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Shen P, Shi Y, Xu P, Rao L, Wang Z, Jiang J, Weng M. The construction of a prognostic model by apoptosis-related genes to predict survival, immune landscape, and medication in cholangiocarcinoma. Clin Res Hepatol Gastroenterol 2024; 48:102430. [PMID: 39069260 DOI: 10.1016/j.clinre.2024.102430] [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: 04/24/2024] [Revised: 07/17/2024] [Accepted: 07/26/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a highly aggressive and invasive malignant tumor of the bile duct, with a poor prognosis and a high mortality rate. Currently, there is a lack of effective targeted treatment methods and reliable biomarkers for prognosis. METHODS We downloaded RNA-seq and clinical data of CCA from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases as training and test sets. The apoptosis-related genes were obtained from the Molecular Signatures Database (MsigDB) database. We used univariate/multivariate Cox regression and Lasso regression analyses to construct a riskscore prognostic model. Based on the median riskscore, we clustered the patients into high-risk (HR) and low-risk (LR) groups. We carried out Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially expressed genes (DEGs) in HR and LR groups. The single sample gene set enrichment analysis (ssGSEA) was employed to analyze the immune infiltration of the HR and LR groups. The CellMiner database was utilized to predict drugs and perform molecular docking on drugs and target proteins. RESULTS We identified 8 genes with prognostic significance to construct a prognostic model. Results of GO and KEGG demonstrated that DEGs were mainly enriched in biological functions such as fatty acid metabolic processes and pathways such as the cAMP signaling pathway. Results of ssGSEA uncovered that immune cells such as DCs and Macrophages in the HR group, as well as immune functions such as Check-point and Parainflammation, were considerably higher than those in the LR group. Drug sensitivity prediction and results of molecular docking revealed that Rigosertib targeted the prognostic genes MAP3K1. HYPOTHEMYCIN and AMG900 effectively targeted JUN. CONCLUSION Our project suggested that the prognostic model with apoptotic features can effectively predict prognosis in CCA patients, proffering prognostic biomarkers and potential therapeutic targets for CCA patients.
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Affiliation(s)
- Peng Shen
- Department of Hepatological surgery, People's Hospital of Qu Zhou, Quzhou City, Zhejiang Province 324000, China
| | - Yinsheng Shi
- Department of Hepatological surgery, People's Hospital of Qu Zhou, Quzhou City, Zhejiang Province 324000, China
| | - Pengcheng Xu
- Department of Hepatological surgery, People's Hospital of Qu Zhou, Quzhou City, Zhejiang Province 324000, China
| | - Linbin Rao
- Department of Hepatological surgery, People's Hospital of Qu Zhou, Quzhou City, Zhejiang Province 324000, China
| | - Zhengfei Wang
- Department of Hepatological surgery, People's Hospital of Qu Zhou, Quzhou City, Zhejiang Province 324000, China
| | - Junjie Jiang
- Department of Hepatological surgery, People's Hospital of Qu Zhou, Quzhou City, Zhejiang Province 324000, China
| | - Meiling Weng
- Department of Medical Oncology, People's Hospital of Qu Zhou, No. 100 Minjiang Avenue, Quzhou City, Zhejiang Province 324000, China.
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Liu B, Liu Y, Yang S, Ye J, Hu J, Chen S, Wu S, Liu Q, Tang F, Liu Y, He Y, Du Y, Zhang G, Guo Q, Yang C. Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER + breast cancer. Cancer Lett 2024; 600:217179. [PMID: 39154704 DOI: 10.1016/j.canlet.2024.217179] [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: 03/26/2024] [Revised: 05/23/2024] [Accepted: 08/06/2024] [Indexed: 08/20/2024]
Abstract
Acquired resistance to endocrine treatments remains a major clinical challenge. In this study, we found that desmoglein-2 (DSG2) plays a major role in acquired endocrine resistance and cellular plasticity in ER+ breast cancer (BC). By analysing the well-established fulvestrant-resistant ER+ BC model using single-cell RNA-seq, we revealed that ER inhibition leads to a specific increase in DSG2 in cancer cell populations, which in turn enhances desmosome formation in vitro and in vivo and cell phenotypic plasticity that promotes resistance to treatment. DSG2 depletion reduced tumorigenesis and metastasis in fulvestrant-resistant xenograft models and promoted fulvestrant efficiency. Mechanistically, DSG2 forms a desmosome complex with JUP and Vimentin and triggers Wnt/PCP signalling. We showed that elevated DSG2 levels, along with reduced ER levels and an activated Wnt/PCP pathway, predicted poor survival, suggesting that a DSG2high signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.
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Affiliation(s)
- Bohan Liu
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuting Liu
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuang Yang
- Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingwen Ye
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajie Hu
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Si Chen
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiyi Wu
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinqing Liu
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fen Tang
- Department of Breast Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiwen Liu
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiqing He
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Du
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guoliang Zhang
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Guo
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cuixia Yang
- Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Deng EZ, Marino GB, Clarke DJB, Diamant I, Resnick AC, Ma W, Wang P, Ma'ayan A. Multiomics2Targets identifies targets from cancer cohorts profiled with transcriptomics, proteomics, and phosphoproteomics. CELL REPORTS METHODS 2024; 4:100839. [PMID: 39127042 PMCID: PMC11384097 DOI: 10.1016/j.crmeth.2024.100839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/06/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024]
Abstract
The availability of data from profiling of cancer patients with multiomics is rapidly increasing. However, integrative analysis of such data for personalized target identification is not trivial. Multiomics2Targets is a platform that enables users to upload transcriptomics, proteomics, and phosphoproteomics data matrices collected from the same cohort of cancer patients. After uploading the data, Multiomics2Targets produces a report that resembles a research publication. The uploaded matrices are processed, analyzed, and visualized using the tools Enrichr, KEA3, ChEA3, Expression2Kinases, and TargetRanger to identify and prioritize proteins, genes, and transcripts as potential targets. Figures and tables, as well as descriptions of the methods and results, are automatically generated. Reports include an abstract, introduction, methods, results, discussion, conclusions, and references and are exportable as citable PDFs and Jupyter Notebooks. Multiomics2Targets is applied to analyze version 3 of the Clinical Proteomic Tumor Analysis Consortium (CPTAC3) pan-cancer cohort, identifying potential targets for each CPTAC3 cancer subtype. Multiomics2Targets is available from https://multiomics2targets.maayanlab.cloud/.
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Affiliation(s)
- Eden Z Deng
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Giacomo B Marino
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Daniel J B Clarke
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Ido Diamant
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Adam C Resnick
- Center for Data Driven Discovery in Biomedicine, Division of Neurosurgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Weiping Ma
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029, USA
| | - Pei Wang
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029, USA
| | - Avi Ma'ayan
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
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Wan H, Teh MT, Mastroianni G, Ahmad US. Comparative Transcriptome Analysis Identifies Desmoglein-3 as a Potential Oncogene in Oral Cancer Cells. Cells 2023; 12:2710. [PMID: 38067138 PMCID: PMC10705960 DOI: 10.3390/cells12232710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/14/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
The role of desmoglein-3 (DSG3) in oncogenesis is unclear. This study aimed to uncover molecular mechanisms through comparative transcriptome analysis in oral cancer cells, defining potential key genes and associated biological processes related to DSG3 expression. Four mRNA libraries of oral squamous carcinoma H413 cell lines were sequenced, and 599 candidate genes exhibited differential expression between DSG3-overexpressing and matched control lines, with 12 genes highly significantly differentially expressed, including 9 upregulated and 3 downregulated. Genes with known implications in cancer, such as MMP-13, KRT84, OLFM4, GJA1, AMOT and ADAMTS1, were strongly linked to DSG3 overexpression. Gene ontology analysis indicated that the DSG3-associated candidate gene products participate in crucial cellular processes such as junction assembly, focal adhesion, extracellular matrix formation, intermediate filament organisation and keratinocyte differentiation. Validation of RNA-Seq was performed through RT-qPCR, Western blotting and immunofluorescence analyses. Furthermore, using transmission electron microscopy, we meticulously examined desmosome morphology and revealed a slightly immature desmosome structure in DSG3-overexpressing cells compared to controls. No changes in desmosome frequency and diameter were observed between the two conditions. This study underscores intricate and multifaceted alterations associated with DSG3 in oral squamous carcinoma cells, implying a potential oncogenic role of this gene in biological processes that enable cell communication, motility and survival.
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Affiliation(s)
- Hong Wan
- Center for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
| | - Muy-Teck Teh
- Center for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
| | - Giulia Mastroianni
- School of Biological and Behavioural Sciences, Faculty of Science and Engineering, Queen Mary University of London, London E1 4NS, UK
| | - Usama Sharif Ahmad
- Center for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
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Madan S, Sinha S, Chang T, Gutkind JS, Cohen EEW, Schäffer AA, Ruppin E. Pan-Cancer Analysis of Patient Tumor Single-Cell Transcriptomes Identifies Promising Selective and Safe Chimeric Antigen Receptor Targets in Head and Neck Cancer. Cancers (Basel) 2023; 15:4885. [PMID: 37835579 PMCID: PMC10571718 DOI: 10.3390/cancers15194885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/30/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical successes for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets, which we define intuitively to be cell surface proteins that are expressed widely by cancer cells but minimally by healthy cells in the tumor microenvironment and other normal tissues. Analyzing patient tumor single-cell transcriptomics data, we first defined and quantified selectivity and safety scores of existing CAR targets for indications in which they are in clinical trials or approved. We then sought new candidate cell surface CAR targets that have better selectivity and safety scores than those currently being tested. Remarkably, in almost all cancer types, we could not find such better targets, testifying to the near optimality of the current target space. However, in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR targets, we identified a total of twenty candidate novel CAR targets, five of which have both superior selectivity and safety scores. These newly identified cell surface targets lay a basis for future investigations that may lead to better CAR treatments in HNSC.
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Affiliation(s)
- Sanna Madan
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA; (S.M.); (S.S.); (T.C.)
- Department of Computer Science, University of Maryland, College Park, MD 20742, USA
| | - Sanju Sinha
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA; (S.M.); (S.S.); (T.C.)
| | - Tiangen Chang
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA; (S.M.); (S.S.); (T.C.)
| | - J. Silvio Gutkind
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; (J.S.G.); (E.E.W.C.)
- Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA
| | - Ezra E. W. Cohen
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; (J.S.G.); (E.E.W.C.)
- Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA
| | - Alejandro A. Schäffer
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA; (S.M.); (S.S.); (T.C.)
| | - Eytan Ruppin
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA; (S.M.); (S.S.); (T.C.)
