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Nguyen MU, Iqbal J, Potgieter S, Huang W, Pfeffer J, Woo S, Zhao C, Lawlor M, Yang R, Rizly R, Halstead A, Dent S, Sáenz JB, Zheng H, Yuan ZF, Sidoli S, Ellison CE, P. Verzi M. KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal. SCIENCE ADVANCES 2024; 10:eadl1584. [PMID: 39110797 PMCID: PMC11305398 DOI: 10.1126/sciadv.adl1584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 07/02/2024] [Indexed: 08/10/2024]
Abstract
Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and sequencing of immunoprecipitated double-stranded RNA were used to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions and maintaining intestinal health.
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Affiliation(s)
- Mai-Uyen Nguyen
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Jahangir Iqbal
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Sarah Potgieter
- Department of Animal Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Winston Huang
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Julie Pfeffer
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Sean Woo
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Caifeng Zhao
- Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Matthew Lawlor
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Richard Yang
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Rahma Rizly
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Angela Halstead
- Division of Gastroenterology, Departments of Medicine and Molecular Cell Biology, Washington University in St. Louis, St. Louis, MO, USA
| | - Sharon Dent
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - José B. Sáenz
- Division of Gastroenterology, Departments of Medicine and Molecular Cell Biology, Washington University in St. Louis, St. Louis, MO, USA
| | - Haiyan Zheng
- Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Zuo-Fei Yuan
- St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Simone Sidoli
- Albert Einstein College of Medicine, The Bronx, NY, USA
| | - Christopher E. Ellison
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Michael P. Verzi
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
- Human Genetics Institute of New Jersey, Rutgers Cancer Institute of New Jersey, Rutgers Center for Lipid Research, Division of Environmental & Population Health Biosciences, EOHSI, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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Nguyen MU, Potgieter S, Huang W, Pfeffer J, Woo S, Zhao C, Lawlor M, Yang R, Halstead A, Dent S, Sáenz JB, Zheng H, Yuan ZF, Sidoli S, Ellison CE, Verzi M. KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.04.556156. [PMID: 37732252 PMCID: PMC10508741 DOI: 10.1101/2023.09.04.556156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.
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Affiliation(s)
- Mai-Uyen Nguyen
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Sarah Potgieter
- Department of Animal Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Winston Huang
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Julie Pfeffer
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Sean Woo
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Caifeng Zhao
- Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Matthew Lawlor
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Richard Yang
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Angela Halstead
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Sharon Dent
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - José B. Sáenz
- Division of Gastroenterology, Departments of Medicine and Molecular Cell Biology, Washington University in St. Louis, St. Louis, MO
| | - Haiyan Zheng
- Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ
| | - Zuo-Fei Yuan
- St. Jude Children’s Research Hospital, Memphis, TN
| | | | | | - Michael Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers Cancer Institute of New Jersey, Rutgers Center for Lipid Research, Division of Environmental & Population Health Biosciences, EOHSI, Rutgers, The State University of New Jersey, Piscataway, NJ
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Yang C, Yang F, Chen X, Li Y, Hu X, Guo J, Yao J. Overexpression of complement C5a indicates poor survival and therapeutic response in metastatic renal cell carcinoma. Int J Biol Markers 2023; 38:124-132. [PMID: 36883235 DOI: 10.1177/03936155231161366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
INTRODUCTION Complement C5a is an important component of the innate immune system. An increasing number of reports have revealed the relevance of C5a in tumor progression; however, its exact role in metastatic renal cell carcinoma (mRCC) remains unknown. METHODS We evaluated C5a expression in tumor tissue microarrays of 231 mRCC patients and analyzed the relationship between C5a levels and clinical outcomes, and the expression of epithelial-mesenchymal transition (EMT)-related proteins, programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). In-vitro functional experiments using exogenous C5a stimulation and C5a silencing in renal cell carcinoma cells were used to validate the tissue findings. RESULTS High C5a expression was associated with poor therapeutic responses, poor overall and progression-free survival, and high expression of EMT-related proteins and PD-1/PD-L1 in mRCC patients. Exogenous C5a promoted proliferation, migration, and invasion of renal cell carcinoma cells, and induced the expression of EMT-related proteins and PD-1/PD-L1. Conversely, C5a silencing inhibited migration and invasion of renal cell carcinoma cells and decreased the expression of EMT-related proteins and PD-1/PD-L1. CONCLUSIONS Our findings indicate that elevated C5a expression is associated with poor outcomes in patients with mRCC, and this effect may be partly attributed to the ability of C5a to promote EMT and PD-1/PD-L1 expression. C5a may be a potential novel target for the treatment of mRCC.
