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Qian Y, Zhao X, Wu F, Wang X, Chen T. TGF-β-induced acetylation of KLF5 drives TNFAIP2 transcription and EMT in nasopharyngeal carcinoma: Unveiling a novel regulatory mechanism. Exp Cell Res 2025; 447:114498. [PMID: 40054652 DOI: 10.1016/j.yexcr.2025.114498] [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: 12/18/2024] [Revised: 02/25/2025] [Accepted: 03/04/2025] [Indexed: 03/12/2025]
Abstract
Epithelial-mesenchymal transition (EMT) is one of the critical mechanisms underlying migration, invasion, and metastasis of nasopharyngeal carcinoma (NPC) cells. The transcription factor KLF5 plays a pivotal role in various cancers, however, its precise functions in NPC remain incompletely understood. This study aims to explore the detailed mechanisms by which TGF-β enhances TNFAIP2 transcription by acetylating KLF5, thereby inducing EMT in NPC. KLF5 was significantly overexpressed in NPC tissues and closely associated with adverse clinicopathological features of the patients. Further studies revealed that TGF-β markedly increased the expression of KLF5 and its acetylated form, Ac-KLF5, in NPC cells, with the acetylation status of KLF5 being crucial for its function. KLF5 induced EMT in NPC cells by directly binding to the TNFAIP2 promoter and promoting its transcription. The pro-migratory and pro-invasive effects of acetylated KLF5 on NPC cells depended on TNFAIP2. Additionally, in vivo experiments confirmed that TGF-β treatment induced tumors in NPC mouse models to exhibit apparent EMT characteristics. These results collectively support the central role of the TGF-β-KLF5-TNFAIP2 axis in EMT of NPC. This study elucidates the specific mechanisms by which TGF-β promotes TNFAIP2 transcription by acetylating KLF5, thereby inducing EMT in NPC. This discovery not only provides new insights into the pathogenesis of NPC but also identifies potential therapeutic targets for NPC treatment.
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Affiliation(s)
- Yi Qian
- Department of Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing City, China
| | - Xuxu Zhao
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Feiyang Wu
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqiang Wang
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Chen
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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2
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Ren W, Liang H, Sun J, Cheng Z, Liu W, Wu Y, Shi Y, Zhou Z, Chen C. TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis. Cell Death Dis 2024; 15:821. [PMID: 39532855 PMCID: PMC11557851 DOI: 10.1038/s41419-024-07223-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Angiogenesis is well known to play a critical role in breast cancer. We previously reported that TNFAIP2 activates Rac1 to promote triple-negative breast cancer (TNBC) cell proliferation, migration, and chemoresistance. However, the potential contribution of TNFAIP2 to tumor angiogenesis remains unknown. In this study, we demonstrated that TNFAIP2 promotes TNBC angiogenesis by activating the Rac1-ERK-AP1-HIF1α signaling axis. Under hypoxia, TNFAIP2 activates Rac1 and ERK sequentially. Following that, ERK activates the AP-1 (c-Jun/Fra1) transcription factor. By employing chromatin immunoprecipitation and luciferase reporter assays, we showed that AP-1 directly interacts with the HIF1α gene promoter, thereby enhancing its transcription. The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.
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MESH Headings
- Humans
- Animals
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- rac1 GTP-Binding Protein/metabolism
- rac1 GTP-Binding Protein/genetics
- Female
- Cell Line, Tumor
- Mice, Nude
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/pathology
- Triple Negative Breast Neoplasms/metabolism
- Triple Negative Breast Neoplasms/drug therapy
- Mice
- Signal Transduction
- Transcription Factor AP-1/metabolism
- Pyrimidinones/pharmacology
- Pyridines/pharmacology
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Transcription, Genetic/drug effects
- Pyridones/pharmacology
- Mice, Inbred BALB C
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Nitriles/pharmacology
- MAP Kinase Signaling System/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Angiogenesis
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Affiliation(s)
- Wenlong Ren
- School of Life Science, University of Science & Technology of China, Hefei, Anhui, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Huichun Liang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jian Sun
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China
| | - Zhuo Cheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Wenjing Liu
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China
| | - Yingying Wu
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yujie Shi
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, China.
| | - Zhongmei Zhou
- The School of Continuing Education, Kunming Medical University, Kunming, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China.
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, ChinaAcademy of Biomedical Engineering, Kunming Medical University, Kunming, China.
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3
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Fu Z, Yuan Y. TNFAIP2 as an emerging therapeutic target in cancer therapy and its underlying mechanisms. Pharmacol Res 2024; 204:107199. [PMID: 38688431 DOI: 10.1016/j.phrs.2024.107199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/02/2024]
Abstract
TNFα-induced protein 2 (TNFAIP2), upregulated under TNFα stimulation, was initially thought to participate in angiogenesis. Still, more and more studies have found that TNFAIP2 plays multiple roles in various physiological and pathological scenarios. The representative functions of TNFAIP2 include motivating the inflammatory response, promoting angiogenesis, facilitating cell proliferation, adhesion, migration, and inducing tunnel nanotube formation. The expression of TNFAIP2 is abnormal in most cancers and can enhance drug resistance in cancer cells. The increasingly recognized significance of TNFAIP2 has been attracting growing attention in recent years. This review focuses on elucidating the relationship between TNFAIP2 and oncogenesis, as well as the latest research advancements in the pharmacological targeting of TNFAIP2, aiming to guide forthcoming endeavors in developing pharmacological agents targeted at modulating TNFAIP2.
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Affiliation(s)
- Zhanqi Fu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
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4
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Yang Y, Zhang Q, Cai H, Feng Y, Wen A, Yang Y, Wen M. RNA-seq analysis of chlorogenic acid intervention in duck embryo fibroblasts infected with duck plague virus. Virol J 2024; 21:60. [PMID: 38454409 PMCID: PMC10921813 DOI: 10.1186/s12985-024-02312-2] [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: 10/07/2023] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
INTRODUCTION Chlorogenic acid, the primary active component in Chinese medicines like honeysuckle, exhibits anti-inflammatory and antiviral effects. It has been demonstrated that chlorogenic acid effectively prevents and treats Duck enteritis virus (DEV) infection. This study aims to further elucidate the mechanism by which chlorogenic acid prevents DEV infection. METHODS Duck embryo fibroblast (DEF) cells were pre-treated with chlorogenic acid before being infected with DEV. Cell samples were collected at different time points for transcriptomic sequencing, while qPCR was used to detect the proliferation of DEV. Additionally, 30-day-old ducks were treated with chlorogenic acid, and their lymphoid organs were harvested for histopathological sections to observe pathological damage. The proliferation of DEV in the lymphoid organs was also detected using qPCR Based on the transcriptomic sequencing results, NF-κB1 gene was silenced by RNAi technology to analyze the effect of NF-κB1 gene on DEV proliferation. RESULTS Compared to the viral infection group, DEF cells in the chlorogenic acid intervention group exhibited significantly reduced DEV load (P < 0.05). Transcriptomic sequencing results suggested that chlorogenic acid inhibited DEV proliferation in DEF cells by regulating NF-κB signaling pathway. The results of RNAi silencing suggested that in the three treatment groups, compared with the DEV experimental group, there was no significant difference in the effect of pre-transfection after transfection on DEV proliferation, while both the pre-transfection after transfection and the simultaneous transfection group showed significant inhibition on DEV proliferation Furthermore, compared to the virus infection group, ducks in the chlorogenic acid intervention group showed significantly decreased DEV load in their lymphoid organs (P < 0.05), along with alleviated pathological damage such as nuclear pyretosis and nuclear fragmentation. CONCLUSIONS Chlorogenic acid effectively inhibits DEV proliferation in DEF and duck lymphatic organs, mitigates viral-induced pathological damage, and provides a theoretical basis for screening targeted drugs against DEV.
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Affiliation(s)
- Yunyun Yang
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Qiandong Zhang
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Haiqing Cai
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Yi Feng
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Anlin Wen
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Ying Yang
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Ming Wen
- School of Animal Science, Guizhou University, Guiyang, China.
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China.