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Wu C, Ma S, Zhao B, Qin C, Wu Y, Di J, Suo L, Fu X. Drivers of plateau adaptability in cashmere goats revealed by genomic and transcriptomic analyses. BMC Genomics 2023; 24:428. [PMID: 37528361 PMCID: PMC10391913 DOI: 10.1186/s12864-023-09333-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 04/25/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND The adaptive evolution of plateau indigenous animals is a current research focus. However, phenotypic adaptation is complex and may involve the interactions between multiple genes or pathways, many of which remain unclear. As a kind of livestock with important economic value, cashmere goat has a high ability of plateau adaptation, which provides us with good materials for studying the molecular regulation mechanism of animal plateau adaptation. RESULTS In this study, 32 Jiangnan (J) and 32 Tibetan (T) cashmere goats were sequenced at an average of 10. Phylogenetic, population structure, and linkage disequilibrium analyses showed that natural selection or domestication has resulted in obvious differences in genome structure between the two breeds. Subsequently, 553 J vs. T and 608 T vs. J potential selected genes (PSGs) were screened. These PSGs showed potential relationships with various phenotypes, including myocardial development and activity (LOC106502520, ATP2A2, LOC102181869, LOC106502520, MYL2, ISL1, and LOC102181869 genes), pigmentation (MITF and KITLG genes), hair follicles/hair growth (YAP1, POGLUT1, AAK1, HES1, WNT1, PRKAA1, TNKS, WNT5A, VAX2, RSPO4, CSNK1G1, PHLPP2, CHRM2, PDGFRB, PRKAA1, MAP2K1, IRS1, LPAR1, PTEN, PRLR, IBSP, CCNE2, CHAD, ITGB7, TEK, JAK2, and FGF21 genes), and carcinogenesis (UBE2R2, PIGU, DIABLO, NOL4L, STK3, MAP4, ADGRG1, CDC25A, DSG3, LEPR, PRKAA1, IKBKB, and ABCG2 genes). Phenotypic analysis showed that Tibetan cashmere goats has finer cashmere than Jiangnan cashmere goats, which may allow cashmere goats to better adapt to the cold environment in the Tibetan plateau. Meanwhile, KRTs and KAPs expression in Jiangnan cashmere goat skin was significantly lower than in Tibetan cashmere goat. CONCLUSIONS The mutations in these PSGs maybe closely related to the plateau adaptation ability of cashmere goats. In addition, the expression differences of KRTs and KAPs may directly determine phenotypic differences in cashmere fineness between the two breeds. In conclusion, this study provide a reference for further studying plateau adaptive mechanism in animals and goat breeding.
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Affiliation(s)
- Cuiling Wu
- Key Laboratory of Special Environments Biodiversity Application and Regulation in Xinjiang, School of Life Sciences, Xinjiang Normal University, Xinjiang, Urumqi, 830017, China
| | - Shengchao Ma
- Key Laboratory of Genetics Breeding and Reproduction of Xinjiang Wool-sheep Cashmere-goat (XJYS1105), Institute of Animal Science, Xinjiang Academy of Animal Sciences, Xinjiang, Urumqi, 830011, China
- College of Animal Science, Xinjiang Agricultural University, Xinjiang, Urumqi, 830052, China
| | - Bingru Zhao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Chongkai Qin
- Xinjiang Aksu Prefecture Animal Husbandry Technology Extension Center, Xinjiang Aksu, 843000, China
| | - Yujiang Wu
- Institute of Animal Science, Tibet Academy of Agricultural and Animal Husbandry Sciences, Tibet Lhasa, 850009, China
| | - Jiang Di
- Key Laboratory of Genetics Breeding and Reproduction of Xinjiang Wool-sheep Cashmere-goat (XJYS1105), Institute of Animal Science, Xinjiang Academy of Animal Sciences, Xinjiang, Urumqi, 830011, China
| | - Langda Suo
- Institute of Animal Science, Tibet Academy of Agricultural and Animal Husbandry Sciences, Tibet Lhasa, 850009, China.
| | - Xuefeng Fu
- Key Laboratory of Genetics Breeding and Reproduction of Xinjiang Wool-sheep Cashmere-goat (XJYS1105), Institute of Animal Science, Xinjiang Academy of Animal Sciences, Xinjiang, Urumqi, 830011, China.
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Viehweger F, Azem A, Gorbokon N, Uhlig R, Lennartz M, Rico SD, Kind S, Reiswich V, Kluth M, Hube-Magg C, Bernreuther C, Büscheck F, Clauditz TS, Fraune C, Jacobsen F, Krech T, Lebok P, Steurer S, Burandt E, Minner S, Marx AH, Simon R, Sauter G, Menz A, Hinsch A. Desmoglein 3 (Dsg3) Expression in Cancer: A Tissue Microarray Study on 15,869 Tumors. Pathol Res Pract 2022; 240:154200. [DOI: 10.1016/j.prp.2022.154200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/07/2022]
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Huang Z, Zhang Z, Zhou C, Liu L, Huang C. Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm (Beijing) 2022; 3:e144. [PMID: 35601657 PMCID: PMC9115588 DOI: 10.1002/mco2.144] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/05/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.
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Affiliation(s)
- Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
| | - Chengwei Zhou
- Department of Thoracic Surgery the Affiliated Hospital of Medical School of Ningbo University Ningbo China
| | - Lin Liu
- Department of Thoracic Surgery the Affiliated Hospital of Medical School of Ningbo University Ningbo China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
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Characterization of Desmoglein 3 (DSG3) as a Sensitive and Specific Marker for Esophageal Squamous Cell Carcinoma. Gastroenterol Res Pract 2022; 2022:2220940. [PMID: 35251162 PMCID: PMC8894070 DOI: 10.1155/2022/2220940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Although P40 and P63 are both sensitive and specific for routine esophageal squamous cell carcinoma (SCC) diagnosis, we recently showed that P40 and P63 immunoreactivities were significantly lower in well-differentiated SCC than those in higher grade tumors. Therefore, a novel esophageal SCC marker, ideally performing better in well-differentiated SCC, is still needed. We characterized desmoglein 3 (DSG3) immunohistochemistry in esophageal SCC, esophageal adenocarcinoma, small-cell lung carcinoma, and large B-cell lymphoma, alongside P40 and CK5/6. The World Health Organization classification was used to grade tumors as well-differentiated (WD), moderately differentiated (MD), or poorly differentiated (PD). There were 20 WD, 26 MD, and 17 PD components among 39 esophageal SCC cases. All esophageal SCC components showed significant DSG3 immunoreactivity (mean, 80%; range, 30%–100%), and the proportions of DSG3 immunoreactive cells were higher in the WD and MD components than in the PD components. No esophageal adenocarcinoma cases showed more than 10% DSG3 immunoreactivity with only weak cytoplasmic staining. With a 5% immunoreactivity cutoff, DSG3 positivity was 100% in all 63 SCC components, 18% in adenocarcinoma cases, and 0% in small-cell lung carcinoma or large B-cell lymphoma cases. The overall DSG3 specificity was 94%. To the best of our knowledge, this is the first study to characterize DSG3 as a sensitive and specific marker for esophageal SCC.
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Zhu JL, Paniagua RT, Chen HW, Florez-Pollack S, Kunzler E, Teske N, Rainwater YB, Li QZ, Hosler GA, Li W, Ramirez DMO, Monson NL, Jacobe HT. Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea. J Transl Med 2022; 20:41. [PMID: 35073943 PMCID: PMC8785566 DOI: 10.1186/s12967-022-03246-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 01/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. METHODS Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera. RESULTS Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11-30, 41-60, 51-70, and 91-110. CONCLUSIONS A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.
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Affiliation(s)
- Jane L Zhu
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
| | - Ricardo T Paniagua
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
| | - Henry W Chen
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
| | - Stephanie Florez-Pollack
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
| | - Elaine Kunzler
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
| | - Noelle Teske
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
| | - Yevgeniya Byekova Rainwater
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
- ProPath, Dallas, TX, USA
| | - Quan-Zhen Li
- Department of Immunology and Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Gregory A Hosler
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA
- ProPath, Dallas, TX, USA
| | - Wenhao Li
- Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Denise M O Ramirez
- Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Nancy L Monson
- Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Heidi T Jacobe
- Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA.
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11
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Ahmad US, Parkinson EK, Wan H. Desmoglein-3 induces YAP phosphorylation and inactivation during collective migration of oral carcinoma cells. Mol Oncol 2022; 16:1625-1649. [PMID: 35000271 PMCID: PMC9019900 DOI: 10.1002/1878-0261.13177] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 11/07/2022] Open
Abstract
Alterations of the Hippo-YAP pathway are potential targets for oral squamous cell carcinoma (OSCC) therapy, but heterogeneity in this pathway could be responsible for therapeutic resistance. We analysed the Hippo-YAP signatures in a cohort of characterised keratinocyte cell lines derived from the mouth floor and buccal mucosa from different stages of OSCC tumour progression and focused on the specific role of YAP on invasive and metastatic potential. We confirmed heterogeneity in the Hippo-YAP pathway in OSCC lines, including overexpression of YAP1, WWTR1 (often referred to as TAZ) and the major Hippo signalling components, as well as the variations in the genes encoding the intercellular anchoring junctional proteins, which could potentially regulate the Hippo pathway. Specifically, desmoglein-3 (DSG3) exhibits a unique and mutually exclusive regulation of YAP via YAP phosphorylation during the collective migration of OSCC cells. Mechanistically, such regulation is associated with inhibition of phosphorylation of epidermal growth factor receptor (EGFR) (S695/Y1086) and its downstream effectors heat shock protein beta-1 (Hsp27) (S78/S82) and transcription factor AP-1 (c-Jun) (S63), leading to YAP phosphorylation coupled with its cytoplasmic translocation and inactivation. Additionally, OSCC lines display distinct phenotypes of YAP dependency or a mixed YAP and TAZ dependency for cell migration, and present distinct patterns in YAP abundance and activity, with the latter being associated with YAP nuclear localisation. In conclusion, this study has provided evidence for a newly identified paradigm in the Hippo-YAP pathway and suggests a new regulation mechanism involved in the control of collective migration in OSCC cells.