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Affiliation(s)
- Changjun Yang
- Department of Urology, Hexi University Affiliated Zhangye People's Hospital, Gansu, China
- Institute of Urology, Hexi University, Zhangye Gansu, China
| | - Faying Yang
- Department of Urology, Hexi University Affiliated Zhangye People's Hospital, Gansu, China
- Institute of Urology, Hexi University, Zhangye Gansu, China
| | - Xiang Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunpeng Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoyi Hu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianming Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiaxi Yao
- Department of Urology, Hexi University Affiliated Zhangye People's Hospital, Gansu, China
- Institute of Urology, Hexi University, Zhangye Gansu, China
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Si Y, Xu J, Meng L, Wu Y, Qi J. Role of STAT3 in the pathogenesis of nasopharyngeal carcinoma and its significance in anticancer therapy. Front Oncol 2022; 12:1021179. [PMID: 36313702 PMCID: PMC9615247 DOI: 10.3389/fonc.2022.1021179] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/27/2022] [Indexed: 11/25/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a type of head and neck tumor with noticeable regional and ethnic differences. It is associated with Epstein-Barr virus infection and has a tendency for local and distant metastasis. NPC is also highly sensitive to radiotherapy and chemotherapy. Over 70% of patients present with locoregionally advanced disease, and distant metastasis is the primary reason for treatment failure. A signal transducer and activator of transcription 3 (STAT3) promotes NPC oncogenesis through mechanisms within cancerous cells and their interactions with the tumor microenvironment, which is critical in the initiation, progression, and metastasis of NPC. Further, p-STAT3 is strongly associated with advanced NPC. Recent research on STAT3 has focused on its expression at the center of various oncogenic pathways. Here, we discuss the role of STAT3 in NPC and its potential therapeutic inhibitors and analogs for the treatment and control of NPC.
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Xiong J, Kuang X, Lu T, Yu K, Liu X, Zhang Z, Wang W, Zhao L, Fang Q, Wu D, Wang J. C3a and C5a facilitates the metastasis of myeloma cells by activating Nrf2. Cancer Gene Ther 2021; 28:265-278. [PMID: 32873871 DOI: 10.1038/s41417-020-00217-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 11/09/2022]
Abstract
Multiple myeloma (MM) is still an incurable hematological malignancy, with even poorer prognosis in MM patients with distant invasion. The present study was designed to explore the effects of C3a and C5a on the migration, invasion, and adhesion of MM tumor cells and to investigate the underlying mechanisms. As a result, the levels of C3a and C5a in plasma of MM patients were significantly higher than those of healthy donors. Consistently, the expression of C3a and C5a receptors on myeloma cells of MM patients was also significantly higher than that on sorted plasma cells of normal donors. C3a and C5a have been confirmed to increase the migration, invasion and adhesion of MM cell lines by activating the MEK/ERK pathway and increasing the nuclear transfer of Nrf2 in vitro. Moreover, the MM cell line U266 with Nrf2 downregulation was incubated with C3a and C5a, followed by injection into the tail vein of NOD-SCID mice. We found that Nrf2 downregulation attenuated the migration of anaphylatoxin C3a and C5a to MM tumor cells in bone marrow, liver and lung in vivo. In conclusion, our results indicate that activation of the complement cascade in MM patients may contribute to the migration, invasion and adhesion of MM cells, and this type of tumor cells dissemination in MM is, at least partially, regulated by Nrf2. Thereby, complement suppression or Nrf2 downregulation might offer a novel therapeutic opportunity for MM.
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Affiliation(s)
- Jie Xiong
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Xingyi Kuang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Tingting Lu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Kunlin Yu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Xu Liu
- Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China
| | - Zhaoyuan Zhang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Weili Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Lu Zhao
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Qin Fang
- Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China
| | - Depei Wu
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China.
| | - Jishi Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China.
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Non-histone protein acetylation by the evolutionarily conserved GCN5 and PCAF acetyltransferases. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1864:194608. [PMID: 32711095 DOI: 10.1016/j.bbagrm.2020.194608] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 01/08/2023]
Abstract
GCN5, conserved from yeast to humans, and the vertebrate specific PCAF, are lysine acetyltransferase enzymes found in large protein complexes. Both enzymes have well documented roles in the histone acetylation and the concomitant regulation of transcription. However, these enzymes also acetylate non-histone substrates to impact diverse aspects of cell physiology. Here, I review our current understanding of non-histone acetylation by GCN5 and PCAF across eukaryotes, from target identification to molecular mechanism and regulation. I focus mainly on budding yeast, where Gcn5 was first discovered, and mammalian systems, where the bulk of non-histone substrates have been characterized. I end the review by defining critical caveats and open questions that apply to all models.
