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Jiang J, Sun M, Wang Y, Huang W, Xia L. Deciphering the roles of the HMGB family in cancer: Insights from subcellular localization dynamics. Cytokine Growth Factor Rev 2024; 78:85-104. [PMID: 39019664 DOI: 10.1016/j.cytogfr.2024.07.004] [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: 06/03/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 07/19/2024]
Abstract
The high-mobility group box (HMGB) family consists of four DNA-binding proteins that regulate chromatin structure and function. In addition to their intracellular functions, recent studies have revealed their involvement as extracellular damage-associated molecular patterns (DAMPs), contributing to immune responses and tumor development. The HMGB family promotes tumorigenesis by modulating multiple processes including proliferation, metabolic reprogramming, metastasis, immune evasion, and drug resistance. Due to the predominant focus on HMGB1 in the literature, little is known about the remaining members of this family. This review summarizes the structural, distributional, as well as functional similarities and distinctions among members of the HMGB family, followed by a comprehensive exploration of their roles in tumor development. We emphasize the distributional and functional hierarchy of the HMGB family at both the organizational and subcellular levels, with a focus on their relationship with the tumor immune microenvironment (TIME), aiming to prospect potential strategies for anticancer therapy.
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Affiliation(s)
- Junqing Jiang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China
| | - Mengyu Sun
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China
| | - Yufei Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, China.
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China; State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi' an 710032, China.
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Chen F, Tang H, Cai X, Lin J, Xiang L, Kang R, Liu J, Tang D. Targeting paraptosis in cancer: opportunities and challenges. Cancer Gene Ther 2024; 31:349-363. [PMID: 38177306 DOI: 10.1038/s41417-023-00722-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/07/2023] [Accepted: 12/12/2023] [Indexed: 01/06/2024]
Abstract
Cell death can be classified into two primary categories: accidental cell death and regulated cell death (RCD). Within RCD, there are distinct apoptotic and non-apoptotic cell death pathways. Among the various forms of non-apoptotic RCD, paraptosis stands out as a unique mechanism characterized by distinct morphological changes within cells. These alterations encompass cytoplasmic vacuolization, organelle swelling, notably in the endoplasmic reticulum and mitochondria, and the absence of typical apoptotic features, such as cell shrinkage and DNA fragmentation. Biochemically, paraptosis distinguishes itself by its independence from caspases, which are conventionally associated with apoptotic death. This intriguing cell death pathway can be initiated by various cellular stressors, including oxidative stress, protein misfolding, and specific chemical compounds. Dysregulated paraptosis plays a pivotal role in several critical cancer-related processes, such as autophagic degradation, drug resistance, and angiogenesis. This review provides a comprehensive overview of recent advancements in our understanding of the mechanisms and regulation of paraptosis. Additionally, it delves into the potential of paraptosis-related compounds for targeted cancer treatment, with the aim of enhancing treatment efficacy while minimizing harm to healthy cells.
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Affiliation(s)
- Fangquan Chen
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China
| | - Hu Tang
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China
| | - Xiutao Cai
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China
| | - Junhao Lin
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China
| | - Limin Xiang
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jiao Liu
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China.
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
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Chen R, Zou J, Zhong X, Li J, Kang R, Tang D. HMGB1 in the interplay between autophagy and apoptosis in cancer. Cancer Lett 2024; 581:216494. [PMID: 38007142 DOI: 10.1016/j.canlet.2023.216494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/25/2023] [Accepted: 11/08/2023] [Indexed: 11/27/2023]
Abstract
Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.
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Affiliation(s)
- Ruochan Chen
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Ju Zou
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Xiao Zhong
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Jie Li
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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4
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Chen X, Liu Q, Wu E, Ma Z, Tuo B, Terai S, Li T, Liu X. The role of HMGB1 in digestive cancer. Biomed Pharmacother 2023; 167:115575. [PMID: 37757495 DOI: 10.1016/j.biopha.2023.115575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 09/29/2023] Open
Abstract
High mobility group box protein B1 (HMGB1) belongs to the HMG family, is widely expressed in the nucleus of digestive mucosal epithelial cells, mesenchymal cells and immune cells, and binds to DNA to participate in genomic structural stability, mismatch repair and transcriptional regulation to maintain normal cellular activities. In the context of digestive inflammation and tumors, HMGB1 readily migrates into the extracellular matrix and binds to immune cell receptors to affect their function and differentiation, further promoting digestive tract tissue injury and tumor development. Notably, HMGB1 can also promote the antitumor immune response. Therefore, these seemingly opposing effects in tumors make targeted HMGB1 therapies important in digestive cancer. This review focuses on the role of HMGB1 in tumors and its effects on key pathways of digestive cancer and aims to provide new possibilities for targeted tumor therapy.
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Affiliation(s)
- Xiangqi Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Qian Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Enqing Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Shuji Terai
- Division of Gastroenterology & Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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Chen F, Kang R, Liu J, Tang D. The ACSL4 Network Regulates Cell Death and Autophagy in Diseases. BIOLOGY 2023; 12:864. [PMID: 37372148 DOI: 10.3390/biology12060864] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/05/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023]
Abstract
Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.