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Affiliation(s)
- Usama Sharif Ahmad
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, School of Medicine and Dentistry, Barts and The London, London, UK
| | - Eric Kenneth Parkinson
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, School of Medicine and Dentistry, Barts and The London, London, UK
| | - Hong Wan
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, School of Medicine and Dentistry, Barts and The London, London, UK
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12
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Angiulli F, Colombo T, Fassetti F, Furfaro A, Paci P. Mining sponge phenomena in RNA expression data. J Bioinform Comput Biol 2021; 20:2150022. [PMID: 34794369 DOI: 10.1142/s0219720021500220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In the last few years, the interactions among competing endogenous RNAs (ceRNAs) have been recognized as a key post-transcriptional regulatory mechanism in cell differentiation, tissue development, and disease. Notably, such sponge phenomena substracting active microRNAs from their silencing targets have been recognized as having a potential oncosuppressive, or oncogenic, role in several cancer types. Hence, the ability to predict sponges from the analysis of large expression data sets (e.g. from international cancer projects) has become an important data mining task in bioinformatics. We present a technique designed to mine sponge phenomena whose presence or absence may discriminate between healthy and unhealthy populations of samples in tumoral or normal expression data sets, thus providing lists of candidates potentially relevant in the pathology. With this aim, we search for pairs of elements acting as ceRNA for a given miRNA, namely, we aim at discovering miRNA-RNA pairs involved in phenomena which are clearly present in one population and almost absent in the other one. The results on tumoral expression data, concerning five different cancer types, confirmed the effectiveness of the approach in mining interesting knowledge. Indeed, 32 out of 33 miRNAs and 22 out of 25 protein-coding genes identified as top scoring in our analysis are corroborated by having been similarly associated with cancer processes in independent studies. In fact, the subset of miRNAs selected by the sponge analysis results in a significant enrichment of annotation for the KEGG32 pathway "microRNAs in cancer" when tested with the commonly used bioinformatic resource DAVID. Moreover, often the cancer datasets where our sponge analysis identified a miRNA as top scoring match the one reported already in the pertaining literature.
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13
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Müller L, Hatzfeld M, Keil R. Desmosomes as Signaling Hubs in the Regulation of Cell Behavior. Front Cell Dev Biol 2021; 9:745670. [PMID: 34631720 PMCID: PMC8495202 DOI: 10.3389/fcell.2021.745670] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/31/2021] [Indexed: 12/19/2022] Open
Abstract
Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.
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Affiliation(s)
- Lisa Müller
- Department for Pathobiochemistry, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Mechthild Hatzfeld
- Department for Pathobiochemistry, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - René Keil
- Department for Pathobiochemistry, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
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14
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Rehman A, Huang Y, Wan H. Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein. Life (Basel) 2021; 11:life11070621. [PMID: 34206820 PMCID: PMC8303937 DOI: 10.3390/life11070621] [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: 06/08/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 01/28/2023] Open
Abstract
The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. There is still no cure to the disease apart from the use of corticosteroids and immunosuppressive agents. Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. Thus, further understanding of the molecular basis underlying this disease process is vital to develop targeted therapies. Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. DSG3 is a pivotal player in mediating outside-in signaling involved in cell junction remodeling, cell proliferation, differentiation, migration or apoptosis, thus validating its biological function in tissue integrity and homeostasis beyond desmosome adhesion. Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. The purpose of this review is to summarize the earlier and recent advances highlighting our recent findings related to PV pathogenesis that may pave the way for future research to develop novel specific therapies in curing this disease.
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Affiliation(s)
- Ambreen Rehman
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.R.); (Y.H.)
- Department of Oral Diagnosis and Medicine, Dr Ishrat Ul Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Yunying Huang
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.R.); (Y.H.)
| | - Hong Wan
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.R.); (Y.H.)
- Correspondence:
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15
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Liu YQ, Zou HY, Xie JJ, Fang WK. Paradoxical Roles of Desmosomal Components in Head and Neck Cancer. Biomolecules 2021; 11:914. [PMID: 34203070 PMCID: PMC8234459 DOI: 10.3390/biom11060914] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 02/05/2023] Open
Abstract
Desmosomes are intercellular adhesion complexes involved in various aspects of epithelial pathophysiology, including tissue homeostasis, morphogenesis, and disease development. Recent studies have reported that the abnormal expression of various desmosomal components correlates with tumor progression and poor survival. In addition, desmosomes have been shown to act as a signaling platform to regulate the proliferation, invasion, migration, morphogenesis, and apoptosis of cancer cells. The occurrence and progression of head and neck cancer (HNC) is accompanied by abnormal expression of desmosomal components and loss of desmosome structure. However, the role of desmosomal components in the progression of HNC remains controversial. This review aims to provide an overview of recent developments showing the paradoxical roles of desmosomal components in tumor suppression and promotion. It offers valuable insights for HNC diagnosis and therapeutics development.
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Affiliation(s)
- Yin-Qiao Liu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China; (Y.-Q.L.); (H.-Y.Z.)
| | - Hai-Ying Zou
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China; (Y.-Q.L.); (H.-Y.Z.)
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China; (Y.-Q.L.); (H.-Y.Z.)
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, China
| | - Wang-Kai Fang
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China; (Y.-Q.L.); (H.-Y.Z.)
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, China
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16
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Lin H, Hu C, Zheng S, Zhang X, Chen R, Zhou Q. A novel gene signature for prognosis prediction and chemotherapy response in patients with pancreatic cancer. Aging (Albany NY) 2021; 13:12493-12513. [PMID: 33901011 PMCID: PMC8148498 DOI: 10.18632/aging.202922] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/16/2021] [Indexed: 12/22/2022]
Abstract
Pancreatic cancer is a lethal disease. Chemoresistance is one of the characteristics of pancreatic cancer and leads to a poor prognosis. This study built an effective predictive model for personalized treatment and explored the molecular mechanism of chemoresistance. A four-gene signature, including serine peptidase inhibitor Kazal type 1 (SPINK1), anoctamin 1 (ANO1), desmoglein 3 (DSG3) and GTPase, IMAP family member 1 (GIMAP1) was identified and associated with prognosis and chemoresistance in the training group. An internal testing dataset and the external dataset, GSE57495, were used for validation and showed a good performance of the gene signature. The high-risk group was enriched with multiple oncological pathways related to immunosuppression and was correlated with epidermal growth factor receptor (EGFR) expression, a target molecule of Erlotinib. In conclusion, this study identified a four-gene signature and established two nomograms for predicting prognosis and chemotherapy responses in patients with pancreatic cancer. The clinical value of the nomogram was evaluated by decision curve analysis (DCA). It showed that these may be helpful for clinical treatment decision-making and the discovery of the potential molecular mechanism and therapy targets for pancreatic cancer.
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Affiliation(s)
- Hongcao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Department of Pancreatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Chonghui Hu
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Shangyou Zheng
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Xiang Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Department of Pancreatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Rufu Chen
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Quanbo Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Department of Pancreatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
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17
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Minabe M, Akiyama Y, Higa K, Tachikawa T, Takahashi S, Nomura T, Kouno M. A potential link between desmoglein 3 and epidermal growth factor receptor in oral squamous cell carcinoma and its effect on cetuximab treatment efficacy. Exp Dermatol 2020; 28:614-617. [PMID: 30907457 DOI: 10.1111/exd.13920] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 01/23/2019] [Accepted: 02/14/2019] [Indexed: 01/21/2023]
Abstract
Desmoglein (DSG) 3 is overexpressed in oral squamous cell carcinoma (OSCC). Epidermal growth factor receptor (EGFR) inhibitor cetuximab is widely used for OSCC treatment. Several evidences suggest a correlation between DSG3 and EGFR in epidermal keratinocytes. EGFR inhibition has been shown to enhance cell-cell adhesion and induce terminal differentiation in epidermal cells. Thus, here we investigated the DSG3-EGFR interaction in OSCC and its effect on cetuximab treatment. Cell lines established from the primary tumor and metastatic lymph nodes of four OSCC patients and three commercial OSCC cell lines were used for the experiments. Cells from metastatic lymph nodes of each patient expressed increased DSG3 and EGFR than cells from the primary tumor in the same patient. Cetuximab treatment increased DSG3 expression by up to 3.5-fold in seven of the 11 cell lines. A high calcium concentration increased the expression of DSG3 and EGFR in a dose-dependent manner. Strikingly, a high calcium-associated DSG3 induction enhanced cetuximab efficacy by up to 23% increase in cetuximab-low-sensitive cell lines. Our findings also suggest a correlation between DSG3 and EGFR in OSCC, and this affects cetuximab treatment efficacy.
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Affiliation(s)
- Masaki Minabe
- Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, Ichikawa-shi, Japan
| | - Yurie Akiyama
- Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, Ichikawa-shi, Japan
| | - Kazunari Higa
- Cornea Center Eye Bank, Tokyo Dental College Ichikawa General Hospital, Ichikawa-shi, Japan
| | - Tetsuhiko Tachikawa
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Kitaadachi-gun, Japan
| | - Shinichi Takahashi
- Department of Dermatology, Tokyo Dental College Ichikawa General Hospital, Ichikawa-shi, Japan
| | - Takeshi Nomura
- Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, Ichikawa-shi, Japan
| | - Michiyoshi Kouno
- Department of Dermatology, Tokyo Dental College Ichikawa General Hospital, Ichikawa-shi, Japan
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18
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Li P, Wang QS, Zhai Y, Xiong RP, Chen X, Liu P, Peng Y, Zhao Y, Ning YL, Yang N, Zhou YG. Ski mediates TGF-β1-induced fibrosarcoma cell proliferation and promotes tumor growth. J Cancer 2020; 11:5929-5940. [PMID: 32922535 PMCID: PMC7477421 DOI: 10.7150/jca.46074] [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: 03/16/2020] [Accepted: 07/20/2020] [Indexed: 11/05/2022] Open
Abstract
Background: TGF-β1 promotes cell proliferation in only some tumors and exerts bidirectional regulatory effects on the proliferation of fibroblasts. This study intends to explore whether the mechanism is related to increased expression of Ski. Methods: Cell proliferation of the fibrosarcoma cell line L929 was assessed with an ELISA BrdU kit. The mRNA and protein expression levels of the corresponding factors were measured by RT-qPCR, immunohistochemistry or Western blotting in vitro and in vivo. Additionally, c-Ski was knocked down using RNAi. The expression of Ski in human dermatofibrosarcoma protuberans (DFSP) specimens was measured by immunohistochemistry. Results: TGF-β1 promoted the continued proliferation of L929 cells in a dose-dependent manner, with increased c-Ski expression levels. Conversely, inhibition of c-Ski significantly abrogated this unidirectional effect, significantly inhibited the decrease in p21 protein levels and did not affect the increase in p-Smad2/3 levels upon TGF-β1 treatment. Similarly, inhibition of c-Ski significantly abrogated the growth-promoting effect of TGF-β1 on xenograft tumors. Furthermore, we found that high expression of Ski in DFSP was correlated with a low degree of tumor differentiation. Conclusions: Our data reveal that high c-Ski expression is a cause of TGF-β1-promoted proliferation in fibrosarcoma tumor cells and show that inhibiting Ski expression might be effective for treating tumors with high Ski levels.