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Zhang L, Wang W, Zhang S, Wang Y, Guo W, Liu Y, Wang Y, Zhang Y. Identification of lysine acetylome in cervical cancer by label-free quantitative proteomics. Cancer Cell Int 2020; 20:182. [PMID: 32489318 PMCID: PMC7247262 DOI: 10.1186/s12935-020-01266-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lysine acetylation is a post-translational modification that regulates a diversity of biological processes, including cancer development. METHODS Here, we performed the quantitative acetylproteomic analysis of three primary cervical cancer tissues and corresponding adjacent normal tissues by using the label-free proteomics approach. RESULTS We identified a total of 928 lysine acetylation sites from 1547 proteins, in which 495 lysine acetylation sites corresponding to 296 proteins were quantified. Further, 41 differentially expressed lysine acetylation sites corresponding to 30 proteins were obtained in cervical cancer tissues compared with adjacent normal tissues (Fold change > 2 and P < 0.05), of which 1 was downregulated, 40 were upregulated. Moreover, 75 lysine acetylation sites corresponding to 58 proteins were specifically detected in cancer tissues or normal adjacent tissues. Motif-X analysis showed that kxxxkxxxk, GkL, AxxEk, kLxE, and kkxxxk are the most enriched motifs with over four-fold increases when compared with the background matches. KEGG analysis showed that proteins identified from differently and specifically expressed peptides may influence key pathways, such as Notch signaling pathway, viral carcinogenesis, RNA transport, and Jak-STAT, which play an important role in tumor progression. Furthermore, the acetylated levels of CREBBP and S100A9 in cervical cancer tissues were confirmed by immunoprecipitation (IP) and Western blot analysis. CONCLUSIONS Taken together, our data provide novel insights into the role of protein lysine acetylation in cervical carcinogenesis.
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Affiliation(s)
- Lu Zhang
- Department of Gynecology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081 Heilongjiang Province China
| | - Wanyue Wang
- School of Basic Medical Sciences, Qiqihar Medical University, Qiqihar, 161006 Heilongjiang China
| | - Shanqiang Zhang
- Medical Research Center, Yue Bei People’s Hospital Affiliated to Shantou University Medical College, Shaoguan, 512025 Guangdong China
| | - Yuxin Wang
- Department of Gynecology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081 Heilongjiang Province China
| | - Weikang Guo
- Department of Gynecology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081 Heilongjiang Province China
| | - Yunduo Liu
- Department of Gynecology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081 Heilongjiang Province China
| | - Yaoxian Wang
- Department of Gynecology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081 Heilongjiang Province China
| | - Yunyan Zhang
- Department of Gynecology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081 Heilongjiang Province China
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Ghanbari M, Safaralizadeh R, Mohammadi K. A Review on Important Histone Acetyltransferase (HAT) Enzymes as Targets for Cancer Therapy. CURRENT CANCER THERAPY REVIEWS 2019. [DOI: 10.2174/1573394714666180720152100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
At the present time, cancer is one of the most lethal diseases worldwide. There are various factors involved in the development of cancer, including genetic factors, lifestyle, nutrition, and so on. Recent studies have shown that epigenetic factors have a critical role in the initiation and development of tumors. The histone post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and other PTMs are important mechanisms that regulate the status of chromatin structure and this regulation leads to the control of gene expression. The histone acetylation is conducted by histone acetyltransferase enzymes (HATs), which are involved in transferring an acetyl group to conserved lysine amino acids of histones and consequently increase gene expression. On the basis of similarity in catalytic domains of HATs, these enzymes are divided into different groups such as families of GNAT, MYST, P300/CBP, SRC/P160, and so on. These enzymes have effective roles in apoptosis, signaling pathways, metastasis, cell cycle, DNA repair and other related mechanisms deregulated in cancer. Abnormal activation of HATs leads to uncontrolled amplification of cells and incidence of malignancy signs. This indicates that HAT might be an important target for effective cancer treatments, and hence there would be a need for further studies and designing of therapeutic drugs on this basis. In this study, we have reviewed the important roles of HATs in different human malignancies.