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Lan G, Wu X, Zhao A, Lan J, Guo Q, Wang B, Shen F, Yu X, Zhao Y, Gao R, Xu T. The miR-146b-3p/TNFAIP2 axis regulates cell differentiation in acute myeloid leukaemia. Aging (Albany NY) 2024; 16:1496-1515. [PMID: 38271140 PMCID: PMC10866442 DOI: 10.18632/aging.205441] [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: 06/29/2023] [Accepted: 12/01/2023] [Indexed: 01/27/2024]
Abstract
Our purpose is to verify that miR-146b-3p targets the downstream transcript TNFAIP2 in order to reveal the machinery underlying the miR-146b-3p/TNFAIP2 axis regulating acute myeloid leukaemia (AML) differentiation. Bioinformatics analyses were performed using multiple databases and R packages. The CD11b+ and CD14+ cell frequencies were detected using flow cytometry and immunofluorescence staining. The TNFAIP2 protein expression was evaluated using western blotting, immunocytochemistry and immunofluorescence staining. The qRT-PCR was conducted to detect the expression of TNFAIP2 and miR-146b-3p. TNFAIP2 and its correlated genes were enriched in multiple cell differentiation pathways. TNFAIP2 was upregulated upon leukaemic cell differentiation. miR-146b-3p directly targeted TNFAIP2, resulting in a decrease in TNFAIP2 expression. Forced expression of TNFAIP2 or knockdown of miR-146b-3p significantly induced the differentiation of MOLM-13 cells. In this study, we demonstrated that TNFAIP2 is a critical driver in inducing differentiation and that the miR-146b-3p/TNFAIP2 axis involves in regulating cell differentiation in AML.
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Affiliation(s)
- Gaochen Lan
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xiaolong Wu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Aiyue Zhao
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Jinjian Lan
- The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiusheng Guo
- Department of Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Bolin Wang
- Institute of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Fenglin Shen
- The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaoling Yu
- Institute of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yanna Zhao
- Institute of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruilan Gao
- Institute of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Tianwen Xu
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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6
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Sarad K, Stefańska M, Kraszewska I, Szade K, Sluimer JC, Błyszczuk P, Dulak J, Jaźwa-Kusior A. Single-cell transcriptomics reveals subtype-specific molecular profiles in Nrf2-deficient macrophages from murine atherosclerotic aortas. Front Immunol 2023; 14:1249379. [PMID: 37965327 PMCID: PMC10641521 DOI: 10.3389/fimmu.2023.1249379] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/17/2023] [Indexed: 11/16/2023] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional regulator of antioxidant and anti-inflammatory response in all cell types. It also activates the transcription of genes important for macrophage function. Nrf2 activity declines with age and has been closely linked to atherosclerosis, but its specific role in this vascular pathology is not clear. Atherosclerotic plaques contain several macrophage subsets with distinct, yet not completely understood, functions in the lesion development. The aim of this study was to analyze the transcriptome of diverse Nrf2-deficient macrophage subpopulations from murine atherosclerotic aortas. Mice with transcriptionally inactive Nrf2 in Cdh5-expressing cells (Nrf2 Cdh5tKO) were used in the experiments. These mice lack transcriptional Nrf2 activity in endothelial cells, but also in a proportion of leukocytes. We confirmed that the bone marrow-derived and tissue-resident macrophages isolated from Nrf2 Cdh5tKO mice exhibit a significant decline in Nrf2 activity. Atherosclerosis was induced in Nrf2 Cdh5tKO and appropriate control mice via adeno-associated viral vector (AAV)-mediated overexpression of murine proprotein convertase subtilisin/kexin type 9 (Pcsk9) in the liver and high-fat diet feeding. After 21 weeks, live aortic cells were sorted on FACS and single-cell RNA sequencing (scRNA-seq) was performed. Unsupervised clustering singled out 13 distinct aortic cell types. Among macrophages, 9 subclusters were identified. Differential gene expression analysis revealed cell subtype-specific expression patterns. A subset of inflammatory macrophages from atherosclerotic Nrf2 Cdh5tKO mice demonstrated downregulation of DNA replication genes (e.g. Mcm7, Lig1, Pola1) concomitant with upregulation of DNA damage sensor Atr gene. Atherosclerotic Nrf2 Cdh5tKO Lyve1+ resident macrophages showed strong upregulation of IFN-stimulated genes, as well as changes in the expression of death pathways-associated genes (Slc40a1, Bcl2a1). Furthermore, we observed subtype-specific expression of core ferroptosis genes (e.g. Cp, Hells, Slc40a1) in inflammatory versus tissue resident macrophages. This observation suggested a link between ferroptosis and inflammatory microenvironment appearing at a very early stage of atherogenesis. Our findings indicate that Nrf2 deficiency in aortic macrophages leads to subtype-specific transcriptomic changes associated with inflammation, iron homeostasis, cell injury or death pathways. This may help understanding the role of aging-associated decline of Nrf2 activity and the function of specific macrophage subtypes in atherosclerotic lesion development.
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Affiliation(s)
- Katarzyna Sarad
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
- Jagiellonian University, Doctoral School of Exact and Natural Sciences, Kraków, Poland
| | - Monika Stefańska
- Department of Clinical Immunology, Jagiellonian University Medical College, Kraków, Poland
| | - Izabela Kraszewska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Krzysztof Szade
- Laboratory of Stem Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Judith C. Sluimer
- Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University Medical Center (UMC), Maastricht, Netherlands
- BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Przemysław Błyszczuk
- Department of Clinical Immunology, Jagiellonian University Medical College, Kraków, Poland
- Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Agnieszka Jaźwa-Kusior
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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Fang H, Ren W, Cui Q, Liang H, Yang C, Liu W, Wang X, Liu X, Shi Y, Feng J, Chen C. Integrin β4 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/RAC1. eLife 2023; 12:RP88483. [PMID: 37787041 PMCID: PMC10547475 DOI: 10.7554/elife.88483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023] Open
Abstract
Anti-tumor drug resistance is a challenge for human triple-negative breast cancer (TNBC) treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote TNBC cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin β4. Integrin β4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in TNBC. These results indicate that the Integrin β4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in TNBC.
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Affiliation(s)
- Huan Fang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- Kunming College of Life Sciences, University of Chinese Academy of SciencesKunming, YunnanChina
| | - Wenlong Ren
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- School of Life Science, University of Science & Technology of ChinaHefeiChina
| | - Qiuxia Cui
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- Affiliated Hospital of Guangdong Medical UniversityGuangdongChina
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Huichun Liang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Chuanyu Yang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Wenjing Liu
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Xinye Wang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Xue Liu
- Shanghai University of Medicine & Health Sciences Affiliated Sixth People’s Hospital South CampusShanghaiChina
| | - Yujie Shi
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou UniversityZhengzhouChina
| | - Jing Feng
- Shanghai University of Medicine & Health Sciences Affiliated Sixth People’s Hospital South CampusShanghaiChina
- The Second Affiliated Hospital of the Chinese University of Hong Kong (Shenzhen)ShenzhenChina
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangdong ProvinceGuangzhouChina
| | - Ceshi Chen
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- Academy of Biomedical Engineering, Kunming Medical UniversityKunmingChina
- The Third Affiliated Hospital, Kunming Medical UniversityKunmingChina
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8
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Hou C, Shi S, Gao M, Ji J, Ma C, Wang T, Chen T, Liu Y, Zhong J, Zheng Y, Ye J, Ke Y. Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy. J Neurooncol 2023; 165:79-90. [PMID: 37819535 DOI: 10.1007/s11060-023-04449-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 09/09/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND The efficacy of current immunotherapeutic strategies for patients with glioblastoma multiforme (GBM) remains unsatisfactory. The purpose of this study was to investigate the correlation between tumor necrosis factor alpha-induced protein 2 (TNFAIP2) and immunogenic cell death (ICD) in GBM, and to examine the effect of TNFAIP2 knockdown and anti-PD-1 combination treatment in a mouse glioma model. METHODS The CGGA and TCGA databases were used to explore the possible function of TNFAIP2 in GBM. Multiplex immunohistochemistry (mIHC) staining was performed to detect the immune infiltration of tissues. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, and enzyme linked immunosorbent assay (ELISA) were utilized to detect the release of damage-associated molecular patterns (DAMPs) and the activation of the immune response. A mouse glioma model was applied to examine the induction of immune response. RESULTS In vitro and in vivo studies demonstrated that TNFAIP2 knockdown increased the surface exposure of calreticulin (CALR), heat shock protein 70 kDa (HSP70), and heat shock protein 90 kDa (HSP90) in GBM cell lines, thereby inducing immunogenic cell death (ICD). Importantly, the study found that TNFAIP2 knockdown in combination with anti-PD-1 therapy significantly improved the overall survival of glioma in a mouse model. CONCLUSIONS TNFAIP2 knockdown induces ICD by downregulating TNFAIP2 in GBM. In addition, TNFAIP2 knockdown sensitized glioma to anti-PD-1 therapy. Hence, targeting TNFAIP2 alone or in combination with anti-PD-1 therapy may be a potential strategy for GBM treatment through ICD.