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Affiliation(s)
- Ping Li
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Qiu-Shi Wang
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China.,Department of Pathology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Yu Zhai
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Ren-Ping Xiong
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Xing Chen
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Ping Liu
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Yan Peng
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Yan Zhao
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Ya-Lei Ning
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Nan Yang
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
| | - Yuan-Guo Zhou
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, People's Republic of China
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19
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Holmes BJ, von Eyben R, Attardi LD, Kong CS, Le QT, Nathan CAO. Pilot study of loss of the p53/p63 target gene PERP at the surgical margin as a potential predictor of local relapse in head and neck squamous cell carcinoma. Head Neck 2020; 42:3188-3196. [PMID: 33034918 DOI: 10.1002/hed.26358] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 05/16/2020] [Accepted: 06/16/2020] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND PERP (p53 apoptosis effector related to PMP22) localizes to desmosomes and suppresses squamous cell carcinoma development. Loss of PERP leads to worse local control in head and neck squamous cell carcinoma (HNSCC), likely by destabilizing desmosomes. We evaluated PERP loss at HNSCC surgical margins as a predictor of local relapse. METHODS Combining discovery (n = 17) and validation (n = 31) cohorts, we examined membranous PERP protein expression by immunohistochemistry in surgical mucosal margins with competing risk analysis of the relationship between local relapse and PERP expression. RESULTS Of the 44 analyzable patients, the 2-year cumulative incidence of local relapse was 44.4% for the PERP-negative group and 16.4% for the PERP-positive group (P = .01). A trend toward worse progression-free survival (P = .09) and overall survival (P = .06) was observed with loss of PERP. CONCLUSIONS PERP loss at surgical margins is associated with higher risk of local recurrence in HNSCC, warranting further evaluation in a larger prospective study.
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Affiliation(s)
- Brittany J Holmes
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Rie von Eyben
- Department of Radiation Oncology, Stanford University, Stanford, California, USA
| | - Laura D Attardi
- Department of Radiation Oncology, Stanford University, Stanford, California, USA.,Department of Genetics, Stanford University, Stanford, California, USA
| | - Christina S Kong
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Quynh-Thu Le
- Department of Radiation Oncology, Stanford University, Stanford, California, USA
| | - Cherie-Ann O Nathan
- Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Science Center, Shreveport, Louisiana, USA
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20
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Fujii E, Funahashi S, Taniguchi K, Kawai S, Nakano K, Kato A, Suzuki M. Tissue-specific effects of an anti-desmoglein-3 ADCC antibody due to expression of the target antigen and physiological characteristics of the mouse vagina. J Toxicol Pathol 2020; 33:67-76. [PMID: 32425339 PMCID: PMC7218237 DOI: 10.1293/tox.2019-0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 11/18/2019] [Indexed: 01/17/2023] Open
Abstract
Desmoglein-3 (DSG3) is a potential target of cytotoxic antibody therapy for squamous cell carcinomas but is also expressed in various normal squamous epithelia. We obtained information about DSG3 distribution in mouse tissues by immunohistochemistry and conducted an intravenous multiple-dose study in mouse to estimate the toxic potential of anti-DSG3 therapy. DSG3 was expressed in the squamous epithelium of several organs including the skin, esophagus, tongue, forestomach, eye, and vagina. It was expressed at all estrous cycles of the vagina with changes in distribution patterns along with the structural changes in each cycle, and expression was reduced in ovariectomized (OVX) mice. On the administration of the antibody, there was disarrangement of the vaginal mucosal epithelium with formation of miroabscess, increased granulocyte infiltration, and single cell necrosis. Despite similar expression levels of DSG3 in other tissues, histopathological changes were limited to the vagina. The severity of the changes was reduced by ovariectomy. From these findings, the lesions were thought to be related to the drastic change in the histological structure of the vaginal mucosa accompanying the estrous cycle. Thus, we have shown that the changing expression of target antigen distribution and its relationship with physiological changes in tissue structure are important features for estimating the toxic potential of cytotoxic antibody therapy.
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Affiliation(s)
- Etsuko Fujii
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 6-1 Komaba 4, Meguro, Tokyo 153-8904, Japan.,Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Shinichi Funahashi
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 6-1 Komaba 4, Meguro, Tokyo 153-8904, Japan
| | - Kenji Taniguchi
- Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Shigeto Kawai
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 6-1 Komaba 4, Meguro, Tokyo 153-8904, Japan
| | - Kiyotaka Nakano
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 6-1 Komaba 4, Meguro, Tokyo 153-8904, Japan
| | - Atsuhiko Kato
- Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Masami Suzuki
- Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 6-1 Komaba 4, Meguro, Tokyo 153-8904, Japan.,Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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21
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Yan J, Wu L, Jia C, Yu S, Lu Z, Sun Y, Chen J. Development of a four-gene prognostic model for pancreatic cancer based on transcriptome dysregulation. Aging (Albany NY) 2020; 12:3747-3770. [PMID: 32081836 PMCID: PMC7066910 DOI: 10.18632/aging.102844] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 02/04/2020] [Indexed: 12/14/2022]
Abstract
We systematically developed a prognostic model for pancreatic cancer that was compatible across different transcriptomic platforms and patient cohorts. After performing quality control measures, we used seven microarray datasets and two RNA sequencing datasets to identify consistently dysregulated genes in pancreatic cancer patients. Weighted gene co-expression network analysis was performed to explore the associations between gene expression patterns and clinical features. The least absolute shrinkage and selection operator (LASSO) and Cox regression were used to construct a prognostic model. We tested the predictive power of the model by determining the area under the curve of the risk score for time-dependent survival. Most of the differentially expressed genes in pancreatic cancer were enriched in functions pertaining to the tumor immune microenvironment. The transcriptome profiles were found to be associated with overall survival, and four genes were identified as independent prognostic factors. A prognostic risk score was then proposed, which displayed moderate accuracy in the training and self-validation cohorts. Furthermore, patients in two independent microarray cohorts were successfully stratified into high- and low-risk prognostic groups. Thus, we constructed a reliable prognostic model for pancreatic cancer, which should be beneficial for clinical therapeutic decision-making.
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Affiliation(s)
- Jie Yan
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Liangcai Wu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Congwei Jia
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Shuangni Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zhaohui Lu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yueping Sun
- Institute of Medical Information, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Uttagomol J, Ahmad US, Rehman A, Huang Y, Laly AC, Kang A, Soetaert J, Chance R, Teh MT, Connelly JT, Wan H. Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces. Int J Mol Sci 2019; 20:ijms20246221. [PMID: 31835537 PMCID: PMC6940936 DOI: 10.3390/ijms20246221] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/05/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022] Open
Abstract
Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in the expression and localization of junction assembly proteins. The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of yes-associated protein (YAP), a mechanosensory, and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to the strain or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. Plakophilin 1 (PKP1) seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected Dsg3 junctional assembly with concomitant loss of phospho-YAP at the cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.
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Affiliation(s)
- Jutamas Uttagomol
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - Usama Sharif Ahmad
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - Ambreen Rehman
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - Yunying Huang
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - Ana C. Laly
- Centre for Cell Biology and Cutaneous Research, Blizard Institute; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.C.L.); (J.S.); (J.T.C.)
| | - Angray Kang
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - Jan Soetaert
- Centre for Cell Biology and Cutaneous Research, Blizard Institute; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.C.L.); (J.S.); (J.T.C.)
| | - Randy Chance
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - Muy-Teck Teh
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
| | - John T. Connelly
- Centre for Cell Biology and Cutaneous Research, Blizard Institute; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.C.L.); (J.S.); (J.T.C.)
| | - Hong Wan
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (J.U.); (U.S.A.); (A.R.); (Y.H.); (A.K.); (R.C.); (M.-T.T.)
- Correspondence: ; Tel.: +(44)-020-7882-7139; Fax: +(44)-020-7882-7137
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Li Y, Carrillo JA, Ding Y, He Y, Zhao C, Liu J, Zan L, Song J. DNA methylation, microRNA expression profiles and their relationships with transcriptome in grass-fed and grain-fed Angus cattle rumen tissue. PLoS One 2019; 14:e0214559. [PMID: 31622349 PMCID: PMC6797229 DOI: 10.1371/journal.pone.0214559] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022] Open
Abstract
Rumen is an organ for supplying nutrients for the growth and production of bovine, which might function differently under grass-fed and grain-fed regimens considering the association of gene expression, DNA methylation, and microRNA expression. The objective of this study was to explore the potential mechanism influencing rumen function of grass-fed and grain-fed animals. Methylated DNA binding domain sequencing (MBD-Seq) and microRNA-Seq were respectively utilized to detect the DNA methylation and microRNA expression in rumen tissue of grass-fed and grain-fed Angus cattle. Combined analysis revealed that the expression of the differentially expressed genes ADAMTS3 and ENPP3 was correlated with the methylation abundance of the corresponding differentially methylated regions (DMRs) inside these two genes, and these two genes were reported to be respectively involved in biosynthesis and regulation of glycosyltransferase activity; the differentially expressed microRNA bta-mir-122 was predicted to possibly target the differentially expressed genes OCLN and RBM47, potentially affecting the rumen function; the microRNA bta-mir-655 was exclusively detected in grain-fed group; its targets were significantly enriched in insulin and TGF-beta signaling pathways, which might worked together to regulate the function of rumen, resulting in different characteristics between grass-fed and grain-fed cattle. Collectively, our results provided insights into understanding the mechanisms determining rumen function and unraveled the biological basis underlying the economic traits to improve the productivity of animals.