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Affiliation(s)
- Fangquan Chen
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiao Liu
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
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de Azevedo BLR, Roni GM, Torrelio RMF, da Gama-de-Souza LN. Fibrosis as a Risk Factor for Cutaneous Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa: A Systematic Review. J Pediatr Genet 2023; 12:97-104. [PMID: 37090823 PMCID: PMC10118679 DOI: 10.1055/s-0043-1763257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 01/16/2023] [Indexed: 02/26/2023]
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe subtype of epidermolysis bullosa caused by changes in collagen VII with a high risk of early development of cutaneous squamous cell carcinoma (cSCC). This review aimed to discuss the relationship between the recurrent healing process, the appearance of fibrosis, and malignant epithelial transformation in RDEB. We searched PubMed, the Regional Portal of the Virtual Health Library, and Embase for articles on the relationship between blistering, recurrent scarring, and fibrosis in the context of cSCC and RDEB. That alterations of collagen VII result in blister formation, scar deficiency associated with inflammation, and increased expression of transforming growth factor β. These events promote the differentiation of myofibroblasts and the expression of profibrotic proteins, leading to structural changes and the establishment of a microenvironment favorable to carcinogenesis. Patients with RDEB and areas of recurrent scarring and fibrosis may be more prone to the development of cSCC.
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Affiliation(s)
| | - Gabriel Marim Roni
- Federal University of Espírito Santo, Health Science Center, Morphology Department, Medical School, Vitória, ES, Brazil
| | | | - Letícia Nogueira da Gama-de-Souza
- Federal University of Espírito Santo, Health Science Center, Morphology Department, Graduate Program in Dental Science, Vitória, ES, Brazil
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Wang H, Guo M, Wei H, Chen Y. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct Target Ther 2023; 8:92. [PMID: 36859359 PMCID: PMC9977964 DOI: 10.1038/s41392-023-01347-1] [Citation(s) in RCA: 342] [Impact Index Per Article: 171.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/19/2022] [Accepted: 02/07/2023] [Indexed: 03/03/2023] Open
Abstract
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
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Affiliation(s)
- Haolan Wang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hudie Wei
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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Galhuber M, Michenthaler H, Heininger C, Reinisch I, Nössing C, Krstic J, Kupper N, Moyschewitz E, Auer M, Heitzer E, Ulz P, Birner-Gruenberger R, Liesinger L, Lenihan-Geels GN, Oster M, Spreitzer E, Zenezini Chiozzi R, Schulz TJ, Schupp M, Madl T, Heck AJR, Prokesch A. Complementary omics strategies to dissect p53 signaling networks under nutrient stress. Cell Mol Life Sci 2022; 79:326. [PMID: 35635656 PMCID: PMC9151573 DOI: 10.1007/s00018-022-04345-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/21/2022] [Accepted: 05/03/2022] [Indexed: 12/04/2022]
Abstract
Signaling trough p53is a major cellular stress response mechanism and increases upon nutrient stresses such as starvation. Here, we show in a human hepatoma cell line that starvation leads to robust nuclear p53 stabilization. Using BioID, we determine the cytoplasmic p53 interaction network within the immediate-early starvation response and show that p53 is dissociated from several metabolic enzymes and the kinase PAK2 for which direct binding with the p53 DNA-binding domain was confirmed with NMR studies. Furthermore, proteomics after p53 immunoprecipitation (RIME) uncovered the nuclear interactome under prolonged starvation, where we confirmed the novel p53 interactors SORBS1 (insulin receptor signaling) and UGP2 (glycogen synthesis). Finally, transcriptomics after p53 re-expression revealed a distinct starvation-specific transcriptome response and suggested previously unknown nutrient-dependent p53 target genes. Together, our complementary approaches delineate several nodes of the p53 signaling cascade upon starvation, shedding new light on the mechanisms of p53 as nutrient stress sensor. Given the central role of p53 in cancer biology and the beneficial effects of fasting in cancer treatment, the identified interaction partners and networks could pinpoint novel pharmacologic targets to fine-tune p53 activity.
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Affiliation(s)
- Markus Galhuber
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Helene Michenthaler
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Christoph Heininger
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Isabel Reinisch
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Christoph Nössing
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
| | - Jelena Krstic
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Nadja Kupper
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Elisabeth Moyschewitz
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Martina Auer
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria
| | - Ellen Heitzer
- Diagnostic and Research Institute of Human Genetics, Medical University of Graz, 8010, Graz, Austria
| | - Peter Ulz
- Diagnostic and Research Institute of Human Genetics, Medical University of Graz, 8010, Graz, Austria
| | - Ruth Birner-Gruenberger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010, Graz, Austria
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060, Vienna, Austria
| | - Laura Liesinger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010, Graz, Austria
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060, Vienna, Austria
| | - Georgia Ngawai Lenihan-Geels
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Moritz Oster
- Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, 10115, Berlin, Germany
| | - Emil Spreitzer
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010, Graz, Austria
| | - Riccardo Zenezini Chiozzi
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584CH, Utrecht, The Netherlands
- Netherlands Proteomics Center, 3584CH, Utrecht, The Netherlands
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
- Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany
| | - Michael Schupp
- Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, 10115, Berlin, Germany
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010, Graz, Austria
- BioTechMed-Graz, 8010, Graz, Austria
| | - Albert J R Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584CH, Utrecht, The Netherlands
- Netherlands Proteomics Center, 3584CH, Utrecht, The Netherlands
| | - Andreas Prokesch
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria.
- BioTechMed-Graz, 8010, Graz, Austria.