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Affiliation(s)
- Mohammad Ghanbari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Kiyanoush Mohammadi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
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Pio R, Ajona D, Ortiz-Espinosa S, Mantovani A, Lambris JD. Complementing the Cancer-Immunity Cycle. Front Immunol 2019; 10:774. [PMID: 31031765 PMCID: PMC6473060 DOI: 10.3389/fimmu.2019.00774] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/25/2019] [Indexed: 12/12/2022] Open
Abstract
Reactivation of cytotoxic CD8+ T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits. To find the best combinations, it is of upmost importance to understand the interplay between cancer cells and all the components of the immune response. This review focuses on the elements of the complement system that come into play in the cancer-immunity cycle. The complement system, an essential part of innate immunity, has emerged as a major regulator of cancer immunity. Complement effectors such as C1q, anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1, have been associated with tolerogenic cell death and inhibition of antitumor T-cell responses through the recruitment and/or activation of immunosuppressive cell subpopulations such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or M2 tumor-associated macrophages (TAMs). Evidence is provided to support the idea that complement blocks many of the effector routes associated with the cancer-immunity cycle, providing the rationale for new therapeutic combinations aimed to enhance the antitumor efficacy of anti-PD-1/PD-L1 checkpoint inhibitors.
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Affiliation(s)
- Ruben Pio
- Program in Solid Tumors (CIMA) and Department of Biochemistry and Genetics (School of Medicine), University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Daniel Ajona
- Program in Solid Tumors (CIMA) and Department of Biochemistry and Genetics (School of Medicine), University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Sergio Ortiz-Espinosa
- Program in Solid Tumors (CIMA) and Department of Biochemistry and Genetics (School of Medicine), University of Navarra, Pamplona, Spain
| | - Alberto Mantovani
- Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
- William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - John D. Lambris
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
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10
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Yoneda M, Imamura R, Nitta H, Taniguchi K, Saito F, Kikuchi K, Ogi H, Tanaka T, Katabuchi H, Nakayama H, Imamura T. Enhancement of cancer invasion and growth via the C5a-C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion. Oncol Lett 2018; 17:913-920. [PMID: 30655847 PMCID: PMC6313068 DOI: 10.3892/ol.2018.9715] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 10/26/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune diseases are caused by immune complex-induced activation of the complement system and subsequent inflammation. Recent studies have revealed an association between autoimmune diseases and worse survival in patients with cancer; however, the underlying mechanism is still unknown. The C5a-C5a receptor (C5aR) system has been shown to enhance cancer activity and recruit myeloid-derived suppressor cells (MDSCs) that suppress the anti-tumor immune response. The Arthus reaction is inflammation caused by complement system activation by the immune complex and thus is a model of autoimmune diseases. To explore the effect of the Arthus reaction on cancer progression, mouse cancer cells were inoculated in syngeneic mouse skin, where the Arthus reaction was induced simultaneously. The Arthus reaction enhanced invasion and tumor growth of C5aR-positive cancer cells, but not control cells, and induced MDSC recruitment. Intravenous injection of C5a-stimulated C5aR-positive cancer cells into nude mice resulted in more lung nodules than injection of nontreated C5aR-positive cells and C5a-stimulated C5aR-negative cells, supporting C5a-C5aR-mediated enhancement of cancer growth. C5aR expression in uterine cervical carcinoma stage I cells, which invade into the deeper tissues, was significantly higher than that in CIN3 cells, which remain in the epithelium. These results indicate that cancer promotion by the C5a-C5aR system may underlie poor prognosis in cancer patients with autoimmune diseases, particularly in patients with C5aR-positive cancer, and may be associated with cervical cancer invasion. The enhancement of cancer cell invasion and growth by the C5a-C5aR system suggests that this system is a possible target of cancer therapy.
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Affiliation(s)
- Masakazu Yoneda
- Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.,Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Ryuji Imamura
- Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.,Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hidetoshi Nitta
- Department of Gastroenterological Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Keisuke Taniguchi
- Pharmaceutical Research Department, Yakult Central Institute for Microbiological Research, Tokyo 186-8650, Japan
| | - Fumitaka Saito
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Ken Kikuchi
- Operations Division, Sakurajyuji Hospital, Kumamoto 861-4173, Japan
| | - Hidenao Ogi
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Takuya Tanaka
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hidetaka Katabuchi
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideki Nakayama
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Takahisa Imamura
- Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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11
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C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation. Oncogene 2018; 37:4821-4837. [PMID: 29773900 PMCID: PMC6117268 DOI: 10.1038/s41388-018-0298-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 03/23/2018] [Accepted: 04/13/2018] [Indexed: 12/21/2022]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.