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Affiliation(s)
- Yaokun Li
- College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China
| | - José A. Carrillo
- Department of Animal & Avian Sciences, University of Maryland, College Park, Maryland, United States of America
| | - Yi Ding
- Department of Animal & Avian Sciences, University of Maryland, College Park, Maryland, United States of America
| | - Yanghua He
- Department of Animal & Avian Sciences, University of Maryland, College Park, Maryland, United States of America
| | - Chunping Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Jianan Liu
- Department of Animal & Avian Sciences, University of Maryland, College Park, Maryland, United States of America
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Jiuzhou Song
- Department of Animal & Avian Sciences, University of Maryland, College Park, Maryland, United States of America
- * E-mail:
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24
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The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53. Cell Death Dis 2019; 10:750. [PMID: 31582719 PMCID: PMC6776551 DOI: 10.1038/s41419-019-1988-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/13/2019] [Accepted: 09/17/2019] [Indexed: 12/16/2022]
Abstract
Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell-cell adhesion and regulates various signaling pathways involved in the progression and metastasis of cancer where it is upregulated. We show here that expression of Dsg3 impacts on the expression and function of p53, a key transcription factor governing the responses to cellular stress. Dsg3 depletion increased p53 expression and activity, an effect enhanced by treating cells with UVB, mechanical stress and genotoxic drugs, whilst increased Dsg3 expression resulted in the opposite effects. Such a pathway in the negative regulation of p53 by Dsg3 was Dsg3 specific since neither E-cadherin nor desmoplakin knockdown caused similar effects. Analysis of Dsg3-/- mouse skin also indicated an increase of p53/p21WAF1/CIP1 and cleaved caspase-3 relative to Dsg3+/- controls. Finally, we evaluated whether this pathway was operational in the autoimmune disease PV in which Dsg3 serves as a major antigen involved in blistering pathogenesis. We uncovered increased p53 with diffuse cytoplasmic and/or nuclear staining in the oral mucosa of patients, including cells surrounding blisters and the pre-lesional regions. This finding was verified by in vitro studies where treatment of keratinocytes with PV sera, as well as a characterized pathogenic antibody specifically targeting Dsg3, evoked pronounced p53 expression and activity accompanied by disruption of cell-cell adhesion. Collectively, our findings suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.
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25
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Xie H, Xu H, Hou Y, Cai Y, Rong Z, Song W, Wang W, Li K. Integrative prognostic subtype discovery in high-grade serous ovarian cancer. J Cell Biochem 2019; 120:18659-18666. [PMID: 31347734 DOI: 10.1002/jcb.29049] [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: 04/02/2019] [Accepted: 04/30/2019] [Indexed: 01/19/2023]
Abstract
OBJECTIVE We sought to identify novel molecular subtypes of high-grade serous ovarian cancer (HGSC) by the integration of gene expression and proteomics data and to find the underlying biological characteristics of ovarian cancer to improve the clinical outcome. METHODS The iCluster method was utilized to analysis 131 common HGSC samples between TCGA and Clinical Proteomic Tumor Analysis Consortium databases. Kaplan-Meier survival curves were used to estimate the overall survival of patients, and the differences in survival curves were assessed using the log-rank test. RESULTS Two novel ovarian cancer subtypes with different overall survival (P = .00114) and different platinum status (P = .0061) were identified. Eighteen messenger RNAs and 38 proteins were selected as differential molecules between subtypes. Pathway analysis demonstrated arrhythmogenic right ventricular cardiomyopathy pathway played a critical role in the discrimination of these two subtypes and desmosomal cadherin DSG2, DSP, JUP, and PKP2 in this pathway were overexpression in subtype I compared with subtype II. CONCLUSION Our study extended the underlying prognosis-related biological characteristics of high-grade serous ovarian cancer. Enrichment of desmosomal cadherin increased the risk for HGSC prognosis among platinum-sensitive patients, the results guided the revision of the treatment options for platinum-sensitive ovarian cancer patients to improve outcomes.
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Affiliation(s)
- Hongyu Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Huan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Yan Hou
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Yuqing Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Zhiwei Rong
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Wei Song
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Wenjie Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Kang Li
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
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26
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Oncoproteomic and gene expression analyses identify prognostic biomarkers for second primary malignancy in patients with head and neck squamous cell carcinoma. Mod Pathol 2019; 32:943-956. [PMID: 30737471 DOI: 10.1038/s41379-019-0211-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 12/21/2018] [Accepted: 01/06/2019] [Indexed: 12/15/2022]
Abstract
Patients with head and neck squamous cell carcinoma are at increased risk of developing a second primary malignancy, which is associated with poor prognosis and early death. To help improve clinical outcome, we aimed to identify biomarkers for second primary malignancy risk prediction using the routinely obtained formalin-fixed paraffin-embedded tissues of the index head and neck cancer. Liquid chromatography-tandem mass spectrometry was initially performed for candidate biomarker discovery in 16 pairs of primary cancer tissues and their matched normal mucosal epithelia from head and neck squamous cell carcinoma patients with or without second primary malignancy. The 32 candidate proteins differentially expressed between head and neck cancers with and without second primary malignancy were identified. Among these, 30 selected candidates and seven more from literature review were further studied using NanoString nCounter gene expression assay in an independent cohort of 49 head and neck cancer patients. Focusing on the p16-negative cases, we showed that a multivariate logistic regression model comprising the expression levels of ITPR3, KMT2D, EMILIN1, and the patient's age can accurately predict second primary malignancy occurrence with 88% sensitivity and 75% specificity. Furthermore, using Cox proportional hazards regression analysis and survival analysis, high expression levels of ITPR3 and DSG3 were found to be significantly associated with shorter time to second primary malignancy development (log-rank test P = 0.017). In summary, we identified a set of genes whose expressions may serve as the prognostic biomarkers for second primary malignancy occurrence in head and neck squamous cell carcinomas. In combination with the histopathologic examination of index tumor, these biomarkers can be used to guide the optimum frequency of second primary malignancy surveillance, which may lead to early diagnosis and better survival outcome.
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Kim JH, Kim SC. Paraneoplastic Pemphigus: Paraneoplastic Autoimmune Disease of the Skin and Mucosa. Front Immunol 2019; 10:1259. [PMID: 31214197 PMCID: PMC6558011 DOI: 10.3389/fimmu.2019.01259] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 05/17/2019] [Indexed: 12/25/2022] Open
Abstract
Paraneoplastic pemphigus (PNP) is a rare but life-threatening mucocutaneous disease mediated by paraneoplastic autoimmunity. Various neoplasms are associated with PNP. Intractable stomatitis and polymorphous cutaneous eruptions, including blisters and lichenoid dermatitis, are characteristic clinical features caused by humoral and cell-mediated autoimmune reactions. Autoreactive T cells and IgG autoantibodies against heterogeneous antigens, including plakin family proteins and desmosomal cadherins, contribute to the pathogenesis of PNP. Several mechanisms of autoimmunity may be at play in this disease on the type of neoplasm present. Diagnosis can be made based on clinical and histopathological features, the presence of anti-plakin autoantibodies, and underlying neoplasms. Immunosuppressive agents and biologics including rituximab have been used for the treatment of PNP; however, the prognosis is poor due to underlying malignancies, severe infections during immunosuppressive treatment, and bronchiolitis obliterans mediated by autoimmunity. In this review, we overview the characteristics of PNP and focus on the immunopathology and the potential pathomechanisms of this disease.
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Affiliation(s)
- Jong Hoon Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Soo-Chan Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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28
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Hoque Apu E, Akram SU, Rissanen J, Wan H, Salo T. Desmoglein 3 - Influence on oral carcinoma cell migration and invasion. Exp Cell Res 2018; 370:353-364. [PMID: 29969588 DOI: 10.1016/j.yexcr.2018.06.037] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 06/26/2018] [Accepted: 06/28/2018] [Indexed: 12/16/2022]
Abstract
Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but its role in carcinoma cell migration and invasion is mostly unknown. Our aim was to quantitatively analyse the motion of Dsg3-modified carcinoma cells in 2D settings and in 3D within tumour microenvironment mimicking (TMEM) matrices. We tested mutant constructs of C-terminally truncated Dsg3 (∆238 and ∆560), overexpressed full-length (FL) Dsg3, and empty vector control (Ct) of buccal mucosa squamous cell carcinoma (SqCC/Y1) cells. We captured live cell images and analysed migration velocities and accumulated and Euclidean distances. We compared rodent collagen and Matrigel® with human Myogel TMEM matrices for these parameters in 3D sandwich, in which we also tested the effects of monoclonal antibody AK23, which targets the EC1 domain of Dsg3. In monolayer culture, FL and both truncated constructs migrated faster and had higher accumulated distances than Ct cells. However, in the 3D assays, only the mutants invaded faster relative to Ct cells. Of the mutants, the shorter form (Δ238) exhibited faster migration and invasion than Δ560 cells. In the Transwell, all of the cells invaded faster through Myogel than Matrigel® coated wells. In 3D sandwich, AK23 antibody inhibited only the invasion of FL cells. We conclude that different experimental 2D and 3D settings can markedly influence the movement of oral carcinoma cells with various Dsg3 modifications.
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Affiliation(s)
- Ehsanul Hoque Apu
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland; Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK
| | - Saad Ullah Akram
- Department of Computer Science and Engineering, University of Oulu, Oulu, Finland
| | - Jouni Rissanen
- Fibre and Particle Engineering, University of Oulu, Oulu, Finland
| | - Hong Wan
- Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK
| | - Tuula Salo
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland; Medical Research Centre, Oulu University Hospital, Oulu, Finland; HUSLAB, Department of Pathology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, Campinas, Brazil.
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Siriwardena SBSM, Tsunematsu T, Qi G, Ishimaru N, Kudo Y. Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma-A Review. Int J Mol Sci 2018; 19:ijms19051462. [PMID: 29758011 PMCID: PMC5983574 DOI: 10.3390/ijms19051462] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 05/07/2018] [Accepted: 05/10/2018] [Indexed: 01/06/2023] Open
Abstract
It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC.
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Affiliation(s)
- Samadarani B S M Siriwardena
- Department of Oral Pathology, Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka.
| | - Takaaki Tsunematsu
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan.
| | - Guangying Qi
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, China.
| | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
| | - Yasusei Kudo
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
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30
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Bruner HC, Derksen PWB. Loss of E-Cadherin-Dependent Cell-Cell Adhesion and the Development and Progression of Cancer. Cold Spring Harb Perspect Biol 2018; 10:a029330. [PMID: 28507022 PMCID: PMC5830899 DOI: 10.1101/cshperspect.a029330] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Classical cadherins are the key molecules that control cell-cell adhesion. Notwithstanding this function, it is also clear that classical cadherins are more than just the "glue" that keeps the cells together. Cadherins are essential regulators of tissue homeostasis that govern multiple facets of cellular function and development, by transducing adhesive signals to a complex network of signaling effectors and transcriptional programs. In cancer, cadherins are often inactivated or functionally inhibited, resulting in disease development and/or progression. This review focuses on E-cadherin and its causal role in the development and progression of breast and gastric cancer. We provide a summary of the biochemical consequences and consider the conceptual impact of early (mutational) E-cadherin loss in cancer. We advocate that carcinomas driven by E-cadherin loss should be considered "actin-diseases," caused by the specific disruption of the E-cadherin-actin connection and a subsequent dependence on sustained actomyosin contraction for tumor progression. Based on the available data from mouse and human studies we discuss opportunities for targeted clinical intervention.