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Affiliation(s)
- Chongxian Hou
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Shenbao Shi
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Mengjiao Gao
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Jingsen Ji
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Chengcheng Ma
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Tianwei Wang
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Taoliang Chen
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Yang Liu
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Jiasheng Zhong
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Yaofeng Zheng
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China
| | - Jing'an Ye
- Department of Neurosurgery, Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, 523059, People's Republic of China.
| | - Yiquan Ke
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People's Republic of China.
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9
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Zhang H, Shen S, Feng C, Chen G, Wang X. MFAP2 promotes the progression of oral squamous cell carcinoma by activating the Wnt/β-catenin signaling pathway through autophagy. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1445-1455. [PMID: 37592847 PMCID: PMC10520470 DOI: 10.3724/abbs.2023079] [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: 12/07/2022] [Accepted: 03/23/2023] [Indexed: 08/19/2023] Open
Abstract
Microfibrillar-associated protein 2 (MFAP2) is a small glycoprotein that is involved in vascular development and metabolic disease. The present study aims to explore the regulatory role of MFAP2 in the development and progression of oral squamous cell carcinoma (OSCC), including the underlying mechanisms. MFAP2 expression and its association with the progression of OSCC are explored using bioinformatics. MFAP2 expression in OSCC tissues is detected by immunohistochemical staining. SCC15 cell migration, invasion, apoptosis, proliferation, and viability are detected by wound healing, Transwell, flow cytometry, colony formation, and cell counting kit-8 assays. An in vivo experiment is used to detect tumor formation. Western blot analysis is used to determine MFAP2's regulatory role in autophagy and the Wnt/β-catenin signaling pathway. MFAP2 is highly expressed in SCC15 cells and OSCC tissues, which correlates positively with the poor prognosis of patients with OSCCs. Functionally, MFAP2 promotes oncogenic autophagy to increase cell invasion, migration, and proliferation but inhibits apoptosis in SCC15 cells and promotes tumor growth in vivo. Mechanistically, MFAP2 upregulates autophagy and Wnt/β-catenin signaling to stimulate OSCC development. Intriguingly, regulation of Wnt/β-catenin signaling dependent on autophagy contributes to the malignant behaviors of SCC15 cells. MFAP2 could serve as a novel biomarker for OSCC and could affect OSCC tumorigenesis and development via autophagic regulation of Wnt/β-catenin signaling.
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Affiliation(s)
- Hao Zhang
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Si Shen
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Chong Feng
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Gang Chen
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Xinxing Wang
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
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10
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Liu Z, Pei M, Liu G, Qiu Z, Wang S, Qiao Z, Wang J, Jin D, Zhang J, Duan K, Nian X, Ma Z, Yang X. CDC20 is a potential target gene to inhibit the tumorigenesis of MDCK cells. Biologicals 2023; 83:101697. [PMID: 37579524 DOI: 10.1016/j.biologicals.2023.101697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 07/05/2023] [Accepted: 08/01/2023] [Indexed: 08/16/2023] Open
Abstract
MDCK is currently the main cell line used for influenza vaccine production in culture. Previous studies have reported that MDCK cells possess tumorigenic ability in nude mice. Although complete cell lysis can be ensured during vaccine production, host cell DNA released after cell lysis may still pose a risk for tumorigenesis. Greater caution is needed in the production of human vaccines; therefore, the use of gene editing to establish cells incapable of forming tumors may significantly improve the safety of influenza vaccines. Knowledge regarding the genes and molecular mechanisms that affect the tumorigenic ability of MDCK cells is crucial; however, our understanding remains superficial. Through monoclonal cell screening, we previously obtained a cell line, CL23, that possesses significantly reduced cell proliferation, migration, and invasion abilities, and tumor-bearing experiments in nude mice showed the absence of tumorigenic cells. With a view to exploring tumorigenesis-related genes in MDCK cells, DIA proteomics was used to compare the differences in protein expression between wild-type (M60) and non-tumorigenic (CL23) cells. Differentially expressed proteins were verified at the mRNA level by RT-qPCR, and a number of genes involved in cell tumorigenesis were preliminarily screened. Immunoblotting further confirmed that related protein expression was significantly reduced in non-tumorigenic cells. Inhibition of CDC20 expression by RNAi significantly reduced the proliferation and migration of MDCK cells and increased the proliferation of the influenza virus; therefore, CDC20 was preliminarily determined to be an effective target gene for the inhibition of cell tumorigenicity. These results contribute to a more comprehensive understanding of the mechanism underlying cell tumorigenesis and provide a basis for the establishment of target gene screening in genetically engineered non-tumorigenic MDCK cell lines.
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Affiliation(s)
- Zhenbin Liu
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University Lanzhou 730030, China; Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, 730030, China
| | - Mengyuan Pei
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China
| | - Geng Liu
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China
| | - Zhenyu Qiu
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China
| | - Siya Wang
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China
| | - Zilin Qiao
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University Lanzhou 730030, China; Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, 730030, China
| | - Jiamin Wang
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University Lanzhou 730030, China; Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, 730030, China
| | - Dongwu Jin
- Gansu Provincial Bioengineering Materials Engineering Research Center, Lanzhou, 730010, China
| | - Jiayou Zhang
- National Engineering Technology Research Center for Combined Vaccines, Wuhan, 430207, China; Wuhan Institute of Biological Products Co., Ltd., Wuhan, 430207, China
| | - Kai Duan
- National Engineering Technology Research Center for Combined Vaccines, Wuhan, 430207, China; Wuhan Institute of Biological Products Co., Ltd., Wuhan, 430207, China
| | - Xuanxuan Nian
- National Engineering Technology Research Center for Combined Vaccines, Wuhan, 430207, China; Wuhan Institute of Biological Products Co., Ltd., Wuhan, 430207, China
| | - Zhongren Ma
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Lanzhou, 730030, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University Lanzhou 730030, China; Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, 730030, China
| | - Xiaoming Yang
- National Engineering Technology Research Center for Combined Vaccines, Wuhan, 430207, China; China National Biotech Group Company Limited, Beijing, 100029, China.
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11
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Baeza-Kallee N, Bergès R, Hein V, Cabaret S, Garcia J, Gros A, Tabouret E, Tchoghandjian A, Colin C, Figarella-Branger D. Deciphering the Action of Neuraminidase in Glioblastoma Models. Int J Mol Sci 2023; 24:11645. [PMID: 37511403 PMCID: PMC10380381 DOI: 10.3390/ijms241411645] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/11/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Glioblastoma (GBM) contains cancer stem cells (CSC) that are resistant to treatment. GBM CSC expresses glycolipids recognized by the A2B5 antibody. A2B5, induced by the enzyme ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyl transferase 3 (ST8Sia3), plays a crucial role in the proliferation, migration, clonogenicity and tumorigenesis of GBM CSC. Our aim was to characterize the resulting effects of neuraminidase that removes A2B5 in order to target GBM CSC. To this end, we set up a GBM organotypic slice model; quantified A2B5 expression by flow cytometry in U87-MG, U87-ST8Sia3 and GBM CSC lines, treated or not by neuraminidase; performed RNAseq and DNA methylation profiling; and analyzed the ganglioside expression by liquid chromatography-mass spectrometry in these cell lines, treated or not with neuraminidase. Results demonstrated that neuraminidase decreased A2B5 expression, tumor size and regrowth after surgical removal in the organotypic slice model but did not induce a distinct transcriptomic or epigenetic signature in GBM CSC lines. RNAseq analysis revealed that OLIG2, CHI3L1, TIMP3, TNFAIP2, and TNFAIP6 transcripts were significantly overexpressed in U87-ST8Sia3 compared to U87-MG. RT-qPCR confirmed these results and demonstrated that neuraminidase decreased gene expression in GBM CSC lines. Moreover, neuraminidase drastically reduced ganglioside expression in GBM CSC lines. Neuraminidase, by its pleiotropic action, is an attractive local treatment against GBM.