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Study on the Expression Profile of Autophagy-Related Genes in Colon Adenocarcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:7525048. [PMID: 35572821 PMCID: PMC9095386 DOI: 10.1155/2022/7525048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/11/2022] [Accepted: 03/23/2022] [Indexed: 12/24/2022]
Abstract
Colon adenocarcinoma (COAD) is a common digestive tract tumor. Autophagy-related genes (ARGs) may play an obbligato role in the biological processes of COAD. This study was aimed at exploring the role of ARGs in COAD. Clinical data and RNA sequencing data of tumor and healthy samples were obtained from The Cancer Genome Atlas (TCGA), and discrepantly expressed ARGs were screened. Statistical differences of ARGs were performed with Gene Ontology (GO) functional annotation and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Eight ARGs were selected by univariate Cox and multivariate Cox regression. Kaplan–Meier (K-M) and multivariate receiver operating characteristic (multi-ROC) were used to check the fitness of the model. Among 398 COAD samples and 39 normal samples obtained from the TCGA database, 37 differentially expressed ARGs were screened. In the training group, eight prognostics-related ARGs (MTMR14, VAMP3, HSPA8, TSC1, DAPK1, CX3CL1, ATG13, and MAP1LC3C) were identified by Cox regression. A gene signature risk prediction model was constructed base on 8 autophagy-related genes. The survival time of the low-risk group was longer than the high-risk group, and the AUC of the model was 0.794. Univariate and multivariate Cox regression analysis showed that age and riskscore were the independent predictor. In conclusion, the prognosis model we built based one ARGs of COAD patients can estimate the prognosis of patients in clinical treatment.
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Rico-Díaz A, Barreiro-Alonso A, Rey-Souto C, Becerra M, Lamas-Maceiras M, Cerdán ME, Vizoso-Vázquez Á. The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis. Biomolecules 2021; 11:biom11091392. [PMID: 34572607 PMCID: PMC8465852 DOI: 10.3390/biom11091392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/10/2021] [Accepted: 09/16/2021] [Indexed: 12/15/2022] Open
Abstract
In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. Kluyveromyces lactis is also a useful eukaryotic model, more similar to many human cells due to its respiratory metabolism. We cloned and functionally characterized by different methodologies KlIXR1, which encodes a protein with only 34.4% amino acid sequence similarity to ScIxr1. Our data indicate that both proteins share common functions, including their involvement in the response to hypoxia or oxidative stress induced by hydrogen peroxide or metal treatments, as well as in the control of key regulators for maintenance of the dNTP (deoxyribonucleotide triphosphate) pool and ribosome synthesis. KlIxr1 is able to bind specific regulatory DNA sequences in the promoter of its target genes, which are well conserved between S. cerevisiae and K. lactis. Oppositely, we found important differences between ScIrx1 and KlIxr1 affecting cellular responses to cisplatin or cycloheximide in these yeasts, which could be dependent on specific and non-conserved domains present in these two proteins.
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Abstract
Colorectal cancer has served as a genetic and biological paradigm for the evolution of solid tumors, and these insights have illuminated early detection, risk stratification, prevention, and treatment principles. Employing the hallmarks of cancer framework, we provide a conceptual framework to understand how genetic alterations in colorectal cancer drive cancer cell biology properties and shape the heterotypic interactions across cells in the tumor microenvironment. This review details research advances pertaining to the genetics and biology of colorectal cancer, emerging concepts gleaned from immune and single-cell profiling, and critical advances and remaining knowledge gaps influencing the development of effective therapies for this cancer that remains a major public health burden.
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Affiliation(s)
- Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Xingdi Ma
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Deepavali Chakravarti
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Shabnam Shalapour
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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12
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Chikhirzhina EV, Starkova TY, Polyanichko AM. The Structural Organization of the HMGB1 Nuclear Protein and Its Effect on the Formation of Ordered Supramolecular Complexes. Biophysics (Nagoya-shi) 2021. [DOI: 10.1134/s0006350921030039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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13
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Chikhirzhina E, Starkova T, Beljajev A, Polyanichko A, Tomilin A. Functional Diversity of Non-Histone Chromosomal Protein HmgB1. Int J Mol Sci 2020; 21:E7948. [PMID: 33114717 PMCID: PMC7662367 DOI: 10.3390/ijms21217948] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/21/2020] [Accepted: 10/23/2020] [Indexed: 12/27/2022] Open
Abstract
The functioning of DNA in the cell nucleus is ensured by a multitude of proteins, whose interactions with DNA as well as with other proteins lead to the formation of a complicated, organized, and quite dynamic system known as chromatin. This review is devoted to the description of properties and structure of the progenitors of the most abundant non-histone protein of the HMGB family-the HmgB1 protein. The proteins of the HMGB family are also known as "architectural factors" of chromatin, which play an important role in gene expression, transcription, DNA replication, and repair. However, as soon as HmgB1 goes outside the nucleus, it acquires completely different functions, post-translational modifications, and change of its redox state. Despite a lot of evidence of the functional activity of HmgB1, there are still many issues to be solved related to the mechanisms of the influence of HmgB1 on the development and treatment of different diseases-from oncological and cardiovascular diseases to pathologies during pregnancy and childbirth. Here, we describe molecular structure of the HmgB1 protein and discuss general mechanisms of its interactions with other proteins and DNA in cell.
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Affiliation(s)
| | | | | | - Alexander Polyanichko
- Laboratory of Molecular Biology of Stem Cells, Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Tikhoretsky Av. 4, Russia; (T.S.); (A.B.); (A.T.)