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Affiliation(s)
- Heather C Bruner
- Department of Medicine, University of California at San Diego, La Jolla, California 92093
| | - Patrick W B Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht 3584CX, The Netherlands
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31
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Affiliation(s)
- Nicole A. Najor
- Department of Biology, University of Detroit Mercy, Detroit, Michigan 48221
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32
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Chen HY, Chang JTC, Chien KY, Lee YS, You GR, Cheng AJ. The Endogenous GRP78 Interactome in Human Head and Neck Cancers: A Deterministic Role of Cell Surface GRP78 in Cancer Stemness. Sci Rep 2018; 8:536. [PMID: 29323121 PMCID: PMC5765009 DOI: 10.1038/s41598-017-14604-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 10/09/2017] [Indexed: 12/04/2022] Open
Abstract
Cell surface glucose regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone, was suggested to be a cancer stem cell marker, but the influence of this molecule on cancer stemness is poorly characterized. In this study, we developed a mass spectrometry platform to detect the endogenous interactome of GRP78 and investigated its role in cancer stemness. The interactome results showed that cell surface GRP78 associates with multiple molecules. The influence of cell population heterogeneity of head and neck cancer cell lines (OECM1, FaDu, and BM2) according to the cell surface expression levels of GRP78 and the GRP78 interactome protein, Progranulin, was investigated. The four sorted cell groups exhibited distinct cell cycle distributions, asymmetric/symmetric cell divisions, and different relative expression levels of stemness markers. Our results demonstrate that cell surface GRP78 promotes cancer stemness, whereas drives cells toward a non-stemlike phenotype when it chaperones Progranulin. We conclude that cell surface GRP78 is a chaperone exerting a deterministic influence on cancer stemness.
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Affiliation(s)
- Hsin-Ying Chen
- Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
| | | | - Kun-Yi Chien
- Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan.,Proteomics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan
| | - Yun-Shien Lee
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Department of Biotechnology, Ming Chuan University, Tao-Yuan, Taiwan
| | - Guo-Rung You
- Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
| | - Ann-Joy Cheng
- Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan. .,Department of Radiation Oncology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan. .,Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
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Lai YH, Liu H, Chiang WF, Chen TW, Chu LJ, Yu JS, Chen SJ, Chen HC, Tan BCM. MiR-31-5p-ACOX1 Axis Enhances Tumorigenic Fitness in Oral Squamous Cell Carcinoma Via the Promigratory Prostaglandin E2. Am J Cancer Res 2018; 8:486-504. [PMID: 29290822 PMCID: PMC5743562 DOI: 10.7150/thno.22059] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 10/24/2017] [Indexed: 02/07/2023] Open
Abstract
During neoplastic development, a multitude of changes in genome-encoded information are progressively selected to confer growth and survival advantages to tumor cells. microRNAs-mRNAs regulatory networks, given their role as a critical layer of robust gene expression control, are frequently altered in neoplasm. However, whether and how these gene perturbations impact metabolic homeostasis remains largely unresolved. Methods: Through targeted miRNA expression screening, we uncovered an oral squamous cell carcinoma (OSCC)-associated miRNAome, among which miR-31-5p was identified based on extent of up-regulation, functional impact on OSCC cell migration and invasion, and direct regulation of the rate-limiting enzyme in peroxisomal β-oxidation, ACOX1. Results: We further found that both miR-31-5p and ACOX1 underpin, in an antagonistic manner, the overall cellular lipidome profiles as well as the migratory and invasive abilities of OSCC cells. Interestingly, the extracellular levels of prostaglandin E2 (PGE2), a key substrate of ACOX1, were controlled by the miR-31-5p-ACOX1 axis, and were shown to positively influence the extent of cell motility in correlation with metastatic status. The promigratory effect of this metabolite was mediated by an elevation in EP1-ERK-MMP9 signaling. Of note, functional significance of this regulatory pathway was further corroborated by its clinicopathologically-correlated expression in OSCC patient specimens. Conclusions: Collectively, our findings outlined a model whereby misregulated miR-31-5p-ACOX1 axis in tumor alters lipid metabolomes, consequently eliciting an intracellular signaling change to enhance cell motility. Our clinical analysis also unveiled PGE2 as a viable salivary biomarker for prognosticating oral cancer progression, further underscoring the importance of lipid metabolism in tumorigenesis.
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Li R, Yanjiao G, Wubin H, Yue W, Jianhua H, Huachuan Z, Rongjian S, Zhidong L. Secreted GRP78 activates EGFR-SRC-STAT3 signaling and confers the resistance to sorafeinib in HCC cells. Oncotarget 2017; 8:19354-19364. [PMID: 28423613 PMCID: PMC5386689 DOI: 10.18632/oncotarget.15223] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/16/2017] [Indexed: 11/25/2022] Open
Abstract
Acquired resistance is a common phenomenon for HCC patients who undergone sorafenib treatment, however the mechanism by which acquired resistance develops remains elusive. In this study, we found that GRP78 could be detected in the serum samples of HCC patients and the conditional medium of multiple HCC cell lines, suggesting that GRP78 is secreted by HCC cells. Further studies showed that secreted GRP78 facilitated the proliferation and inhibited the apoptosis induced by sorafenib both in HCC cell lines and in tumor xenografts. We further found that secreted GRP78 could interact physically with EGFR, therefore activates EGFR signaling pathway. knockdown of EGFR decreased secreted GRP78 induced phosphorylation of SRC and STAT3. By contrast, overexpression of EGFR further enhanced the phosphorylation of SRC and STAT3 induced by secreted GRP78, suggesting the critical role of EGFR in secreted GRP78 conferred resistance to sorafeinib. Moreover, inhibition of SRC by PP2 antagonized the resistance to sorafenib and inhibited the activation of STAT3 conferred by secreted GRP78. Taken together, our results showed that secreted GRP78 could interact with EGFR, activate EGFR-SRC-STAT3 signaling, conferring the resistance to sorafenib.
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Affiliation(s)
- Rui Li
- Department of Cell Biology, College of Basic Medicine, Jinzhou Medical University, Jinzhou, China
| | - Gu Yanjiao
- Department of Pathology, College of Basic Medicine, Jinzhou Medical University, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - He Wubin
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Wang Yue
- Department of Cell Biology, College of Basic Medicine, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Huang Jianhua
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Zheng Huachuan
- Life Science Institute of Jinzhou Medical University, Jinzhou, China
| | - Su Rongjian
- Life Science Institute of Jinzhou Medical University, College of Basic Medicine of Jinzhou Medical University, Cell Biology and Genetic Department of Jinzhou Medical University, Key Lab of Molecular and Cellular Biology of the Education Department of Liaoning Province, Jinzhou, China
| | - Luan Zhidong
- Development Department of Jinzhou Medical University, Life Science Institute of Jinzhou Medical University, Jinzhou, China
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Zhou G, Yang L, Gray A, Srivastava AK, Li C, Zhang G, Cui T. The role of desmosomes in carcinogenesis. Onco Targets Ther 2017; 10:4059-4063. [PMID: 28860814 PMCID: PMC5565390 DOI: 10.2147/ott.s136367] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Desmosomes, which are intercellular adhesive complexes, are essential for the maintenance of epithelial homeostasis. They are located at the cell membrane, where they act as anchors for intermediate filaments. Downregulation of desmosome proteins in various cancers promotes tumor progression. However, the role of desmosomes in carcinogenesis is still being elucidated. Recent studies revealed that desmosome family members play a crucial role in tumor suppression or tumor promotion. This review focuses on studies that provide insights into the role of desmosomes in carcinogenesis and address their molecular functions.
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Affiliation(s)
- Guangxin Zhou
- Department of Oncology, Central Hospital of Binzhou, Binzhou Medical College, Binzhou, People's Republic of China
| | - Linlin Yang
- Department of Radiation Oncology, Arthur G James Hospital/Ohio State Comprehensive Cancer Center
| | | | - Amit Kumar Srivastava
- Division of Radiobiology, Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Gongwen Zhang
- Department of Cardiac Surgery, Central Hospital of Binzhou, Binzhou Medical College, Binzhou, People's Republic of China
| | - Tiantian Cui
- Department of Radiation Oncology, Arthur G James Hospital/Ohio State Comprehensive Cancer Center
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Li YL, Chang JT, Lee LY, Fan KH, Lu YC, Li YC, Chiang CH, You GR, Chen HY, Cheng AJ. GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway. Oncotarget 2017; 8:1508-1528. [PMID: 27903972 PMCID: PMC5352073 DOI: 10.18632/oncotarget.13649] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 11/12/2016] [Indexed: 12/22/2022] Open
Abstract
Radiotherapy is an integral part for the treatment of head and neck cancer (HNC), while radioresistance is a major cause leads to treatment failure. GDF15, a member of the TGF-β superfamily, is hypothesized to participate in various types of homeostasis. However, the potential role of this molecule in regulation of radiosensitivity remains unclear. In this study, we demonstrated that GDF15 contributed to radioresistance of HNC, as determined by both gain- and lost-of-functional experiments. These results were achieved by the induction of mitochondrial membrane potential and suppression of intracellular reactive oxygen species (ROS). We further showed that GDF15 facilitated the conversion of cancer stemness, as assessed by the promotion of CD44+ and ALDH1+ cell populations and spheroid cell formation. At molecular level, GDF15 conferred to these cellular functions was through phosphorylated SMAD1 proteins to elite downstream signaling molecules. These cellular results were further confirmed in a tumor xenograft mouse study. Taken together, our results demonstrated that GDF15 contributed to radioresistance and cancer stemness by regulating cellular ROS levels via a SMAD-associated signaling pathway. GDF15 may serve as a prediction marker of radioresistance and a therapeutic target for the development of radio-sensitizing agents for the treatment of refractory HNC.