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Affiliation(s)
| | - Raphaël Bergès
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Victoria Hein
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Stéphanie Cabaret
- ChemoSens Platform, Centre des Sciences du Goût et de l'Alimentation, InstitutAgro, CNRS, INRAE, Université de Bourgogne Franche-Comté, 21000 Dijon, France
| | - Jeremy Garcia
- APHM, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, 13005 Marseille, France
| | - Abigaëlle Gros
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
- APHM, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, 13005 Marseille, France
| | - Emeline Tabouret
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
- APHM, CHU Timone, Service de Neurooncologie, 13005 Marseille, France
| | | | - Carole Colin
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
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12
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Bhowmik KK, Barek MA, Aziz MA, Islam MS. Susceptibility of TNFAIP8, TNFAIP8L1, and TNFAIP2 Gene Polymorphisms on Cancer Risk: A Comprehensive Review and Meta-Analysis of Case-Control Studies. Technol Cancer Res Treat 2022; 21:15330338221123109. [PMID: 36254562 PMCID: PMC9580160 DOI: 10.1177/15330338221123109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Objectives: The TNFAIP8 gene family and TNFAIP2 gene are inextricably linked to an elevated risk of cancer development. This systemic review and meta-analysis seeks to establish the relationship between TNFAIP8 (rs11064, rs1045241, rs1045242, and rs3813308), TNFAIP8L1 (rs1060555), and TNFAIP2 (rs710100 and rs8126) polymorphisms with the risk of cancer. Methods and Materials: A systematic search of multiple databases from January 2022 to April 2022 was used to identify relevant studies. Odds ratios (ORs) with corresponding 95% CI and p-value were calculated to assess the association. Bonferroni correction was performed to correct p-values. Trial sequential analysis (TSA) and in-silico messenger RNA expression were also performed. Review Manager 5.4 software was used for performing this meta-analysis. Results: This study comprised 6909 cancer patients and 7087 healthy participants from 14 studies. Four genetic models of rs11064 (codominant 2 [COD2]: OR = 2.30, p = 7.83 × 10-5; codominant 3 [COD3]: OR = 2.10, p = .0006; recessive model [RM]: OR = 2.24, p = .0001; AC: OR = 1.47, p = .037), two genetic models of rs1045241 (codominant 1 [COD1]: OR = 1.27, p = .009; overdominant model [ODM]: OR = 1.24, p = .018), four genetic models of rs1045242 (COD1: OR = 1.52, p = .005; dominant model (DM): OR = 1.56, p = .002; OD: OR = 1.48, p = .008; AC: OR = 1.48, p = .002), and three genetic models of rs8126 (COD2: OR = 1.41, p = .0005; COD3: OR = 1.44, p = .0002; RM: OR = 1.43, p = .0001) were statistically linked to cancer risk. Only one genetic model of rs1060555 polymorphism showed a significant protective association with cancer (COD2: OR = 0.80, p = .048). The outcomes of TSA also validated the findings of the meta-analysis. Conclusion: This study summarizes that rs11064, rs1045241, and rs1045242 polymorphisms of TNFAIP8 gene and rs8126 polymorphism of TNFAIP2 gene are significantly linked with the risk of cancer development. This meta-analysis was registered at INPLASY (registration number: INPLASY202270073).
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Affiliation(s)
- Khokon Kanti Bhowmik
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh,Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md Abdul Barek
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh,Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md. Abdul Aziz
- Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh
| | - Mohammad Safiqul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh,Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh,Mohammad Safiqul Islam, Department of Pharmacy, Noakhali Science and Technology University, Noakhali-3814, Bangladesh.
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13
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Jin G, Liu Y, Xu W, Li Y, Zhang H, Qiu S, Gao C, Liu S. Tnfaip2 promotes atherogenesis by enhancing oxidative stress induced inflammation. Mol Immunol 2022; 151:41-51. [PMID: 36084515 DOI: 10.1016/j.molimm.2022.08.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022]
Abstract
The inflammation is considered to be the crucial determinants of lesion progression and plaque stability during atherogenesis. Tnfaip2 appears to be a regulator for carcinogenesis and infectious diseases. But its role in atherosclerosis is not clear. Here we first report that Tnfaip2 promotes the formation of atherosclerosis through enhancing the inflammation under oxidative stress condition. Although the endogenous expression of Tnfaip2 was upregulated under oxidative stress condition, the overexpressed Tnfaip2 could promote cells proliferation. This might result from the ability of promoting cells entering G2/M phase. Conversely, the cells proliferation and migration were significantly reduced in Tnfaip2 knockdown cells through inhibiting the activation of NF-κB/MAPK/Akt signaling pathways. However, the efferocytosis increased markedly due to the upregulation of "eat me" receptors, such as CD36, SR-A, and SR-B1, and the downregulation of "don't eat me" signal CD47. As a consequence, Tnfaip2 deficiency in bone marrow-derived cells inhibited atherosclerosis development in Ldlr-/- mice fed a high-fat diet accompanied by decreased inflammatory cytokines and shTnfaip2 could reduce the plaque lesions in ApoE-/- mice. These results indicate that Tnfaip2 might play an important role during atherogenesis.
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Affiliation(s)
- Guiyuan Jin
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China; Medical Research Centre, Affiliated Hospital of Ji'ning Medical University, Ji'ning, Shandong Province, PR China
| | - Ying Liu
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China
| | - Wenwen Xu
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China
| | - Yan Li
- Department of Blood Transfusion, Qilu Hospital of Shandong University, Ji'nan, PR China
| | - Heng Zhang
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China
| | - Shuoke Qiu
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China
| | - Chengjiang Gao
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China
| | - Suxia Liu
- Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, PR China.
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14
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Shin CM, Park K, Kim N, Won S, Ohn JH, Lee S, Park JH, Kang SJ, Kim JS, Lee DH. rs2671655 single nucleotide polymorphism modulates the risk for gastric cancer in Helicobacter pylori-infected individuals: a genome-wide association study in the Korean population. Gastric Cancer 2022; 25:573-585. [PMID: 35325318 PMCID: PMC8943788 DOI: 10.1007/s10120-022-01285-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 02/04/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection. METHODS This study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction. RESULTS In the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori-positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori-negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori-negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori-positive group (P = 0.0112). CONCLUSION After H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC.
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Affiliation(s)
- Cheol Min Shin
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea
| | - Kyungtaek Park
- grid.31501.360000 0004 0470 5905Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, Korea
| | - Nayoung Kim
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea ,grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Sungho Won
- grid.31501.360000 0004 0470 5905Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, Korea ,grid.31501.360000 0004 0470 5905Department of Public Health Sciences, Seoul National University, Seoul, South Korea
| | - Jung Hun Ohn
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea
| | - Sejoon Lee
- grid.412480.b0000 0004 0647 3378Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Ji Hyun Park
- grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung Joo Kang
- grid.412484.f0000 0001 0302 820XDepartment of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
| | - Joo Sung Kim
- grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea ,grid.412484.f0000 0001 0302 820XDepartment of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
| | - Dong Ho Lee
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea ,grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
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15
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Nawrocka PM, Galka-Marciniak P, Urbanek-Trzeciak MO, M-Thirusenthilarasan I, Szostak N, Philips A, Susok L, Sand M, Kozlowski P. Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants. Front Oncol 2021; 11:752579. [PMID: 34900699 PMCID: PMC8656283 DOI: 10.3389/fonc.2021.752579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/08/2021] [Indexed: 11/13/2022] Open
Abstract
Basal cell carcinoma (BCC) of the skin is the most common cancer in humans, characterized by the highest mutation rate among cancers, and is mostly driven by mutations in genes involved in the hedgehog pathway. To date, almost all BCC genetic studies have focused exclusively on protein-coding sequences; therefore, the impact of noncoding variants on the BCC genome is unrecognized. In this study, with the use of whole-exome sequencing of 27 tumor/normal pairs of BCC samples, we performed an analysis of somatic mutations in both protein-coding sequences and gene-associated noncoding regions, including 5'UTRs, 3'UTRs, and exon-adjacent intron sequences. Separately, in each region, we performed hotspot identification, mutation enrichment analysis, and cancer driver identification with OncodriveFML. Additionally, we performed a whole-genome copy number alteration analysis with GISTIC2. Of the >80,000 identified mutations, ~50% were localized in noncoding regions. The results of the analysis generally corroborated the previous findings regarding genes mutated in coding sequences, including PTCH1, TP53, and MYCN, but more importantly showed that mutations were also clustered in specific noncoding regions, including hotspots. Some of the genes specifically mutated in noncoding regions were identified as highly potent cancer drivers, of which BAD had a mutation hotspot in the 3'UTR, DHODH had a mutation hotspot in the Kozak sequence in the 5'UTR, and CHCHD2 frequently showed mutations in the 5'UTR. All of these genes are functionally implicated in cancer-related processes (e.g., apoptosis, mitochondrial metabolism, and de novo pyrimidine synthesis) or the pathogenesis of UV radiation-induced cancers. We also found that the identified BAD and CHCHD2 mutations frequently occur in melanoma but not in other cancers via The Cancer Genome Atlas analysis. Finally, we identified a frequent deletion of chr9q, encompassing PTCH1, and unreported frequent copy number gain of chr9p, encompassing the genes encoding the immune checkpoint ligands PD-L1 and PD-L2. In conclusion, this study is the first systematic analysis of coding and noncoding mutations in BCC and provides a strong basis for further analyses of the variants in BCC and cancer in general.