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14
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Gorgulho CM, Romagnoli GG, Bharthi R, Lotze MT. Johnny on the Spot-Chronic Inflammation Is Driven by HMGB1. Front Immunol 2019; 10:1561. [PMID: 31379812 PMCID: PMC6660267 DOI: 10.3389/fimmu.2019.01561] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Although much has been made of the role of HMGB1 acting as an acute damage associated molecular pattern (DAMP) molecule, prompting the response to tissue damage or injury, it is also released at sites of chronic inflammation including sites of infection, autoimmunity, and cancer. As such, the biology is distinguished from homeostasis and acute inflammation by the recruitment and persistence of myeloid derived suppressor cells, T regulatory cells, fibrosis and/or exuberant angiogenesis depending on the antecedents and the other individual inflammatory partners that HMGB1 binds and focuses, including IL-1β, CXCL12/SDF1, LPS, DNA, RNA, and sRAGE. High levels of HMGB1 released into the extracellular milieu and its persistence in the microenvironment can contribute to the pathogenesis of many if not all autoimmune disorders and is a key factor that drives inflammation further and worsens symptoms. HMGB1 is also pivotal in the maintenance of chronic inflammation and a “wound healing” type of immune response that ultimately contributes to the onset of carcinogenesis and tumor progression. Exosomes carrying HMGB1 and other instructive molecules are released and shape the response of various cells in the chronic inflammatory environment. Understanding the defining roles of REDOX, DAMPs and PAMPs, and the host response in chronic inflammation requires an alternative means for positing HMGB1's central role in limiting and focusing inflammation, distinguishing chronic from acute inflammation.
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Affiliation(s)
- Carolina M Gorgulho
- Tumor Immunology Laboratory, Department of Microbiology and Immunology, Botucatu Institute of Biosciences, São Paulo State University, Botucatu, Brazil.,DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Graziela G Romagnoli
- Tumor Immunology Laboratory, Department of Microbiology and Immunology, Botucatu Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Rosh Bharthi
- DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Michael T Lotze
- DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
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15
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Schröder M, Yusein-Myashkova S, Todorova J, Pasheva E, Ugrinova I. High mobility group box 1 protein (HMGB1) stimulates the nuclear accumulation of p53. BIOTECHNOL BIOTEC EQ 2019. [DOI: 10.1080/13102818.2019.1604159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
- Maria Schröder
- Department of Structure and Function of Chromatin, Institute of Molecular Biology “Roumen Tsanev’’, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Shazie Yusein-Myashkova
- Department of Structure and Function of Chromatin, Institute of Molecular Biology “Roumen Tsanev’’, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Jordana Todorova
- Department of Structure and Function of Chromatin, Institute of Molecular Biology “Roumen Tsanev’’, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Evdokia Pasheva
- Department of Structure and Function of Chromatin, Institute of Molecular Biology “Roumen Tsanev’’, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Iva Ugrinova
- Department of Structure and Function of Chromatin, Institute of Molecular Biology “Roumen Tsanev’’, Bulgarian Academy of Sciences, Sofia, Bulgaria
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16
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Khan A, Wani MY, Al-Bogami AS, Subramanian K, Kandhavelu J, Ruff P, Penny C. Anticancer Activity of Novel Gabexate Mesilate Mimetics in Colorectal Cancer Cells. ChemistrySelect 2018. [DOI: 10.1002/slct.201800629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Amber Khan
- Department of Internal Medicine; Faculty of Health Sciences; University of the Witwatersrand; 7 York Road, Parktown Johannesburg 2193 South Africa
| | - Mohmmad Younus Wani
- Chemistry Department; Faculty of Science; University of Jeddah, P.O. Box 80327; Jeddah 21589 Kingdom of Saudi Arabia
| | - Abdullah Saad Al-Bogami
- Chemistry Department; Faculty of Science; University of Jeddah, P.O. Box 80327; Jeddah 21589 Kingdom of Saudi Arabia
| | - Kumar Subramanian
- Department of Internal Medicine; Faculty of Health Sciences; University of the Witwatersrand; 7 York Road, Parktown Johannesburg 2193 South Africa
| | - Jeyalakshmi Kandhavelu
- Department of Internal Medicine; Faculty of Health Sciences; University of the Witwatersrand; 7 York Road, Parktown Johannesburg 2193 South Africa
| | - Paul Ruff
- Department of Internal Medicine; Faculty of Health Sciences; University of the Witwatersrand; 7 York Road, Parktown Johannesburg 2193 South Africa
| | - Clement Penny
- Department of Internal Medicine; Faculty of Health Sciences; University of the Witwatersrand; 7 York Road, Parktown Johannesburg 2193 South Africa
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17
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A. Richard S. High-mobility group box 1 is a promising diagnostic and therapeutic monitoring biomarker in Cancers: A review. AIMS MOLECULAR SCIENCE 2018. [DOI: 10.3934/molsci.2018.4.183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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18
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He SJ, Cheng J, Feng X, Yu Y, Tian L, Huang Q. The dual role and therapeutic potential of high-mobility group box 1 in cancer. Oncotarget 2017; 8:64534-64550. [PMID: 28969092 PMCID: PMC5610024 DOI: 10.18632/oncotarget.17885] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 04/24/2017] [Indexed: 12/31/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is an abundant protein in most eukaryocytes. It can bind to several receptors such as advanced glycation end products (RAGE) and Toll-like receptors (TLRs), in direct or indirect way. The biological effects of HMGB1 depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it possesses more complicated functions, including regulating cell proliferation, autophagy, inflammation and immunity. During tumor development, HMGB1 has been characterized as both a pro- and anti-tumoral protein by either promoting or suppressing tumor growth, proliferation, angiogenesis, invasion and metastasis. However, the current knowledge concerning the positive and negative effects of HMGB1 on tumor development is not explicit. Here, we evaluate the role of HMGB1 in tumor development and attempt to reconcile the dual effects of HMGB1 in carcinogenesis. Furthermore, we would like to present current strategies targeting against HMGB1, its receptor or release, which have shown potentially therapeutic value in cancer intervention.