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12
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Apigenin inhibits C5a-induced proliferation of human nasopharyngeal carcinoma cells through down-regulation of C5aR. Biosci Rep 2018; 38:BSR20180456. [PMID: 29685955 PMCID: PMC6048209 DOI: 10.1042/bsr20180456] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/20/2018] [Accepted: 04/23/2018] [Indexed: 01/23/2023] Open
Abstract
Complement 5a (C5a) is able to induce the proliferation of human nasopharyngeal carcinoma (NPC) cells. Therefore, an effective method or drug that can specifically inhibit C5a-induced proliferation of human NPC cells needs to be developed. Reportedly, Apigenin has antiproliferative effects on a variety of cancer cells. However, the effect of Apigenin on NPC cell proliferation and its underlying mechanism are still unclear. Herein, the present study aimed to evaluate the effect of Apigenin on C5a-induced proliferation of human NPC cells and its possible mechanism through down-regulation of C5aR. We revealed that Apigenin in vitro could not only inhibit proliferation of NPC cells and but also reduce the expression of C5aR and P300/CBP-associated factor (PCAF) as well as the activation of signal transducer and activator of transcription 3 (STAT3) in NPC cells. Furthermore, Apigenin reduced the proliferation of human NPC cells triggered by C5a through negative regulation of C5aR/PCAF/STAT3 axis. These might provide a new insight into the function of Apigenin in cancer treatment, and also provide a potential strategy for treating human NPC through inhibition of C5aR expression on cancer cells.
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13
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Bondy-Chorney E, Denoncourt A, Sai Y, Downey M. Nonhistone targets of KAT2A and KAT2B implicated in cancer biology 1. Biochem Cell Biol 2018; 97:30-45. [PMID: 29671337 DOI: 10.1139/bcb-2017-0297] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Lysine acetylation is a critical post-translation modification that can impact a protein's localization, stability, and function. Originally thought to only occur on histones, we now know thousands of nonhistone proteins are also acetylated. In conjunction with many other proteins, lysine acetyltransferases (KATs) are incorporated into large protein complexes that carry out these modifications. In this review we focus on the contribution of two KATs, KAT2A and KAT2B, and their potential roles in the development and progression of cancer. Systems biology demands that we take a broad look at protein function rather than focusing on individual pathways or targets. As such, in this review we examine KAT2A/2B-directed nonhistone protein acetylations in cancer in the context of the 10 "Hallmarks of Cancer", as defined by Hanahan and Weinberg. By focusing on specific examples of KAT2A/2B-directed acetylations with well-defined mechanisms or strong links to a cancer phenotype, we aim to reinforce the complex role that these enzymes play in cancer biology.
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Affiliation(s)
- Emma Bondy-Chorney
- Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada.,Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada
| | - Alix Denoncourt
- Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada.,Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada
| | - Yuka Sai
- Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada.,Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada
| | - Michael Downey
- Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada.,Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, 451 Smyth Rd., Ottawa, ON KIH 8M5, Canada
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14
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Gallenkamp J, Spanier G, Wörle E, Englbrecht M, Kirschfink M, Greslechner R, Braun R, Schäfer N, Bauer RJ, Pauly D. A novel multiplex detection array revealed systemic complement activation in oral squamous cell carcinoma. Oncotarget 2017; 9:3001-3013. [PMID: 29423024 PMCID: PMC5790441 DOI: 10.18632/oncotarget.22963] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/11/2017] [Indexed: 11/25/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common tumors within the oral cavity. Early diagnosis and prognosis tools are urgently needed. This study aimed to investigate the activation of the complement system in OSCC patients as potential biomarker. Therefore, an innovative complement activation array was developed. Characterized antibodies detecting the complement activation specific epitopes C3a, C5a and sC5b-9 along with control antibodies were implemented into a suspension bead array. Human serum from a healthy (n = 46) and OSCC patient (n = 57) cohort were used to investigate the role of complement activation in oral tumor progression. The novel multiplex assay detected C3a, C5a and sC5b-9 from a minimal sample volume of human tears, aqueous humor and blood samples. Limits of detection were 0.04 ng/mL for C3a, 0.03 ng/mL for C5a and 18.9 ng/mL for sC5b-9, respectively. Biological cut-off levels guaranteed specific detections from serum. The mean serum concentration of a healthy control cohort was 680 ng/mL C3a, 70 ng/mL C5a and 2247 ng/mL sC5b-9, respectively. The assay showed an intra-assay precision of 2.9-6.4% and an inter-assay precision of 9.2-18.2%. Increased systemic C5a (p < 0.0001) and sC5b-9 (p = 0.01) concentrations in OSCC patients were determined using the validated multiplex complement assay. Higher C5a concentrations correlated with tumor differentiation and OSCC extension state. Systemic sC5b-9 determination provided a novel biomarker for infiltrating tumor growth and C3a levels were associated with local tumor spreading. Our study suggests that systemic complement activation levels in OSCC patients may be useful to assess disease progression.