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Affiliation(s)
- Paulina Maria Nawrocka
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Paulina Galka-Marciniak
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | | | | | - Natalia Szostak
- Laboratory of Bioinformatics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Anna Philips
- Laboratory of Bioinformatics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Laura Susok
- Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Michael Sand
- Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.,Department of Plastic Surgery, St. Josef Hospital, Catholic Clinics of the Ruhr Peninsula, Essen, Germany Department of Plastic, Reconstructive and Aesthetic Surgery, St. Josef Hospital, Essen, Germany
| | - Piotr Kozlowski
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
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16
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Hiyoshi M, Takahashi N, Eltalkhawy YM, Noyori O, Lotfi S, Panaampon J, Okada S, Tanaka Y, Ueno T, Fujisawa JI, Sato Y, Suzuki T, Hasegawa H, Tokunaga M, Satou Y, Yasunaga JI, Matsuoka M, Utsunomiya A, Suzu S. M-Sec induced by HTLV-1 mediates an efficient viral transmission. PLoS Pathog 2021; 17:e1010126. [PMID: 34843591 PMCID: PMC8659635 DOI: 10.1371/journal.ppat.1010126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/09/2021] [Accepted: 11/17/2021] [Indexed: 11/19/2022] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) infects target cells primarily through cell-to-cell routes. Here, we provide evidence that cellular protein M-Sec plays a critical role in this process. When purified and briefly cultured, CD4+ T cells of HTLV-1 carriers, but not of HTLV-1- individuals, expressed M-Sec. The viral protein Tax was revealed to mediate M-Sec induction. Knockdown or pharmacological inhibition of M-Sec reduced viral infection in multiple co-culture conditions. Furthermore, M-Sec knockdown reduced the number of proviral copies in the tissues of a mouse model of HTLV-1 infection. Phenotypically, M-Sec knockdown or inhibition reduced not only plasma membrane protrusions and migratory activity of cells, but also large clusters of Gag, a viral structural protein required for the formation of viral particles. Taken together, these results suggest that M-Sec induced by Tax mediates an efficient cell-to-cell viral infection, which is likely due to enhanced membrane protrusions, cell migration, and the clustering of Gag.
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Affiliation(s)
- Masateru Hiyoshi
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan
| | - Naofumi Takahashi
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Youssef M. Eltalkhawy
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Osamu Noyori
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Sameh Lotfi
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Jutatip Panaampon
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Seiji Okada
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Yuetsu Tanaka
- School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Takaharu Ueno
- Department of Microbiology, Kansai Medical University, Osaka, Japan
| | | | - Yuko Sato
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Tadaki Suzuki
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hideki Hasegawa
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masahito Tokunaga
- Department of Hematology, Imamura General Hospital, Kagoshima, Japan
| | - Yorifumi Satou
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Jun-ichirou Yasunaga
- Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan
| | - Masao Matsuoka
- Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan
| | - Atae Utsunomiya
- Department of Hematology, Imamura General Hospital, Kagoshima, Japan
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shinya Suzu
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
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17
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Tao L, Pang Y, Wang A, Li L, Shen Y, Xu X, Li J. Functional miR-142a-3p Induces Apoptosis and Macrophage Polarization by Targeting tnfaip2 and glut3 in Grass Carp ( Ctenopharyngodon idella). Front Immunol 2021; 12:633324. [PMID: 34262558 PMCID: PMC8273434 DOI: 10.3389/fimmu.2021.633324] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/08/2021] [Indexed: 11/13/2022] Open
Abstract
In the process of microbial invasion, the inflammation reaction is induced to eliminate the pathogen. However, un-controlled or un-resolved inflammation can lead to tissue damage and death of the host. MicroRNAs (miRNAs) are the signaling regulators that prevent the uncontrolled progress of an inflammatory response. Our previous work strongly indicated that miR-142a-3p is related to the immune regulation in grass carp. In the present study, we found that the expression of miR-142a-3p was down-regulated after infection by Aeromonas hydrophila. tnfaip2 and glut3 were confirmed as be the target genes of miR-142a-3p, which were confirmed by expression correlation analysis, gene overexpression, and dual luciferase reporter assay. The miR-142a-3p can reduce cell viability and stimulate cell apoptosis by targeting tnfaip2 and glut3. In addition, miR-142a-3p also regulates macrophage polarization induced by A. hydrophila. Our results suggest that miR-142a-3p has multiple functions in host antibacterial immune response. Our research provides further understanding of the molecular mechanisms between miRNAs and their target genes, and provides a new insights for the development of pro-resolution strategies for the treatment of complex inflammatory diseases in fish.
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Affiliation(s)
- Lizhu Tao
- Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.,Institute of Fisheries of Chengdu Agriculture and Forestry Academy, Chengdu, China
| | - Yifan Pang
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
| | - Anqi Wang
- Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Lisen Li
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade Do Algarve, Faro, Portugal
| | - Yubang Shen
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
| | - Xiaoyan Xu
- Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.,Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Jiale Li
- Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.,National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China.,Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
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18
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Qin R, Peng W, Wang X, Li C, Xi Y, Zhong Z, Sun C. Identification of Genes Related to Immune Infiltration in the Tumor Microenvironment of Cutaneous Melanoma. Front Oncol 2021; 11:615963. [PMID: 34136377 PMCID: PMC8202075 DOI: 10.3389/fonc.2021.615963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 04/28/2021] [Indexed: 01/02/2023] Open
Abstract
Cutaneous melanoma (CM) is the leading cause of skin cancer deaths and is typically diagnosed at an advanced stage, resulting in a poor prognosis. The tumor microenvironment (TME) plays a significant role in tumorigenesis and CM progression, but the dynamic regulation of immune and stromal components is not yet fully understood. In the present study, we quantified the ratio between immune and stromal components and the proportion of tumor-infiltrating immune cells (TICs), based on the ESTIMATE and CIBERSORT computational methods, in 471 cases of skin CM (SKCM) obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were analyzed by univariate Cox regression analysis, least absolute shrinkage, and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis to identify prognosis-related genes. The developed prognosis model contains ten genes, which are all vital for patient prognosis. The areas under the curve (AUC) values for the developed prognostic model at 1, 3, 5, and 10 years were 0.832, 0.831, 0.880, and 0.857 in the training dataset, respectively. The GSE54467 dataset was used as a validation set to determine the predictive ability of the prognostic signature. Protein–protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were used to verify “real” hub genes closely related to the TME. These hub genes were verified for differential expression by immunohistochemistry (IHC) analyses. In conclusion, this study might provide potential diagnostic and prognostic biomarkers for CM.