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Affiliation(s)
- Si-Jia He
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin Cheng
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Feng
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Yu
- Oncology Department, Henan Provincial People's Hospital, Zhengzhou, China
| | - Ling Tian
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Huang
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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19
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Zhang T, Wei W, Dirsch O, Krüger T, Kan C, Xie C, Kniemeyer O, Fang H, Settmacher U, Dahmen U. Identification of Proteins Interacting with Cytoplasmic High-Mobility Group Box 1 during the Hepatocellular Response to Ischemia Reperfusion Injury. Int J Mol Sci 2017; 18:ijms18010167. [PMID: 28275217 PMCID: PMC5297800 DOI: 10.3390/ijms18010167] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 01/03/2017] [Accepted: 01/09/2017] [Indexed: 01/22/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) occurs inevitably in liver transplantations and frequently during major resections, and can lead to liver dysfunction as well as systemic disorders. High-mobility group box 1 (HMGB1) plays a pathogenic role in hepatic IRI. In the normal liver, HMGB1 is located in the nucleus of hepatocytes; after ischemia reperfusion, it translocates to the cytoplasm and it is further released to the extracellular space. Unlike the well-explored functions of nuclear and extracellular HMGB1, the role of cytoplasmic HMGB1 in hepatic IRI remains elusive. We hypothesized that cytoplasmic HMGB1 interacts with binding proteins involved in the hepatocellular response to IRI. In this study, binding proteins of cytoplasmic HMGB1 during hepatic IRI were identified. Liver tissues from rats with warm ischemia reperfusion (WI/R) injury and from normal rats were subjected to cytoplasmic protein extraction. Co-immunoprecipitation using these protein extracts was performed to enrich HMGB1-protein complexes. To separate and identify the immunoprecipitated proteins in eluates, 2-dimensional electrophoresis and subsequent mass spectrometry detection were performed. Two of the identified proteins were verified using Western blotting: betaine–homocysteine S-methyltransferase 1 (BHMT) and cystathionine γ-lyase (CTH). Therefore, our results revealed the binding of HMGB1 to BHMT and CTH in cytoplasm during hepatic WI/R. This finding may help to better understand the cellular response to IRI in the liver and to identify novel molecular targets for reducing ischemic injury.
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Affiliation(s)
- Tianjiao Zhang
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany.
| | - Weiwei Wei
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany.
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, 09116 Chemnitz, Germany.
| | - Thomas Krüger
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany.
| | - Chunyi Kan
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany.
- Department of Obstetrics and Gynecology, Wuhan Central Hospital, Wuhan 430014, China.
| | - Chichi Xie
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany.
| | - Olaf Kniemeyer
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany.
| | - Haoshu Fang
- Department of Pathophysiology, Anhui Medical University, Hefei 230032, China.
| | - Utz Settmacher
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany.
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany.
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20
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Patel S, Hurez V, Nawrocki ST, Goros M, Michalek J, Sarantopoulos J, Curiel T, Mahalingam D. Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. Oncotarget 2016; 7:59087-59097. [PMID: 27463016 PMCID: PMC5312297 DOI: 10.18632/oncotarget.10824] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 06/30/2016] [Indexed: 12/20/2022] Open
Abstract
Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.
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Affiliation(s)
- Sukeshi Patel
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Vincent Hurez
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Steffan T. Nawrocki
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Martin Goros
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Joel Michalek
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - John Sarantopoulos
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Tyler Curiel
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Devalingam Mahalingam
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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21
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Wang Z, Wang X, Li J, Yang C, Xing Z, Chen R, Xu F. HMGB1 knockdown effectively inhibits the progression of rectal cancer by suppressing HMGB1 expression and promoting apoptosis of rectal cancer cells. Mol Med Rep 2016; 14:1026-32. [PMID: 27220399 DOI: 10.3892/mmr.2016.5340] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 05/03/2016] [Indexed: 11/05/2022] Open
Abstract
Rectal cancer is a malignant gastrointestinal tumor, which is associated with high morbidity and mortality. High‑mobility group protein 1 (HMGB1) is widely present in the nucleus of eukaryotic cells, and is highly conserved between humans and rodents. Recently, HMGB1 has been reported to be involved in the progression and metastasis of human cancer; however, its role in the development and metastasis of human rectal cancer remains unclear. The present study detected the expression levels of HMGB1 in pathological specimens from patients with clinically identified rectal cancer using immunohistochemistry and western blotting. The results demonstrated that HMGB1 was highly expressed in samples from patients with rectal cancer. The positive rate of HMGB1 in rectal cancer tissues was 96.08% (49/51), which was significantly higher compared with 3.92% (2/51) in normal tissues. In addition, western blotting indicated that HMGB1 was distributed and located not only in the nucleus, but also in the cytoplasm of colorectal cancer cells. HMGB1‑specific short hairpin (sh)RNA was used to silence the endogenous expression of HMGB1 in colorectal cancer cells. A functional assay demonstrated that knockdown of endogenous HMGB1 expression significantly inhibited the proliferation of SW620 and Colo320 cells. Furthermore, western blotting revealed that knockdown of endogenous HMGB1 expression contributed to activation of caspase‑3 and the substrate poly (ADP‑ribose) polymerase. The expression levels of B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) were also detected by western blotting. As expected, decreased levels of Bcl‑2 and increased levels of Bax were detected in the HMGB1 shRNA‑transfected colorectal cancer cells, and the Bax/Bcl‑2 ratio was increased in HMGB1 shRNA‑transfected cells. These data indicated that HMGB1 may act as an oncogene in rectal cancer, and knockdown of endogenous HMGB1 expression may significantly inhibit the proliferation of colorectal cancer cells and promote apoptosis of tumor cells. Further research regarding the mechanisms underlying the effects of HMGB1 on the progression of rectal cancer may provide novel targets for the treatment of rectal cancer, and provide a theoretical reference for clinical treatment.
