transcriptional regulation of the genes involved in the various tumor suppression pathways is essential for them to be expressed when needed and to function properly. BRG1, an ATPase catalytic subunit of the SWI/SNF chromatin remodeling complex, has been identified as a tumor suppressor protein, as it has been shown to play a role in Nucleotide Excision Repair (NER) of CPDs, suppress apoptosis, and restore checkpoint deficiency, in response to UV exposure. Although BRG1 has been shown to regulate transcription of some genes that are instrumental in proper DNA damage repair and cell cycle maintenance in response to UV, its role in transcriptional regulation of the whole genome in response to UV has not yet been elucidated. With whole genome expression profiling in SW13 cells, we show that upon UV induction, BRG1 regulates transcriptional expression of many genes involved in cell stress response. Additionally, our results also highlight BRG1's general role as a master regulator of the genome, as it transcriptionally regulates approximately 4.8% of the human genome, including expression of genes involved in many pathways. RT-PCR and ChIP were used to validate our genome expression analysis. Importantly, our study identifies several novel transcriptional targets of BRG1, such as ATF3. Thus, BRG1 has a larger impact on human genome expression than previously thought, and our studies will provide inroads for future analysis of BRG1's role in gene regulation.
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Affiliation(s)
- Ling Zhang
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Leah Nemzow
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Hua Chen
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Jennifer J. Hu
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Feng Gong
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- * E-mail:
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42
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Liu BW, Liu Y, Liu JR, Feng ZX, Liu T. Prognostic effect of p53 expression in patients with completely resected colorectal cancer. Tumour Biol 2014; 35:9893-6. [PMID: 24993094 DOI: 10.1007/s13277-014-2219-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 06/10/2014] [Indexed: 02/06/2023] Open
Abstract
The p53 protein is closely involved in the carcinogenesis of many kinds of cancers. Though the prognostic role of p53 expression for the survival of colorectal cancer (CRC) patients has been preliminarily identified, the prognostic effect of p53 expression in patients with completely resected CRC is still unclear. Therefore, a retrospective cohort study was performed to assess the prognostic role of p53 expression for overall survival in patients with completely resected CRC. A total of 153 patients (mean age 50.9 years) with completely resected CRC was finally included in the retrospective cohort study. Kaplan-Meier product-limit methods and log-rank test were used to estimate overall survival distribution and test the difference. In addition, multivariable analysis by Cox regression model was also used to test the prognostic role of p53 expression on overall survival by adjusting for other confounding factors. Of those 153 CRC patients, 62 (40.5 %) were positive for p53 protein expression in the tumor tissues. The log-rank test showed that there was an obvious difference in the overall survival between the p53-positive group and the p53-negative group (P < 0.001). Multivariable analysis by Cox regression model further showed that p53 protein expression was an independent predictor of shorter overall survival in patients with completely resected CRC (hazard ratio [HR] = 1.77; 95 % confidence interval [95 % CI] 1.15-2.71, P = 0.009). Therefore, p53 protein expression in the tumor tissue is an independent predictor of shorter overall survival in patients with completely resected CRC.
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Affiliation(s)
- Bin-Wei Liu
- Department of General Surgery, Tianjin Medical University General Hospital, No.154, Anshan Road, Heping District, Tianjin, 300000, China
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Lim R, Morwood CJ, Barker G, Lappas M. Effect of silibinin in reducing inflammatory pathways in in vitro and in vivo models of infection-induced preterm birth. PLoS One 2014; 9:e92505. [PMID: 24647589 PMCID: PMC3960267 DOI: 10.1371/journal.pone.0092505] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 02/21/2014] [Indexed: 12/21/2022] Open
Abstract
Infection-induced preterm birth is the largest cause of infant death and of neurological disabilities in survivors. Silibinin, from milk thistle, exerts potent anti-inflammatory activities in non-gestational tissues. The aims of this study were to determine the effect of silibinin on pro-inflammatory mediators in (i) human fetal membranes and myometrium treated with bacterial endotoxin lipopolysaccharide (LPS) or the pro-inflammatory cytokine IL-1β, and (ii) in preterm fetal membranes with active infection. The effect of silibinin on infection induced inflammation and brain injury in pregnant mice was also assessed. Fetal membranes and myometrium (tissue explants and primary cells) were treated with 200 μM silibinin in the presence or absence of 10 μg/ml LPS or 1 ng/ml IL-1β. C57BL/6 mice were injected with 70 mg/kg silibinin with or without 50 μg LPS on embryonic day 16. Fetal brains were collected after 6 h. In human fetal membranes, silibinin significantly decreased LPS-stimulated expression of IL-6 and IL-8, COX-2, and prostaglandins PGE2 and PGF2α. In primary amnion and myometrial cells, silibinin also decreased IL-1β-induced MMP-9 expression. Preterm fetal membranes with active infection treated with silibinin showed a decrease in IL-6, IL-8 and MMP-9 expression. Fetal brains from mice treated with silibinin showed a significant decrease in LPS-induced IL-8 and ninjurin, a marker of brain injury. Our study demonstrates that silibinin can reduce infection and inflammation-induced pro-labour mediators in human fetal membranes and myometrium. Excitingly, the in vivo results indicate a protective effect of silibinin on infection-induced brain injury in a mouse model of preterm birth.