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Affiliation(s)
- Rujia Qin
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Wen Peng
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Xuemin Wang
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Chunyan Li
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Yan Xi
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Zhaoming Zhong
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China.,Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chuanzheng Sun
- Department of Head and Neck Surgery Section II, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
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19
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Ainiwaer Z, Maisaidi R, Liu J, Han L, Husaiyin S, Lu J, Niyazi M. Genetic polymorphisms of PGF and TNFAIP2 genes related to cervical cancer risk among Uygur females from China. BMC MEDICAL GENETICS 2020; 21:212. [PMID: 33109108 PMCID: PMC7590450 DOI: 10.1186/s12881-020-01144-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/12/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND PGF and TNFAIP2 are important angiogenic factors, which were abnormal expression in cervical cancer (CC). However, there is currently no report investigating the relationship of PGF and TNFAIP2 gene polymorphisms to CC risk. METHODS We conducted a case-control study of 342 CC patients and 498 cancer-free controls in a Chinese Uygur female population. Three SNPs (PGF rs8019391, PGF rs2268615, and TNFAIP2 rs710100) were selected and genotyped to assess the possible association of PGF and TNFAIP2 polymorphisms with CC susceptibility. Logistic regression analysis adjusted by age was used. RESULTS PGF rs2268615 (OR = 1.39, 95% CI = 1.04-1.86, p = 0.024) and TNFAIP2 rs710100 (OR = 1.44, 95% CI =1.07-1.95, p = 0.018) polymorphisms were associated with the increased risk of CC. Moreover, T allele of PGF rs8019391 was highly represented in patients with stage III-IV compared with stage I-II (OR = 2.17, p = 4.58 × 10- 4). MDR analysis revealed a positive interaction between the SNPs. CONCLUSION Our data indicated that PGF rs2268615, and TNFAIP2 rs710100 polymorphisms might be risk factors for CC susceptibility, which contributed to the increased risk of CC. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Zumurelaiti Ainiwaer
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China
| | - Reyilanmu Maisaidi
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China
| | - Jing Liu
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China
| | - Lili Han
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China.
| | - Sulaiya Husaiyin
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China
| | - Jing Lu
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China
| | - Mayinuer Niyazi
- Department of Gynecology, Xinjiang Medical University, People's Hospital of Xinjiang Uygur Autonomous Region, No 91 Tianqi Road, Urumqi, Xinjiang, 830001, China
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20
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Li J, Song Y, Yu B, Yu Y. TNFAIP2 Promotes Non-Small Cell Lung Cancer Cells and Targeted by miR-145-5p. DNA Cell Biol 2020; 39:1256-1263. [PMID: 32456459 DOI: 10.1089/dna.2020.5415] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFα) is an inflammatory cytokine that regulates inflammation and tumor progression in non-small cell lung cancer (NSCLC). The higher levels of TNF α are known to induce expression of several genes such as TNFα-induced protein 2 (TNFAIP2) with a largely unknown role in NSCLC. We provide the preliminary evidence for the role of TNFAIP2 in NSCLC progression and its epigenetic regulation mediated by microRNA, miR-145-5p. The expression of TNFAIP2 was confirmed using quantitative real-time PCR, immunohistochemistry, and Western blot in NSCLC tissue and paired adjacent normal tissue. All in vitro assays were undertaken in A549 and H23 cells and chemoresistance assays were undertaken in A549/Cisplatin (DDP) and H23/DDP cell types. TNFAIP2 silencing was undertaken using lipofectamine transfection of specific siRNA. Cells were co-transfected with miR-145-5p, and TNFAIP2-3' untranslated region (UTR) or TNFAIP2 with mutated 3'UTR using the luciferase vector pGL. Cell viability, transwell migration, and invasion were assessed. The role of caspase 3 proteins in cell viability was ascertained using Western blot. The tumor tissues (and cisplatin-resistant cell lines A549/DDP and H23/DDP) expressed significantly higher levels of TNAIP2 mRNA and protein. Silencing of TNFAIP2 resulted in reduced cell viability, reduced invasion, and migration in vitro. Silencing of TNFAIP2 in A549/DDP and H23/DDP had higher expression of TNFAIP2, reduced cell viability, and increased induction of caspase 3. MiR-145-5p binds to the 3'UTR of TNFAIP2. Overexpression of MiR-145-5p reduced expression of TNFAIP2, decreased cell viability, reduced cell migration and invasion, and significantly reduced expression of caspase 3 protein. TNFAIP2 mediates tumorigenesis in NSCLC through, not completely known pathways. miR-145-5p negatively regulates TNFAIP2 expression. miR-145-5p-mediated therapies may be explored in NSCLC.
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Affiliation(s)
- Jianing Li
- Department of Respiratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongfeng Song
- Department of Respiratory, The 10th Hospital of Harbin, Harbin, China
| | - Baiquan Yu
- Department of Respiratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yao Yu
- Department of Respiratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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21
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Chen QY, Shen S, Sun H, Wu F, Kluz T, Kibriya MG, Chen Y, Ahsan H, Costa M. PBMC gene expression profiles of female Bangladeshi adults chronically exposed to arsenic-contaminated drinking water. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 259:113672. [PMID: 31918125 PMCID: PMC11062206 DOI: 10.1016/j.envpol.2019.113672] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/06/2019] [Accepted: 11/22/2019] [Indexed: 06/10/2023]
Abstract
Arsenic, a class I human carcinogen, is ubiquitously found throughout the environment and around the globe, posing a great public health concern. Notably, Bangladesh and regions of West Bengal have been found to have high levels (0.5-4600 μg/L) of arsenic drinking water contamination, and approximately 50 million of the world's 200 million people chronically exposed to arsenic in Bangladesh alone. This study was carried out to examine genome-wide gene expression changes in individuals chronically exposed to arsenic-contaminated drinking water. Our study population includes twenty-nine Bangladeshi female participants with urinary arsenic levels ranging from 22.32 to 1828.12 μg/g creatinine. RNA extracted from peripheral blood mononuclear cells (PBMCs) were evaluated using RNA-Sequencing analysis. Our results indicate that a total of 1,054 genes were significantly associated with increasing urinary arsenic levels (FDR p < 0.05), which include 418 down-regulated and 636 up-regulated genes. Further Ingenuity Pathway Analysis revealed potential target genes (DAPK1, EGR2, APP), microRNAs (miR-155, -338, -210) and pathways (NOTCH signaling pathway) related to arsenic carcinogenesis. The selection of female-only participants provides a homogenous study population since arsenic has significant sex dependent effects, and the wide exposure range provides new insight for key gene expression changes that correlate with increasing urinary arsenic levels.
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Affiliation(s)
- Qiao Yi Chen
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA.
| | - Steven Shen
- Institute of Health Informatics, University of Minnesota, 55455, Minneapolis, MN, USA
| | - Hong Sun
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA
| | - Fen Wu
- Department of Population Health and Environmental Medicine, 10016, New York University School of Medicine, New York, NY, USA
| | - Thomas Kluz
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA
| | - Muhammad G Kibriya
- Institute for Population and Precision Health, Department of Public Health Sciences, The University of Chicago, Chicago, IL, 60637, USA
| | - Yu Chen
- Department of Population Health and Environmental Medicine, 10016, New York University School of Medicine, New York, NY, USA
| | - Habibul Ahsan
- Institute for Population and Precision Health, Department of Public Health Sciences, The University of Chicago, Chicago, IL, 60637, USA
| | - Max Costa
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA.
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22
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Garcia-Villatoro EL, DeLuca JAA, Callaway ES, Allred KF, Davidson LA, Hensel ME, Menon R, Ivanov I, Safe SH, Jayaraman A, Chapkin RS, Allred CD. Effects of high-fat diet and intestinal aryl hydrocarbon receptor deletion on colon carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2020; 318:G451-G463. [PMID: 31905023 PMCID: PMC7137094 DOI: 10.1152/ajpgi.00268.2019] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/13/2019] [Accepted: 12/20/2019] [Indexed: 02/06/2023]
Abstract
Consumption of a high-fat diet has been associated with an increased risk of developing colorectal cancer (CRC). However, the effects of the interaction between dietary fat content and the aryl hydrocarbon receptor (AhR) on colorectal carcinogenesis remain unclear. Mainly known for its role in xenobiotic metabolism, AhR has been identified as an important regulator for maintaining intestinal epithelial homeostasis. Although previous research using whole body AhR knockout mice has revealed an increased incidence of colon and cecal tumors, the unique role of AhR activity in intestinal epithelial cells (IECs) and modifying effects of fat content in the diet at different stages of sporadic CRC development are yet to be elucidated. In the present study, we have examined the effects of a high-fat diet on IEC-specific AhR knockout mice in a model of sporadic CRC. Although loss of AhR activity in IECs significantly induced the development of premalignant lesions, in a separate experiment, no significant changes in colon mass incidence were observed. Moreover, consumption of a high-fat diet promoted cell proliferation in crypts at the premalignant colon cancer lesion stage and colon mass multiplicity as well as β-catenin expression and nuclear localization in actively proliferating cells in colon masses. Our data demonstrate the modifying effects of high-fat diet and AhR deletion in IECs on tumor initiation and progression.NEW & NOTEWORTHY Through the use of an intestinal-specific aryl hydrocarbon receptor (AhR) knockout mouse model, this study demonstrates that the expression of AhR in intestinal epithelial cells is required to reduce the formation of premalignant colon cancer lesions. Furthermore, consumption of a high-fat diet and the loss of AhR in intestinal epithelial cells influences the development of colorectal cancer at various stages.