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Affiliation(s)
- Zhiwei Wang
- Qingdao Medical College, Qingdao University, Qingdao, Shandong 266042, P.R. China
| | - Xiaoyan Wang
- Healthcare Ward, Qingdao Central Medical Group, Qingdao, Shandong 266042, P.R. China
| | - Jiantian Li
- Department of Gastrointestinal and Anorectal Surgery, Qingdao Central Medical Group, Qingdao, Shandong 266042, P.R. China
| | - Cheng Yang
- Department of Gastrointestinal and Anorectal Surgery, Qingdao Central Medical Group, Qingdao, Shandong 266042, P.R. China
| | - Zhiyuan Xing
- Qingdao Medical College, Qingdao University, Qingdao, Shandong 266042, P.R. China
| | - Ruiyun Chen
- Department of Gastrointestinal and Anorectal Surgery, Qingdao Central Medical Group, Qingdao, Shandong 266042, P.R. China
| | - Fei Xu
- Department of Gastrointestinal and Anorectal Surgery, Qingdao Central Medical Group, Qingdao, Shandong 266042, P.R. China
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22
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Huang J, Liu K, Song D, Ding M, Wang J, Jin Q, Ni J. Krüppel-like factor 4 promotes high-mobility group box 1-induced chemotherapy resistance in osteosarcoma cells. Cancer Sci 2016; 107:242-9. [PMID: 26676883 PMCID: PMC4814257 DOI: 10.1111/cas.12864] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 12/08/2015] [Accepted: 12/14/2015] [Indexed: 01/24/2023] Open
Abstract
Osteosarcoma is the most common primary malignant bone tumor, and the frequent acquisition of chemoresistance is often an obstacle to achieving favorable outcomes during chemotherapy. Recently, Krüppel-like factor 4 (KLF4) has been shown to be associated with chemotherapy resistance in a few tumors; however, the involvement of KLF4 in chemotherapy resistance in osteosarcoma cells remains unknown. In this study, quantitative real-time PCR and western blot analysis revealed that KLF4 expression was significantly increased in response to cisplatin, methotrexate and doxorubicin treatment in osteosarcoma cells, and knockdown of KLF4 increased sensitivity to these anticancer drugs by decreasing cellular clonogenic ability and increasing apoptosis. Moreover, our data suggest that KLF4-regulated drug resistance might, at least partially, positively regulate high-mobility group box 1 (HMGB1), which was found to be a significant contributor to chemoresistance in osteosarcoma cells in our previous study. In summary, this study highlights the significance of KLF4/HMGB1 interaction in regulating chemotherapy resistance, and suggests that targeting KLF4/high-mobility group box 1 may be a therapeutic strategy for osteosarcoma chemotherapy.
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Affiliation(s)
- Jun Huang
- Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha, China
| | - Ke Liu
- Department of Ophthalmology, The 2nd Xiangya Hospital, Central South University, Changsha, China
| | - Deye Song
- Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha, China
| | - Muliang Ding
- Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha, China
| | - Junjie Wang
- Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha, China
| | - Qingping Jin
- Department of Orthopaedics, The First People's Hospital of Xiangtan City, Xiangtan, China
| | - Jiangdong Ni
- Department of Orthopaedics, The 2nd Xiangya Hospital, Central South University, Changsha, China
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23
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Fretland AA, Sokolov A, Postriganova N, Kazaryan AM, Pischke SE, Nilsson PH, Rognes IN, Bjornbeth BA, Fagerland MW, Mollnes TE, Edwin B. Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial. Medicine (Baltimore) 2015; 94:e1786. [PMID: 26496309 PMCID: PMC4620756 DOI: 10.1097/md.0000000000001786] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial.This was a predefined exploratory substudy within the Oslo CoMet-study. Forty-five patients with CLM were randomized to laparoscopic (n = 23) or open (n = 22) resection. Ethylenediaminetetraacetic acid-plasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at -80 C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cell-free DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation.Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1β, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, C-reactive protein, and macrophage inflammatory protein -1β, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.Laparoscopic resection of CLM reduced the inflammatory response compared with open resection. The lower level of HMGB-1 is interesting because of the known association with oncogenesis.
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Affiliation(s)
- Aasmund Avdem Fretland
- From the Intervention Centre (AAF, NP, AMK, SEP, BE); Department of HPB surgery (AAF, BAB, BE); Department of Immunology, Oslo University Hospital, Oslo (AS, PHN, INR, TEM); Institute of Clinical Medicine (AAF, AMK, BE), University of Oslo, Oslo; Department of Surgery, Finnmark Hospital, Kirkenes (AMK); Division of Emergencies and Critical Care (SEP); Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo (MWF); Research Laboratory, Nordland Hospital, Bodo, and Faculty of Health Sciences, University of Tromso (TEM); and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (TEM)
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24
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Reeves R. High mobility group (HMG) proteins: Modulators of chromatin structure and DNA repair in mammalian cells. DNA Repair (Amst) 2015; 36:122-136. [PMID: 26411874 DOI: 10.1016/j.dnarep.2015.09.015] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
It has been almost a decade since the last review appeared comparing and contrasting the influences that the different families of High Mobility Group proteins (HMGA, HMGB and HMGN) have on the various DNA repair pathways in mammalian cells. During that time considerable progress has been made in our understanding of how these non-histone proteins modulate the efficiency of DNA repair by all of the major cellular pathways: nucleotide excision repair, base excision repair, double-stand break repair and mismatch repair. Although there are often similar and over-lapping biological activities shared by all HMG proteins, members of each of the different families appear to have a somewhat 'individualistic' impact on various DNA repair pathways. This review will focus on what is currently known about the roles that different HMG proteins play in DNA repair processes and discuss possible future research areas in this rapidly evolving field.