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Affiliation(s)
- Ratana Lim
- Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Carrington J. Morwood
- Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Gillian Barker
- Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Martha Lappas
- Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
- * E-mail:
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44
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Fischer M, Steiner L, Engeland K. The transcription factor p53: not a repressor, solely an activator. Cell Cycle 2014; 13:3037-58. [PMID: 25486564 PMCID: PMC4612452 DOI: 10.4161/15384101.2014.949083] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/10/2014] [Indexed: 12/12/2022] Open
Abstract
The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway.
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Key Words
- CDE, cell cycle-dependent element
- CDKN1A
- CHR, cell cycle genes homology region
- ChIP, chromatin immunoprecipitation
- DREAM complex
- DREAM, DP, RB-like, E2F4, and MuvB complex
- E2F/RB complex
- HPV, human papilloma virus
- NF-Y, Nuclear factor Y
- cdk, cyclin-dependent kinase
- genome-wide meta-analysis
- p53
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Affiliation(s)
- Martin Fischer
- Molecular Oncology; Medical School; University of Leipzig; Leipzig, Germany
| | - Lydia Steiner
- Center for Complexity & Collective Computation; Wisconsin Institute for Discovery; Madison, WI USA
- Computational EvoDevo Group & Bioinformatics Group; Department of Computer Science and Interdisciplinary Center for Bioinformatics; University of Leipzig; Leipzig, Germany
| | - Kurt Engeland
- Molecular Oncology; Medical School; University of Leipzig; Leipzig, Germany
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Ahn BJ, Le H, Shin MW, Bae SJ, Lee EJ, Wee HJ, Cha JH, Lee HJ, Lee HS, Kim JH, Kim CY, Seo JH, Lo EH, Jeon S, Lee MN, Oh GT, Yin GN, Ryu JK, Suh JK, Kim KW. Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice. J Biol Chem 2013; 289:3328-38. [PMID: 24347169 DOI: 10.1074/jbc.m113.498212] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Ninjurin1 is a homotypic adhesion molecule that contributes to leukocyte trafficking in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, in vivo gene deficiency animal studies have not yet been done. Here, we constructed Ninjurin1 knock-out (KO) mice and investigated the role of Ninjurin1 on leukocyte trafficking under inflammation conditions such as EAE and endotoxin-induced uveitis. Ninjurin1 KO mice attenuated EAE susceptibility by reducing leukocyte recruitment into the injury regions of the spinal cord and showed less adhesion of leukocytes on inflamed retinal vessels in endotoxin-induced uveitis mice. Moreover, the administration of a custom-made antibody (Ab26-37) targeting the Ninjurin1 binding domain ameliorated the EAE symptoms, showing the contribution of its adhesion activity to leukocyte trafficking. In addition, we addressed the transendothelial migration (TEM) activity of bone marrow-derived macrophages and Raw264.7 cells according to the expression level of Ninjurin1. TEM activity was decreased in Ninjurin1 KO bone marrow-derived macrophages and siNinj1 Raw264.7 cells. Consistent with this, GFP-tagged mNinj1-overexpressing Raw264.7 cells increased their TEM activity. Taken together, we have clarified the contribution of Ninjurin1 to leukocyte trafficking in vivo and delineated its direct functions to TEM, emphasizing Ninjurin1 as a beneficial therapeutic target against inflammatory diseases such as multiple sclerosis.
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Affiliation(s)
- Bum Ju Ahn
- From the SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences and
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