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Affiliation(s)
- Yan-Liang Li
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Joseph T. Chang
- Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Li-Yu Lee
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Kang-Hsing Fan
- Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ya-Ching Lu
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Yi-Chen Li
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chang-Hsu Chiang
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Guo-Rung You
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Hsin-Ying Chen
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ann-Joy Cheng
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Oka R, Nakashiro KI, Goda H, Iwamoto K, Tokuzen N, Hamakawa H. Annexin A8 is a novel molecular marker for detecting lymph node metastasis in oral squamous cell carcinoma. Oncotarget 2016; 7:4882-9. [PMID: 26700817 PMCID: PMC4826250 DOI: 10.18632/oncotarget.6639] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 12/05/2015] [Indexed: 01/17/2023] Open
Abstract
Cervical lymph node metastasis is an important prognostic factor in oral squamous cell carcinoma (OSCC), but its accurate assessment after sentinel node biopsy or neck dissection is often limited to the histopathological examination of only one or two sections. Previous our study showed the usefulness of the reverse transcription loop-mediated isothermal amplification (RT-LAMP) targeting keratin 19 (KRT19) mRNA for the genetic detection of lymph node metastasis, but the sensitivity was insufficient. Here, we have attempted to identify novel molecular markers for OSCC cells in lymph nodes. We performed microarray analysis to identify genes overexpressed in 7 metastatic lymph nodes from OSCC patients, compared to 1 normal lymph node and 5 salivary glands from non-cancer patients. We then used real-time quantitative RT-PCR (qRT-PCR) and RT-LAMP to compare the expression of these genes in newly resected metastatic and normal lymph nodes. Of 4 genes identified by microarray analysis, annexin A8 (ANXA8) and desmoglein 3 mRNA were detected by qRT-PCR in metastatic lymph nodes but not in normal lymph nodes. Furthermore, ANXA8 mRNA expression was detected in all KRT19-negative metastatic lymph nodes. Both KRT19 and ANXA8 mRNA may be useful markers for detecting lymph node metastases in OSCC patients.
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Affiliation(s)
- Ryota Oka
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Hiroyuki Goda
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Kazuki Iwamoto
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Norihiko Tokuzen
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Hiroyuki Hamakawa
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
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Cirillo N, Hassona Y, Celentano A, Lim K, Manchella S, Parkinson E, Prime S. Cancer-associated fibroblasts regulate keratinocyte cell–cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer. Carcinogenesis 2016; 38:76-85. [DOI: 10.1093/carcin/bgw113] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 09/11/2016] [Accepted: 10/28/2016] [Indexed: 11/14/2022] Open
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Celentano A, Mignogna MD, McCullough M, Cirillo N. Pathophysiology of the Desmo-Adhesome. J Cell Physiol 2016; 232:496-505. [PMID: 27505028 DOI: 10.1002/jcp.25515] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 08/08/2016] [Indexed: 01/18/2023]
Abstract
Advances in our understanding of desmosomal diseases have provided a clear demonstration of the key role played by desmosomes in tissue and organ physiology, highlighting the importance of their dynamic and finely regulated structure. In this context, non-desmosomal regulatory molecules have acquired increasing relevance in the study of this organelle resulting in extending the desmosomal interactome, named the "desmo-adhesome." Spatiotemporal changes in the expression and regulation of the desmo-adhesome underlie a number of genetic, infectious, autoimmune, and malignant conditions. The aim of the present article was to examine the structural and functional relationship of the desmosome, by providing a comprehensive, yet focused overview of the constituents targeted in human disease. The inclusion of the novel regulatory network in the desmo-adhesome pathophysiology opens new avenues to a deeper understanding of desmosomal diseases, potentially unveiling pathogenic mechanisms waiting to be explored. J. Cell. Physiol. 232: 496-505, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Antonio Celentano
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy.,Melbourne Dental School, University of Melbourne, Carlton, Victoria, Australia
| | - Michele Davide Mignogna
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy
| | - Michael McCullough
- Melbourne Dental School, University of Melbourne, Carlton, Victoria, Australia.,Oral Health Cooperative Research Centre (CRC), University of Melbourne, Carlton, Victoria, Australia
| | - Nicola Cirillo
- Melbourne Dental School, University of Melbourne, Carlton, Victoria, Australia.,Oral Health Cooperative Research Centre (CRC), University of Melbourne, Carlton, Victoria, Australia
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Lo AS, Mao X, Mukherjee EM, Ellebrecht CT, Yu X, Posner MR, Payne AS, Cavacini LA. Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris. PLoS One 2016; 11:e0156800. [PMID: 27304671 PMCID: PMC4909199 DOI: 10.1371/journal.pone.0156800] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/19/2016] [Indexed: 12/17/2022] Open
Abstract
Pemphigus vulgaris (PV) is characterized by IgG1 and IgG4 autoantibodies to desmoglein (Dsg) 3, causing suprabasal blistering of skin and mucous membranes. IgG4 is the dominant autoantibody subclass in PV and correlates with disease activity, whereas IgG1 can be associated with remittent disease. It is unknown if switching the same variable region between IgG4 and IgG1 directly impacts pathogenicity. Here, we tested whether three pathogenic PV monoclonal antibodies (mAbs) from three different patients demonstrate differences in antigen affinity, epitope specificity, or pathogenicity when expressed as IgG1 or IgG4. F706 anti-Dsg3 IgG4 and F779 anti-Dsg3 IgG1, previously isolated as heterohybridomas, and Px43, a monovalent anti-Dsg3/Dsg1 IgG antibody isolated by phage display, were subcloned to obtain paired sets of IgG1 and IgG4 mAbs. Using ELISA and cell surface staining assays, F706 and F779 demonstrated similar antigen binding affinities of IgG1 and IgG4, whereas Px43 showed 3- to 8-fold higher affinity of IgG4 versus IgG1 by ELISA, but identical binding affinities to human skin, perhaps due to targeting of a quaternary epitope best displayed in tissues. All 3 mAb pairs targeted the same extracellular cadherin (EC) domain on Dsg3, caused Dsg3 internalization in primary human keratinocytes, and caused suprabasal blisters in human skin at comparable doses. We conclude that switching IgG1 and IgG4 subclasses of pathogenic PV mAbs does not directly affect their antigen binding or pathogenic properties.
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Affiliation(s)
- Agnes S. Lo
- Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Xuming Mao
- Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Eric M. Mukherjee
- Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Christoph T. Ellebrecht
- Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Xiaocong Yu
- Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Marshall R. Posner
- Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Aimee S. Payne
- Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Lisa A. Cavacini
- Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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Chao TB, Li CF, Lin CY, Tian YF, Chang IW, Sheu MJ, Lee YE, Chan TC, He HL. Prognostic significance of DSG3 in rectal adenocarcinoma treated with preoperative chemoradiotherapy. Future Oncol 2016; 12:1457-1467. [PMID: 27040321 DOI: 10.2217/fon-2016-0071] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 03/21/2016] [Indexed: 02/07/2023] Open
Abstract
AIM This study aimed to investigate the prognostic significance of DSG3 and its association with response to neoadjuvant concurrent chemoradiotherapy (CCRT) in rectal cancer. MATERIALS & METHODS Data mining of a publicly available dataset was performed to find genes associated with CCRT response. Immunohistochemistry was applied to evaluate DSG3 expression. The relationships between DSG3 expression and various clinicopathological parameters and survival were analyzed. RESULTS The DSG3 gene was significantly associated with CCRT response. The expression of DSG3 negatively correlated with poorer tumor regression (p < 0.001) and had an independent negative impact on disease-specific survival (p = 0.011), local recurrence-free survival (p = 0.031) and metastasis-free survival (p = 0.029). CONCLUSION DSG3 was a key prognostic factor and predictor for CCRT response in rectal cancer patients.
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Affiliation(s)
- Tung-Bo Chao
- Department of Colorectal Surgery, Yuan's General Hospital, Kaohsiung, Taiwan
- Department of Health Business Administration, Meiho University, Pingtung, Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Biotechnology, Southern Taiwan University of Science & Technology, Tainan, Taiwan
- Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Yih Lin
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
- Department of Leisure, Recreation, & Tourism Management, Southern Taiwan University of Science & Technology, Tainan, Taiwan
| | - Yu-Feng Tian
- Division of General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
- Department of Health & Nutrition, Chia Nan University of Pharmacy & Science, Tainan, Taiwan
| | - I-Wei Chang
- Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Ming-Jen Sheu
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Ying-En Lee
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital & Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ti-Chun Chan
- Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan
| | - Hong-Lin He
- Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Determining the potential of desmoglein 3 as a sensitive and specific immunohistochemical marker for the detection of micrometastasis in patients with primary oral squamous cell carcinoma. Contemp Oncol (Pozn) 2016; 20:374-380. [PMID: 28373818 PMCID: PMC5371703 DOI: 10.5114/wo.2016.64596] [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: 02/23/2016] [Accepted: 06/22/2016] [Indexed: 12/01/2022] Open
Abstract
Aim of the study Despite advances in surgical and radiotherapy techniques, the presence of lymph node metastasis drastically decreases the survival rate of patients with primary oral squamous cell carcinoma (OSCC). Thus the accurate pathological staging of the neck is critical. Desmoglein 3 (DSG3), a desmosomal cadherin protein is said to be highly expressed in head and neck squamous cell carcinoma (HNSCC) and in metastatic cervical lymph nodes, but absent in non-invaded nodes. With an aim to improve the sensitivity of tumour cell detection, we investigated the potential of DSG3 as an immunohistochemical marker for the detection of occult lymph node metastasis in patients with primary OSCC. Material and methods Forty-seven lymph node specimens from 10 patients who underwent neck dissection for primary OSCC were immunostained with DSG3. Results The DSG3 positivity was noted in the six positive lymph nodes. However, when using DSG3 as an immunohistochemical marker, no additional micrometastatic deposits were evident in the histologically negative nodes. Interestingly, tumour marker DSG3-positive macrophages could be identified within the subcapsular sinuses, medullary sinuses, and the interfollicular areas. Conclusions Our findings suggest that although DSG3 is overexpressed in HNSCC, it is not specific and may not prove to be a potent immunohistochemical marker to detect micrometastasis. The role of tumour marker-positive macrophages within the lymph nodes needs to be investigated further.