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Affiliation(s)
- Raymond Reeves
- School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-4660, USA.
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25
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Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med 2014; 40:1-116. [PMID: 25010388 PMCID: PMC4254084 DOI: 10.1016/j.mam.2014.05.001] [Citation(s) in RCA: 742] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
| | - Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Sha Wu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhengwen Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xiaofang Sun
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Qiu G, Li Y, Liu Z, Wang M, Ge J, Bai X. Clinical value of serum HMGB1 in diagnosis and prognosis of laryngeal squamous cell carcinoma. Med Oncol 2014; 31:316. [DOI: 10.1007/s12032-014-0316-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 10/30/2014] [Indexed: 01/15/2023]
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Srinivasan M, Banerjee S, Palmer A, Zheng G, Chen A, Bosland MC, Kajdacsy-Balla A, Kalyanasundaram R, Munirathinam G. HMGB1 in hormone-related cancer: a potential therapeutic target. Discov Oncol 2014; 5:127-39. [PMID: 24718937 DOI: 10.1007/s12672-014-0175-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 03/20/2014] [Indexed: 02/06/2023] Open
Abstract
High-mobility group box 1 (HMGB1) is a dynamic nuclear protein participating in transcription, chromatin remodelling, and DNA recombination and repair processes. Accumulating evidence indicates that its function now extends beyond the nucleus, notably its extracellular role in inflammation. HMGB1 is implicated as a late mediator of sepsis and is also believed to promote atherosclerosis and other inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus. Interestingly, deregulation of HMGB1 is shown to be associated with the hallmarks of cancer development. Moreover, several clinical studies have shown that HMGB1 is a promising biomarker for a variety of cancer types. In this review, we provide novel insights into the role and mechanisms of HMGB1, in particular, to hormone-related cancers and its potential to serve as a therapeutic target.
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Affiliation(s)
- Madhuwanti Srinivasan
- Department of Biomedical Sciences, University of Illinois, College of Medicine, 1601 Parkview Ave, Rockford, IL, 61107, USA
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The chemosensitivity of testicular germ cell tumors. Cell Oncol (Dordr) 2014; 37:79-94. [PMID: 24692098 DOI: 10.1007/s13402-014-0168-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2014] [Indexed: 12/13/2022] Open
Abstract
Although rare cancers overall, testicular germ cell tumors (TGCTs) are the most common type of cancer in young males below 40 years of age. Both subtypes of TGCTs, i.e., seminomas and non-seminomas, are highly curable and the majority of even metastatic patients may expect to be cured. These high cure rates are not due to the indolent nature of these cancers, but rather to their sensitivity to chemotherapy (and for seminomas to radiotherapy). The delineation of the cause of chemosensitivity at the molecular level is of paramount importance, because it may provide insights into the minority of TGCTs that are chemo-resistant and, thereby, provide opportunities for specific therapeutic interventions aimed at reverting them to chemosensitivity. In addition, delineation of the molecular basis of TGCT chemo-sensitivity may be informative for the cause of chemo-resistance of other more common types of cancer and, thus, may create new therapeutic leads. p53, a frequently mutated tumor suppressor in cancers in general, is not mutated in TGCTs, a fact that has implications for their chemo-sensitivity. Oct4, an embryonic transcription factor, is uniformly expressed in the seminoma and embryonic carcinoma components of non-seminomas, and its interplay with p53 may be important in the chemotherapy response of these tumors. This interplay, together with other features of TGCTs such as the gain of genetic material from the short arm of chromosome 12 and the association with disorders of testicular development, will be discussed in this paper and integrated in a unifying hypothesis that may explain their chemo-sensitivity.
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Schonewolf CA, Mehta M, Schiff D, Wu H, Haffty BG, Karantza V, Jabbour SK. Autophagy inhibition by chloroquine sensitizes HT-29 colorectal cancer cells to concurrent chemoradiation. World J Gastrointest Oncol 2014; 6:74-82. [PMID: 24653797 PMCID: PMC3955781 DOI: 10.4251/wjgo.v6.i3.74] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 01/16/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate whether the inhibition of autophagy by chloroquine (CQ) sensitizes rectal tumors to radiation therapy (RT) or concurrent chemoradiation (chemoRT).
METHODS: In vitro, HCT-116 and HT-29 colorectal cancer (CRC) cell lines were treated as following: (1) PBS; (2) CQ; (3) 5-fluorouracil (5-FU); (4) RT; (5) CQ and RT; (6) 5-FU and RT; (7) CQ and 5-FU; and (8) 5-FU and CQ and RT. Each group was then exposed to various doses of radiation (0-8 Gy) depending on the experiment. Cell viability and proliferative capacity were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assays. Clonogenic survival curves were constructed and compared across treatment groups. Autophagy status was determined by assessing the LC3-II to LC3-I ratio on western blot analysis, autophagosome formation on electron microscopy and identification of a perinuclear punctate pattern with GFP-labeled LC3 on fluorescence microscopy. Cell cycle arrest and cell death were evaluated by FACS and Annexin V analysis. All experiments were performed in triplicate and statistical analysis was performed by the student’s t test to compare means between treatment groups.