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Affiliation(s)
- Juliane Gallenkamp
- University Hospital Regensburg, Department of Oral and Maxillofacial Surgery, Regensburg, Germany
| | - Gerrit Spanier
- University Hospital Regensburg, Department of Oral and Maxillofacial Surgery, Regensburg, Germany
| | - Elisabeth Wörle
- University Hospital Regensburg, Department of Ophthalmology, Regensburg, Germany
| | - Markus Englbrecht
- University Hospital Regensburg, Department of Ophthalmology, Regensburg, Germany
| | | | - Roman Greslechner
- University Hospital Regensburg, Department of Ophthalmology, Regensburg, Germany
| | - Regine Braun
- University Hospital Regensburg, Department of Ophthalmology, Regensburg, Germany
| | - Nicole Schäfer
- University Hospital Regensburg, Department of Ophthalmology, Regensburg, Germany
| | - Richard J Bauer
- University Hospital Regensburg, Department of Oral and Maxillofacial Surgery, Regensburg, Germany.,Center for Medical Biotechnology, Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Diana Pauly
- University Hospital Regensburg, Department of Ophthalmology, Regensburg, Germany
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15
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Berraondo P, Minute L, Ajona D, Corrales L, Melero I, Pio R. Innate immune mediators in cancer: between defense and resistance. Immunol Rev 2017; 274:290-306. [PMID: 27782320 DOI: 10.1111/imr.12464] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic inflammation in the tumor microenvironment and evasion of the antitumor effector immune response are two of the emerging hallmarks required for oncogenesis and cancer progression. The innate immune system not only plays a critical role in perpetuating these tumor-promoting hallmarks but also in developing antitumor adaptive immune responses. Thus, understanding the dual role of the innate system in cancer immunology is required for the design of combined immunotherapy strategies able to tackle established tumors. Here, we review recent advances in the understanding of the role of cell populations and soluble components of the innate immune system in cancer, with a focus on complement, the adapter molecule Stimulator of Interferon Genes, natural killer cells, myeloid cells, and B cells.
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Affiliation(s)
- Pedro Berraondo
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
| | - Luna Minute
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
| | - Daniel Ajona
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Program of Solid Tumors and Biomarkers, CIMA, Pamplona, Spain.,Deparment of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | | | - Ignacio Melero
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
| | - Ruben Pio
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain. .,Program of Solid Tumors and Biomarkers, CIMA, Pamplona, Spain. .,Deparment of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
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16
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Nan J, Hu H, Sun Y, Zhu L, Wang Y, Zhong Z, Zhao J, Zhang N, Wang Y, Wang Y, Ye J, Zhang L, Hu X, Zhu W, Wang J. TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression. Circ Res 2017. [PMID: 28637784 PMCID: PMC5542782 DOI: 10.1161/circresaha.117.311143] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Supplemental Digital Content is available in the text. Rationale: Mitochondria are important cellular organelles and play essential roles in maintaining cell structure and function. Emerging evidence indicates that in addition to having proinflammatory and proapoptotic effects, TNFα (tumor necrosis factor α) can, under certain circumstances, promote improvements in mitochondrial integrity and function, phenomena that can be ascribed to the existence of TNFR2 (TNFα receptor 2). Objective: The present study aimed to investigate whether and how TNFR2 activation mediates the effects of TNFα on mitochondria. Methods and Results: Freshly isolated neonatal mouse cardiac myocytes treated with shRNA targeting TNFR1 were used to study the effects of TNFR2 activation on mitochondrial function. Neonatal mouse cardiac myocytes exhibited increases in mitochondrial fusion, a change that was associated with increases in mitochondrial membrane potential, intracellular ATP levels, and oxygen consumption capacity. Importantly, TNFR2 activation–induced increases in OPA1 (optic atrophy 1) protein expression were responsible for the above enhancements, and these changes could be attenuated using siRNA targeting OPA1. Moreover, both Stat3 and RelA bound to the promoter region of OPA1 and their interactions synergistically upregulated OPA1 expression at the transcriptional level. Stat3 acetylation at lysine 370 or lysine 383 played a key role in the ability of Stat3 to form a supercomplex with RelA. Meanwhile, p300 modulated Stat3 acetylation in HEK293T (human embryonic kidney 293T) cells, and p300-mediated Stat3/RelA interactions played an indispensable role in OPA1 upregulation. Finally, TNFR2 activation exerted beneficial effects on OPA1 expression in an in vivo transverse aortic constriction model, whereby TNFR1-knockout mice exhibited better outcomes than in mice with both TNFR1 and TNFR2 knocked out. Conclusions: TNFR2 activation protects cardiac myocytes against stress by upregulating OPA1 expression. This process was facilitated by p300-mediated Stat3 acetylation and Stat3/RelA interactions, leading to improvements in mitochondrial morphology and function.