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Hoover H, Li J, Marchese J, Rothwell C, Borawoski J, Jeffery DA, Gaither LA, Finkel N. Quantitative Proteomic Verification of Membrane Proteins as Potential Therapeutic Targets Located in the 11q13 Amplicon in Cancers. J Proteome Res 2015; 14:3670-9. [PMID: 26151158 DOI: 10.1021/acs.jproteome.5b00508] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tumor types can be defined cytologically by their regions of chromosomal amplification, which often results in the high expression of both mRNA and proteins of certain genes contained within the amplicon. An important strategy for defining therapeutically relevant targets in these situations is to ascertain which genes are amplified at the protein level and, concomitantly, are key drivers for tumor growth or maintenance. Furthermore, so-called passenger genes that are amplified with driver genes and a manifest on the cell surface can be attractive targets for an antibody-drug conjugate approach (ADC). We employed a tandem mass spectrometry proteomics approach using tumor cell lines to identify the cell surface proteins whose expression correlates with the 11q13 amplicon. The 11q13 amplicon is one of the most frequently amplified chromosomal regions in human cancer, being present in 45% of head and neck and oral squamous cell carcinoma (OSCC) and 13-21% of breast and liver carcinomas. Using a panel of tumor cell lines with defined 11q13 genomic amplification, we identified the membrane proteins that are differentially expressed in an 11q13 amplified cell line panel using membrane-enriched proteomic profiling. We found that DSG3, CD109, and CD14 were differentially overexpressed in head and neck and breast tumor cells with 11q13 amplification. The level of protein expression of each gene was confirmed by Western blot and FACS analysis. Because proteins with high cell surface expression on selected tumor cells could be potential antibody drug conjugate targets, we tested DSG3 and CD109 in antibody piggyback assays and validated that DSG3 and CD109 expression was sufficient to induce antibody internalization and cell killing in 11q13-amplified cell lines. Our results suggest that proteomic profiling using genetically stratified tumors can identify candidate antibody drug conjugate targets. Data are available via ProteomeXchange with the identifier PXD002486.
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Affiliation(s)
- Heather Hoover
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - Jun Li
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - Jason Marchese
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - Christopher Rothwell
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - Jason Borawoski
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - Douglas A Jeffery
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - L Alex Gaither
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
| | - Nancy Finkel
- Novartis Institutes for Biomedical Research , Cambridge, Massachusetts 02139, United States
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Abstract
Desmosomes represent adhesive, spot-like intercellular junctions that in association with intermediate filaments mechanically link neighboring cells and stabilize tissue architecture. In addition to this structural function, desmosomes also act as signaling platforms involved in the regulation of cell proliferation, differentiation, migration, morphogenesis, and apoptosis. Thus, deregulation of desmosomal proteins has to be considered to contribute to tumorigenesis. Proteolytic fragmentation and downregulation of desmosomal cadherins and plaque proteins by transcriptional or epigenetic mechanisms were observed in different cancer entities suggesting a tumor-suppressive role. However, discrepant data in the literature indicate that context-dependent differences based on alternative intracellular, signal transduction lead to altered outcome. Here, modulation of Wnt/β-catenin signaling by plakoglobin or desmoplakin and of epidermal growth factor receptor signaling appears to be of special relevance. This review summarizes current evidence on how desmosomal proteins participate in carcinogenesis, and depicts the molecular mechanisms involved.
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Affiliation(s)
- Otmar Huber
- a Institute of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena , Nonnenplan 2-4, 07743 Jena , Germany.,b Center for Sepsis Control and Care, Jena University Hospital , Erlanger Allee 101, 07747 Jena , Germany
| | - Iver Petersen
- c Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University Jena , Ziegelmühlenweg 1, 07743 Jena , Germany
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Jimenez L, Jayakar SK, Ow TJ, Segall JE. Mechanisms of Invasion in Head and Neck Cancer. Arch Pathol Lab Med 2015; 139:1334-48. [PMID: 26046491 DOI: 10.5858/arpa.2014-0498-ra] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
CONTEXT The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed. OBJECTIVES To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion. DATA SOURCES A literature review of peer-reviewed articles in PubMed on HNSCC invasion. CONCLUSIONS Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.
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Affiliation(s)
| | | | | | - Jeffrey E Segall
- From the Departments of Pathology (Mss Jimenez and Jayakar, and Drs Ow and Segall) and Anatomy and Structural Biology (Mss Jimenez and Jayakar, and Dr Segall), Albert Einstein College of Medicine, Bronx, New York
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Ganjare A, Bagul N, Kathariya R, Oberoi J. ‘Cell junctions of oral mucosa’- in a nutshell. QSCIENCE CONNECT 2015. [DOI: 10.5339/connect.2015.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Junctional complexes are specialized contacts between neighboring cells and between cells and the extracellular matrix. They play an important role in embryogenesis, growth and development, as well as being the cause of pathologies. These contacts lead to a number of different interactions that have a profound effect on cellular biology. Cell junctions are best visualized using conventional or freeze-fracture electron microscopy, which reveals the interacting plasma membranes are highly specialized in these regions.
Cell adhesion molecules (CAMs) are proteins responsible for homophillic and heterophillic adhesions. They consist of various groups, including cadherins, selectins and intergrins and they facilitate cell adhesion, cell signaling, and motility. Dysregulation of these molecules can lead to various pathologies, for example mucocutaneous diseases and invasion of cancer. This review focuses on the pathophysiology of cell junctions and related diseases.
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Affiliation(s)
- Anjali Ganjare
- 1Department of Oral Pathology and Microbiology, Dr. D. Y Patil Dental College and Hospital, Dr. D. Y Patil Vidyapeeth, Pune-18, India
| | - Neeta Bagul
- 1Department of Oral Pathology and Microbiology, Dr. D. Y Patil Dental College and Hospital, Dr. D. Y Patil Vidyapeeth, Pune-18, India
| | - Rahul Kathariya
- 2Department of Periodontics and Oral Implantology, Dr. D. Y Patil Dental College and Hospital, Dr. D.Y Patil Vidyapeeth, Pune-18, India
| | - Jyoti Oberoi
- 3Department of Preventive and Pediatric Dentistry, Dr. D. Y Patil School of Dentistry, Nerul, Navi Mumbai- 400706, India
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Abstract
Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement integrates adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, which occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on the way in which human diseases can inform our understanding of basic desmosome biology and in turn, the means by which fundamental advances in the cell biology of desmosomes might lead to new treatments for acquired diseases of the desmosome.
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Broussard JA, Getsios S, Green KJ. Desmosome regulation and signaling in disease. Cell Tissue Res 2015; 360:501-12. [PMID: 25693896 DOI: 10.1007/s00441-015-2136-5] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023]
Abstract
Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to mechanical stress, such as the heart and skin. More recently, desmosome components have also emerged as cell signaling regulators. Loss of expression or interference with the function of desmosome molecules results in diseases of the heart and skin and contributes to cancer progression. However, the underlying molecular mechanisms that result in inherited and acquired disorders remain poorly understood. To address this question, researchers are directing their studies towards determining the functions that occur inside and outside of the junctions and the extent to which functions are adhesion-dependent or independent. This review focuses on recent discoveries that provide insights into the role of desmosomes and desmosome components in cell signaling and disease; wherever possible, we address molecular functions within and outside of the adhesive structure.
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Affiliation(s)
- Joshua A Broussard
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
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Brown L, Wan H. Desmoglein 3: a help or a hindrance in cancer progression? Cancers (Basel) 2015; 7:266-86. [PMID: 25629808 PMCID: PMC4381258 DOI: 10.3390/cancers7010266] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/09/2015] [Accepted: 01/16/2015] [Indexed: 02/07/2023] Open
Abstract
Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and structural integrity. Like adherens junctions, desmosomes function as tumour suppressors and are down regulated in the process of epithelial-mesenchymal transition and in tumour cell invasion and metastasis. However, recently several studies have shown that various desmosomal components, including desmoglein 3, are up-regulated in cancer with increased levels of expression correlating with the clinical stage of malignancy, implicating their potentiality to serve as a diagnostic and prognostic marker. Furthermore, in vitro studies have demonstrated that overexpression of desmoglein 3 in cancer cell lines activates several signal pathways that have an impact on cell morphology, adhesion and locomotion. These additional signalling roles of desmoglein 3 may not be associated to its adhesive function in desmosomes but rather function outside of the junctions, acting as a key regulator in the control of actin based cellular processes. This review will discuss recent advances which support the role of desmoglein 3 in cancer progression.
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Affiliation(s)
- Louise Brown
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Center for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Blizard Building, London E1 2AT, UK.
| | - Hong Wan
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Center for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Blizard Building, London E1 2AT, UK.
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FANG WANGKAI, LIAO LIANDI, ZENG FAMIN, ZHANG PIXIAN, WU JIANYI, SHEN JIAN, XU LIYAN, LI ENMIN. Desmocollin‑2 affects the adhesive strength and cytoskeletal arrangement in esophageal squamous cell carcinoma cells. Mol Med Rep 2014; 10:2358-64. [PMID: 25119898 PMCID: PMC4214350 DOI: 10.3892/mmr.2014.2485] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Accepted: 08/08/2014] [Indexed: 02/05/2023] Open
Abstract
Desmocollin‑2 (DSC2), a transmembrane glycoprotein belonging to the desmosomal cadherin family, has been found to be differentially expressed in several types of cancer and to be involved in tumor progression. The tumor metastasis suppressing property of DSC2 in esophageal squamous cell carcinoma (ESCC) has been described, however, its contribution to cell cohesion in ESCC remains to be elucidated. In the present study, using RNA interference (RNAi), the expression of DSC2 was silenced in SHEEC and KYSE510 cells. Hanging drop and fragmentation assays were performed to investigate the role of DSC2 in cell‑cell adhesion. Western blot analysis and confocal microscopy were used to analyze the expression and localization of cell adhesion molecules and cytoskeletal arrangement. The results demonstrated that DSC2 knock down by RNAi caused defects in cell‑cell adhesion and a concomitant reduction in desmosomal protein expression and adherens junction molecule distribution. A decrease in the expression of DSC2 caused an increase in free γ‑catenin levels, thus promoting its recruitment to the adherens junction complex. In addition, the RNAi‑mediated inhibition of DSC2 led to keratin intermediate filament retraction and filamentous‑actin cytoskeleton rearrangement. Taken together, these data support our previous findings and the proposal that DSC2 may be involved in the regulation of the invasive behavior of cells by a mechanism that controls cell‑cell attachment and cytoskeleton rearrangement.
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Affiliation(s)
- WANG-KAI FANG
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - LIAN-DI LIAO
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - FA-MIN ZENG
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - PI-XIAN ZHANG
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - JIAN-YI WU
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - JIAN SHEN
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - LI-YAN XU
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Correspondence to: Professor Li-Yan Xu, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, P.R. China, E-mail: . Professor En-Min Li, Department of Biochemistry and Molecular Biology, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, P.R. China, E-mail:
| | - EN-MIN LI
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Correspondence to: Professor Li-Yan Xu, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, P.R. China, E-mail: . Professor En-Min Li, Department of Biochemistry and Molecular Biology, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, P.R. China, E-mail:
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