RESULTS: RT (2-8 Gy) induced autophagy in HCT-116 and HT-29 CRC cell lines at 4 and 6 h post-radiation, respectively, as measured by increasing LC3-II to LC3-I ratio on western blot. Additionally, electron microscopy demonstrated autophagy induction in HT-29 cells 24 h following irradiation at a dose of 8 Gy. Drug treatment with 5-FU (25 μmol/L) induced autophagy and the combination of 5-FU and RT demonstrated synergism in autophagy induction. CQ (10 μmol/L) alone and in combination with RT effectively inhibited autophagy and sensitized both HCT-116 and HT-29 cells to treatment with radiation (8 Gy; P < 0.001 and 0.00001, respectively). Significant decrease in clonogenic survival was seen only in the HT-29 cell line, when CQ was combined with RT at doses of 2 and 8 Gy (P < 0.5 and P = 0.05, respectively). There were no differences in cell cycle progression or Annexin V staining upon CQ addition to RT.
CONCLUSION: Autophagy inhibition by CQ increases CRC cell sensitivity to concurrent treatment with 5-FU and RT in vitro, suggesting that addition of CQ to chemoRT improves CRC treatment response.
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Xiong XD, Wang J, Zheng H, Jing X, Liu Z, Zhou Z, Liu X. Identification of FAM96B as a novel prelamin A binding partner. Biochem Biophys Res Commun 2013; 440:20-4. [PMID: 24041693 DOI: 10.1016/j.bbrc.2013.08.099] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 08/30/2013] [Indexed: 12/20/2022]
Abstract
Prelamin A accumulation causes nuclear abnormalities, impairs nuclear functions, and eventually promotes cellular senescence. However, the underlying mechanism of how prelamin A promotes cellular senescence is still poorly understood. Here we carried out a yeast two-hybrid screen using a human skeletal muscle cDNA library to search for prelamin A binding partners, and identified FAM96B as a prelamin A binding partner. The interaction of FAM96B with prelamin A was confirmed by GST pull-down and co-immunoprecipitation experiments. Furthermore, co-localization experiments by fluorescent confocal microscopy revealed that FAM96B colocalized with prelamin A in HEK-293 cells. Taken together, our data demonstrated the physical interaction between FAM96B and prelamin A, which may provide some clues to the mechanisms of prelamin A in premature aging.
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Affiliation(s)
- Xing-Dong Xiong
- Institute of Aging Research, Guangdong Medical College, Dongguan 523808, PR China; Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023, PR China; Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan 523808, PR China
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Li G, Tang D, Lotze MT. Ménage à Trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol 2013; 23:380-90. [PMID: 23994764 DOI: 10.1016/j.semcancer.2013.08.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/08/2013] [Accepted: 08/20/2013] [Indexed: 12/30/2022]
Abstract
Cells have evolved rather sophisticated mechanisms to deal with stress positively and efficiently. Accumulation of reactive oxygen species (ROS), release of damage-associated molecular pattern molecule (DAMPs), and autophagy induction, are three inter-related processes occurring during most if not all cellular adaptations to stress. They influence each other reciprocally, initiating individual pathways, mediating and/or inducing effector mechanisms and modifying cellular function. High-mobility group box 1 (HMGB1), is a prototypic DAMP molecule, with various roles depending on its compartmental localization (nuclear, cytosolic, extracellular), well-defined but rather promiscuous binding partners, and the redox status within or without the cell. Typically, HMGB1 serves as a redox sensor, where redox modification also defines its translocation, release and activity, illustrative of the coordinate and multiply determined paths involved in the response to cell stress. Since DAMPs, redox and autophagy are essential and multifaceted in their roles in host defense, inflammation, and homeostasis, understanding how they interact and coordinate various signaling pathways to adjust to the stressful environment is important in the development of various potential therapeutic strategies, including application to patients with cancer.
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Affiliation(s)
- Guanqiao Li
- Department of Surgery, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, United States; Department of Immunology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, United States; Tsinghua University, School of Medicine, Beijing, China
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The multifunctional alarmin HMGB1 with roles in the pathophysiology of sepsis and cancer. Immunol Cell Biol 2013; 91:443-50. [PMID: 23797067 DOI: 10.1038/icb.2013.25] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 05/11/2013] [Accepted: 05/12/2013] [Indexed: 12/20/2022]
Abstract
Although originally described as a highly conserved nuclear protein involved in DNA replication, transcription and repair, high-mobility group box-1 protein (HMGB1) has emerged as a key mediator in the regulation of immune responses to infection and sterile injury by exhibiting all the properties of a prototypic 'alarmin'. These include rapid passive release in response to pathogenic infection and/or traumatic injury, active secretion providing for chemotactic and cytokine-like function and an ability to resolve inflammation, including tissue repair and remodelling. In this review, we will give an overview of the post-translational modifications necessary for such diversity in biological activity, concentrating particularly on how differences in oxidation of highly conserved redox-sensitive cysteine residues can potentiate inflammatory responses and dictate cellular fate. We will also review the most recent literature on HMGB1 and its involvement in the pathophysiology of sepsis and cancer, as well as cancer therapy-induced mucositis.
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