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Affiliation(s)
- Jinliang Nan
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hengxun Hu
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yong Sun
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lianlian Zhu
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yingchao Wang
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhiwei Zhong
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Zhao
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Na Zhang
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ya Wang
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaping Wang
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Ye
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ling Zhang
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyang Hu
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Zhu
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian'an Wang
- From the Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology (J.N., H.H., Y.S., L.Z., Y.W., Z.Z., J.Z., N.Z., Y.W., Y.W., J.Y., L.Z., X.H., W.Z., J.W.) and Clinical Research Center (L.Z., Y.W., Z.Z., J.Z.), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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17
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Laguesse S, Close P, Van Hees L, Chariot A, Malgrange B, Nguyen L. Loss of Elp3 Impairs the Acetylation and Distribution of Connexin-43 in the Developing Cerebral Cortex. Front Cell Neurosci 2017; 11:122. [PMID: 28507509 PMCID: PMC5410572 DOI: 10.3389/fncel.2017.00122] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 04/12/2017] [Indexed: 12/19/2022] Open
Abstract
The Elongator complex is required for proper development of the cerebral cortex. Interfering with its activity in vivo delays the migration of postmitotic projection neurons, at least through a defective α-tubulin acetylation. However, this complex is already expressed by cortical progenitors where it may regulate the early steps of migration by targeting additional proteins. Here we report that connexin-43 (Cx43), which is strongly expressed by cortical progenitors and whose depletion impairs projection neuron migration, requires Elongator expression for its proper acetylation. Indeed, we show that Cx43 acetylation is reduced in the cortex of Elp3cKO embryos, as well as in a neuroblastoma cell line depleted of Elp1 expression, suggesting that Cx43 acetylation requires Elongator in different cellular contexts. Moreover, we show that histones deacetylase 6 (HDAC6) is a deacetylase of Cx43. Finally, we report that acetylation of Cx43 regulates its membrane distribution in apical progenitors of the cerebral cortex.
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Affiliation(s)
- Sophie Laguesse
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
| | - Pierre Close
- Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium.,GIGA-Molecular Biology of Diseases, University of LiègeLiège, Belgium
| | - Laura Van Hees
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
| | - Alain Chariot
- Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium.,GIGA-Molecular Biology of Diseases, University of LiègeLiège, Belgium.,Walloon Excellence in Lifesciences and Biotechnology (WELBIO)Wallonia, Belgium
| | - Brigitte Malgrange
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
| | - Laurent Nguyen
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
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18
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Cai K, Wang B, Dou H, Luan R, Bao X, Chu J. IL-17A promotes the proliferation of human nasopharyngeal carcinoma cells through p300-mediated Akt1 acetylation. Oncol Lett 2017; 13:4238-4244. [PMID: 28588706 PMCID: PMC5452892 DOI: 10.3892/ol.2017.5962] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 02/07/2017] [Indexed: 12/12/2022] Open
Abstract
Interleukin (IL)-17A is a T helper (Th)17 cell-secreted cytokine that is able to induce various inflammatory responses. There is emerging evidence that IL-17A is generated in the cancer microenvironment of human nasopharyngeal carcinoma (NPC). However, the role of IL-17A in NPC remains unclear. Thus, the present study aimed to examine the direct influence of IL-17A stimulation on the proliferation of human NPC cells and identify the underlying molecular mechanisms. Furthermore, E1A binding protein p300 (p300)-mediated AKT serine/threonine kinase 1 (Akt1) acetylation and its role in regulating the proliferation of NPC cells was investigated. The results of the current study demonstrated that IL-17A stimulation in vitro increased the proliferation of human NPC cells. Furthermore, Akt1 acetylation was identified to be enhanced in human NPC cells induced by IL-17A. Additionally, p300 induction was demonstrated to be required for Akt1 acetylation in human NPC cells following exposure to IL-17A. Functionally, p300-mediated Akt1 acetylation contributed to the proliferation of human NPC cells stimulated by IL-17A. In conclusion, the results of the present demonstrate a novel activity of IL-17A that promotes human NPC cell proliferation via p300-mediated Akt1 acetylation. This may provide a potential strategy for the treatment of patients with NPC through the inhibition of IL-17A or its receptors.