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MESH Headings
- Animals
- Azoxymethane
- Basic Helix-Loop-Helix Transcription Factors/deficiency
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colon/metabolism
- Colon/pathology
- Colonic Neoplasms/chemically induced
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- DNA Damage
- Diet, High-Fat
- Disease Models, Animal
- Epithelial Cells/metabolism
- Epithelial Cells/pathology
- Gene Deletion
- Gene Expression Regulation, Neoplastic
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
- Mice, Inbred C57BL
- Mice, Knockout
- Precancerous Conditions/chemically induced
- Precancerous Conditions/genetics
- Precancerous Conditions/metabolism
- Precancerous Conditions/pathology
- Receptors, Aryl Hydrocarbon/deficiency
- Receptors, Aryl Hydrocarbon/genetics
- Signal Transduction
- beta Catenin/genetics
- beta Catenin/metabolism
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Affiliation(s)
| | - Jennifer A A DeLuca
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Evelyn S Callaway
- Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Kimberly F Allred
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Laurie A Davidson
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
| | - Martha E Hensel
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas
| | - Rani Menon
- Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Ivan Ivanov
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Stephen H Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Robert S Chapkin
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
| | - Clinton D Allred
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
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23
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Niwa N, Tanaka N, Hongo H, Miyazaki Y, Takamatsu K, Mizuno R, Kikuchi E, Mikami S, Kosaka T, Oya M. TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells. J Transl Med 2019; 99:1702-1713. [PMID: 31263157 DOI: 10.1038/s41374-019-0285-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 05/02/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023] Open
Abstract
Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.
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Affiliation(s)
- Naoya Niwa
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Nobuyuki Tanaka
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
| | - Hiroshi Hongo
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Yasumasa Miyazaki
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Kimiharu Takamatsu
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Ryuichi Mizuno
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Eiji Kikuchi
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Shuji Mikami
- Department of Diagnostic Pathology, Keio University Hospital, Tokyo, 160-8582, Japan
| | - Takeo Kosaka
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
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24
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Qu X, Li Q, Zhang X, Wang Z, Wang S, Zhou Z. Amentoflavone protects the hematopoietic system of mice against γ-irradiation. Arch Pharm Res 2019; 42:1021-1029. [PMID: 31549342 DOI: 10.1007/s12272-019-01187-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 09/14/2019] [Indexed: 10/25/2022]
Abstract
Some flavonoids have been shown to exhibit good antioxidant activity and protect mice from damage induced by radiation. Amentoflavone (AMF), a biflavonoid derived from the traditional herb-Selaginella tamariscina, has been reported to have antioxidant properties. The protective effects and mechanism of action of AMF against radiation injury remain unknown. In this study, male C57BL/6 mice were subjected to total-body 60Co γ-irradiation at 7.5 or 3.0 Gy. The survival rate and mean survival time were evaluated to determine the radioprotective effect of AMF. Number of peripheral blood cells, frequency of colony forming unit-granulocytes, monocytes and micronuclei were measured to assess the protective effects of AMF on the hematopoietic system. Levels of superoxide dismutase and glutathione, and pathological changes in the bone marrow were determined. Additionally, next-generation sequencing technology was used to explore potential targets of AMF. We observed that AMF markedly extends average survival time, reduces injury to the hematopoietic system and promotes its recovery. Furthermore, treatment with AMF significantly attenuated radiation-induced oxidative stress. In addition, AMF had a significant effect on gene tumor necrosis factor alpha-induced protein 2. Together, the results of this study suggest that AMF is a potential protective agent against radiation injury.
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Affiliation(s)
- Xinyan Qu
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.,Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, Shandong, China
| | - Qingjun Li
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Xiaojuan Zhang
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.,Public Health Department of Medical School of Qinghai University, Xining, 810001, Qinghai, China
| | - Zhaofen Wang
- Public Health Department of Medical School of Qinghai University, Xining, 810001, Qinghai, China
| | - Shengqi Wang
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Zhe Zhou
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
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25
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Carter KP, Hanna S, Genna A, Lewis D, Segall JE, Cox D. Macrophages enhance 3D invasion in a breast cancer cell line by induction of tumor cell tunneling nanotubes. Cancer Rep (Hoboken) 2019; 2:e1213. [PMID: 32467880 DOI: 10.1002/cnr2.1213] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Metastasis is the cause of most cancer-related deaths. It is known that breast cancer cells in proximity to macrophages become more invasive in an Epidermal Growth Factor (EGF) dependent manner. Tunneling nanotubes (TNTs) are thin, F-actin containing, cellular protrusions that mediate intercellular communication and have been identified in many tumors. The mechanism of TNT formation varies between different cell types. M-Sec (TNFAIP2) has been demonstrated to be involved in TNT formation in some cell types including macrophages. Yet, the requirement of M-Sec in tumor cell TNT formation in response to macrophages has not been explored. Aim The aim of this study was to determine whether EGF was required for macrophage induced tumor cell TNTs in an M-Sec dependent manner and what possible roles tumor cell TNTs play in tumor cell migration and invasion. Methods and Results Macrophage Conditioned Media (CM) was used to induce an increase in TNTs in a number of breast cancer cell lines as measured by live cell microscopy. Tumor cell TNT formation by CM was dependent on the presence of EGF which was sufficient to induce TNT formation. CM treatment enhanced the level of M-Sec identified using western blot analysis. Reduction of endogenous M-Sec levels via shRNA in MTLn3 mammary adenocarcinoma cells inhibited the formation of TNTs. The role of tumor cell TNTs in cell behavior was tested using in vitro transwell and 3D invasion assays. No effect on chemotaxis was detected but 3D invasion was reduced following the knockdown of M-Sec in tumor cell TNTs. Conclusions Our results show that EGF was necessary and sufficient for tumor cell TNT formation which was dependent on cellular M-Sec levels. While tumor cell TNTs may not play a role in individual cell behaviors like chemotaxis, they may be important in more complex tumor cell behaviors such as 3D invasion.
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Affiliation(s)
- Kiersten P Carter
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Samer Hanna
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Alessandro Genna
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Jeffrey E Segall
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.,Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Dianne Cox
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.,Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.,Department of Molecular and Developmental Biology, Albert Einstein College of Medicine, Bronx, NY, USA
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26
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Du FY, Zhou QF, Sun WJ, Chen GL. Targeting cancer stem cells in drug discovery: Current state and future perspectives. World J Stem Cells 2019; 11:398-420. [PMID: 31396368 PMCID: PMC6682504 DOI: 10.4252/wjsc.v11.i7.398] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (e.g., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.