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Affiliation(s)
- Kemin Cai
- Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Bing Wang
- Department of Neurosurgery, Suzhou Kowloon Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Suzhou, Jiangsu 215021, P.R. China
| | - Hongmei Dou
- Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Ronglan Luan
- Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Xueli Bao
- Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Jiusheng Chu
- Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
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19
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Abdelbaset-Ismail A, Borkowska-Rzeszotek S, Kubis E, Bujko K, Brzeźniakiewicz-Janus K, Bolkun L, Kloczko J, Moniuszko M, Basak GW, Wiktor-Jedrzejczak W, Ratajczak MZ. Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1. Leukemia 2017; 31:446-458. [PMID: 27451975 PMCID: PMC5288274 DOI: 10.1038/leu.2016.198] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/06/2016] [Accepted: 07/08/2016] [Indexed: 02/07/2023]
Abstract
As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase-polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK-HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated.
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Affiliation(s)
- A Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | | | - E Kubis
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | - K Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | | | - L Bolkun
- Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
- Department of Hematology, Medical University of Bialystok, Bialystok, Poland
| | - J Kloczko
- Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
- Department of Hematology, Medical University of Bialystok, Bialystok, Poland
| | - M Moniuszko
- Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
| | - G W Basak
- Department of Hematology, Warsaw Medical University, Warsaw, Poland
| | | | - M Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
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Nitta H, Shimose T, Emi Y, Imamura T, Ohnishi K, Kusumoto T, Yamamoto M, Fukuzawa K, Takahashi I, Higashi H, Tsuji A, Akagi Y, Oki E, Maehara Y, Baba H. Expression of the anaphylatoxin C5a receptor in gastric cancer: implications for vascular invasion and patient outcomes. Med Oncol 2016; 33:118. [DOI: 10.1007/s12032-016-0834-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/24/2016] [Indexed: 02/06/2023]
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21
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Hu WH, Hu Z, Shen X, Dong LY, Zhou WZ, Yu XX. C5a receptor enhances hepatocellular carcinoma cell invasiveness via activating ERK1/2-mediated epithelial–mesenchymal transition. Exp Mol Pathol 2016; 100:101-8. [DOI: 10.1016/j.yexmp.2015.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 09/19/2015] [Accepted: 10/12/2015] [Indexed: 10/22/2022]
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22
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Tang Z, Yu W, Zhang C, Zhao S, Yu Z, Xiao X, Tang R, Xuan Y, Yang W, Hao J, Xu T, Zhang Q, Huang W, Deng W, Guo W. CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway. Mol Oncol 2016; 10:317-29. [PMID: 26628108 PMCID: PMC5528962 DOI: 10.1016/j.molonc.2015.10.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 10/19/2015] [Indexed: 12/14/2022] Open
Abstract
CBP (CREB-binding protein) is a transcriptional co-activator which possesses HAT (histone acetyltransferases) activity and participates in many biological processes, including embryonic development, growth control and homeostasis. However, its roles and the underlying mechanisms in the regulation of carcinogenesis and tumor development remain largely unknown. Here we investigated the molecular mechanisms and potential targets of CBP involved in tumor growth and survival in lung cancer cells. Elevated expression of CBP was detected in lung cancer cells and tumor tissues compared to the normal lung cells and tissues. Knockdown of CBP by siRNA or inhibition of its HAT activity using specific chemical inhibitor effectively suppressed cell proliferation, migration and colony formation and induced apoptosis in lung cancer cells by inhibiting MAPK and activating cytochrome C/caspase-dependent signaling pathways. Co-immunoprecipitation and immunofluorescence analyses revealed the co-localization and interaction between CBP and CPSF4 (cleavage and polyadenylation specific factor 4) proteins in lung cancer cells. Knockdown of CPSF4 inhibited hTERT transcription and cell growth induced by CBP, and vice versa, demonstrating the synergetic effect of CBP and CPSF4 in the regulation of lung cancer cell growth and survival. Moreover, we found that high expression of both CBP and CPSF4 predicted a poor prognosis in the patients with lung adenocarcinomas. Collectively, our results indicate that CBP regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathways.
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Affiliation(s)
- Zhipeng Tang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wendan Yu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Changlin Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Shilei Zhao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhenlong Yu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xiangsheng Xiao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Ranran Tang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yang Xuan
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wenjing Yang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Jiaojiao Hao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Tingting Xu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Qianyi Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wenlin Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China
| | - Wuguo Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
| | - Wei Guo
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
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Influence of the C5a–C5a receptor system on breast cancer progression and patient prognosis. Breast Cancer 2015; 23:876-885. [DOI: 10.1007/s12282-015-0654-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 10/07/2015] [Indexed: 12/20/2022]
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24
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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