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Affiliation(s)
- Fang-Yu Du
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Qi-Fan Zhou
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Wen-Jiao Sun
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Guo-Liang Chen
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
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27
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Pergu R, Dagar S, Kumar H, Kumar R, Bhattacharya J, Mylavarapu SVS. The chaperone ERp29 is required for tunneling nanotube formation by stabilizing MSec. J Biol Chem 2019; 294:7177-7193. [PMID: 30877198 DOI: 10.1074/jbc.ra118.005659] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 02/14/2019] [Indexed: 01/23/2023] Open
Abstract
Tunneling nanotubes (TNTs) are membrane conduits that mediate long-distance intercellular cross-talk in several organisms and play vital roles during development, pathogenic transmission, and cancer metastasis. However, the molecular mechanisms of TNT formation and function remain poorly understood. The protein MSec (also known as TNFα-induced protein 2 (TNFAIP2) and B94) is essential for TNT formation in multiple cell types. Here, using affinity protein purification, mass spectrometric identification, and confocal immunofluorescence microscopy assays, we found that MSec interacts with the endoplasmic reticulum (ER) chaperone ERp29. siRNA-mediated ERp29 depletion in mammalian cells significantly reduces TNT formation, whereas its overexpression induces TNT formation, but in a strictly MSec-dependent manner. ERp29 stabilized MSec protein levels, but not its mRNA levels, and the chaperone activity of ERp29 was required for maintaining MSec protein stability. Subcellular ER fractionation and subsequent limited proteolytic treatment suggested that MSec is associated with the outer surface of the ER. The ERp29-MSec interaction appeared to require the presence of other bridging protein(s), perhaps triggered by post-translational modification of ERp29. Our study implicates MSec as a target of ERp29 and reveals an indispensable role for the ER in TNT formation, suggesting new modalities for regulating TNT numbers in cells and tissues.
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Affiliation(s)
- Rajaiah Pergu
- From the Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, and.,the Manipal Academy of Higher Education, Manipal Karnataka 576104, and
| | - Sunayana Dagar
- From the Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, and.,the Kalinga Institute of Industrial Technology, Bhubaneswar Odisha 751024, India
| | - Harsh Kumar
- From the Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, and.,the Manipal Academy of Higher Education, Manipal Karnataka 576104, and
| | - Rajesh Kumar
- the HIV Vaccine Translational Research Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad Haryana 121001
| | - Jayanta Bhattacharya
- the HIV Vaccine Translational Research Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad Haryana 121001
| | - Sivaram V S Mylavarapu
- From the Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, and .,the Manipal Academy of Higher Education, Manipal Karnataka 576104, and.,the Kalinga Institute of Industrial Technology, Bhubaneswar Odisha 751024, India
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28
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Guzhi Zengsheng Zhitongwan, a Traditional Chinese Medicinal Formulation, Stimulates Chondrocyte Proliferation through Control of Multiple Genes Involved in Chondrocyte Proliferation and Differentiation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:7265939. [PMID: 30275866 PMCID: PMC6157105 DOI: 10.1155/2018/7265939] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 08/07/2018] [Accepted: 08/19/2018] [Indexed: 11/30/2022]
Abstract
Chinese materia medica (CMM) are essential components of traditional Chinese medicine, and Chinese medicinal formulas consisting of 2 or more types of CMM are widely used. These formulations have played a pivotal role in health protection and disease control for thousands of years. Guzhi Zengsheng Zhitongwan (GZZSZTW), which represents one of the Chinese medicinal formulations, has been used for several decades to treat joint diseases. However, the exact molecular mechanism underlying its efficacy in treating osteoarthritis remains to be elucidated. In the present study, we investigated the effects of GZZSZTW on primary chondrocytes. We demonstrated that GZZSZTW significantly promoted chondrocyte viability, maintained chondrocytes in a continuous proliferative state, and prevented their further differentiation. These effects were achieved by the synergistic interactions of various herbs and their active components in GZZSZTW through an increase in the expression levels of functional genes participating in chondrocyte commitment and proliferation and a decrease in the expression levels of genes involved in chondrocyte differentiation. GZZSZTW treatment also decreased the expression levels of genes that inhibited chondrocyte proliferation. Thus, this study has greatly deepened the current knowledge about the molecular effects of GZZSZTW on chondrocytes. It has also shed new light on possible strategies to further prevent and treat cartilage-related diseases by using traditional Chinese medicinal formulations.
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29
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Jia L, Shi Y, Wen Y, Li W, Feng J, Chen C. The roles of TNFAIP2 in cancers and infectious diseases. J Cell Mol Med 2018; 22:5188-5195. [PMID: 30145807 PMCID: PMC6201362 DOI: 10.1111/jcmm.13822] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/21/2018] [Accepted: 07/05/2018] [Indexed: 12/30/2022] Open
Abstract
TNFα‐induced protein 2 (TNFAIP2) is a primary response gene of TNFα. TNFAIP2 is highly expressed in immune cells and the urinary bladder. The expression of TNFAIP2 is regulated by multiple transcription factors and signalling pathways, including NF‐κB, KLF5 and retinoic acid. Physiologically, TNFAIP2 appears to be a multiple functional mediator not only for inflammation, angiogenesis and tunneling nanotube (TNT) formation but also as a regulator of cell proliferation and migration. The expression of TNFAIP2 is frequently abnormal in human cancers and in infectious diseases. Due to its significant functions in cell proliferation, angiogenesis, migration and invasion, TNFAIP2 could be a potential diagnostic biomarker and therapeutic target for cancer.
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Affiliation(s)
- Lin Jia
- Department of Biology, Yuxi Normal University, Yuxi, China
| | - Yundong Shi
- Department of Biology, Yuxi Normal University, Yuxi, China
| | - Yi Wen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Wei Li
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming, China.,Medical College of Kunming University of Science and Technology, Kunming, China
| | - Jing Feng
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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30
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Gu S, Liang H, Qi D, Mao L, Mao G, Qian L, Zhang S. Knockdown of KIF26B inhibits breast cancer cell proliferation, migration, and invasion. Onco Targets Ther 2018; 11:3195-3203. [PMID: 29881293 PMCID: PMC5985780 DOI: 10.2147/ott.s163346] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Background Kinesin family member 26B (KIF26B) plays a key role in the development and progression of many human cancers. However, the role and underlying mechanisms of KIF26B in breast cancer cells remain unknown. Materials and methods In this study, we inhibited the expression of KIF26B in MDA-MB-231 and MCF-7 cells using lentivirus-delivered shRNA. Results Lentivirus-mediated KIF26B knockdown significantly suppressed cell proliferation, colony formation, migration, and invasion. Furthermore, cell cycle analyses revealed that the percentage of cells in the G0/G1 phase was significantly increased in KIF26B knockdown cells. Moreover, the knockdown of KIF26B significantly promoted cell apoptosis via the upregulation of cleaved caspase-3 and Bax. Conclusion Our data indicate that KIF26B plays a pivotal role in tumor growth and metastasis in breast cancer cells and may be a potential therapeutic target for treating breast cancer.
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Affiliation(s)
- Shudong Gu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Donghui Qi
- Medical College of Nantong University, Nantong 226001, China
| | - Liyan Mao
- Department of Endoscopic Diagnosis and Treatment of Digestive Diseases, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guoxin Mao
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Li Qian
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, China
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31
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Tang X, Zha L, Li H, Liao G, Huang Z, Peng X, Wang Z. Upregulation of GNL3 expression promotes colon cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway. Oncol Rep 2017; 38:2023-2032. [PMID: 28849076 PMCID: PMC5652940 DOI: 10.3892/or.2017.5923] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 08/03/2017] [Indexed: 11/09/2022] Open
Abstract
G protein nucleolar 3 (GNL3), a nucleolar GTP-binding protein, is highly expressed in progenitor cells, stem cells, and various types of cancer cells. Therefore, it is considered to have an important role in cancer pathogenesis. GNL3 has been reported to play crucial roles in cell proliferation, cell cycle regulation, inhibition of differentiation, ribosome biogenesis, and the maintenance of stemness, genome stability and telomere integrity. Furthermore, GNL3 has recently been shown to be involved in cancer invasion and metastasis. However, the biological significance of GNL3 in the invasion and metastasis of colon cancer remains unclear. This study was performed to address this gap in knowledge. GNL3 expression was upregulated in colon cancer tissue specimens and correlated with tumor differentiation, invasion and metastasis. GNL3 overexpression promoted cell proliferation, invasion, migration and the epithelial-mesenchymal transition (EMT) in colon cancer cells. Moreover, inhibition of the EMT and the Wnt/β-catenin signaling pathway induced by GNL3 knockdown was partially reversed by lithium chloride (LiCl). Based on these data, GNL3 promotes the EMT in colon cancer by activating the Wnt/β-catenin signaling pathway. In summary, GNL3 is upregulated in colon cancer and plays an important role in tumor growth, invasion and metastasis. Strategies targeting GNL3 are potential treatments for colon cancer.
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Affiliation(s)
- Xi Tang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Lang Zha
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hui Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Gang Liao
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zhen Huang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xudong Peng
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ziwei Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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