DOCSLIB.ORG

Blockade of B-Catenin–Induced CCL28 Suppresses Gastric Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Blockade of B-Catenin–Induced CCL28 Suppresses Gastric Cancer Published OnlineFirst March 10, 2020; DOI: 10.1158/0008-5472.CAN-19-3074 CANCER RESEARCH | TUMOR BIOLOGY AND IMMUNOLOGY Blockade of b-Catenin–Induced CCL28 Suppresses Gastric Cancer Progression via Inhibition of Treg Cell Infiltration Lu Ji1,2, Wei Qian3, Liming Gui1,2, Zhongzhong Ji1,2, Pan Yin1,2, Guan Ning Lin3, You Wang4, Bin Ma1,2, and Wei-Qiang Gao1,2 ABSTRACT ◥ Dysregulation of Wnt/b-catenin signaling is frequently observed the stomach. Moreover, an anti-CCL28 antibody attenuated Treg cell in human gastric cancer. Elucidation of the tumor immune micro- infiltration and tumor progression in H. felis/MNU mouse models. environment is essential for understanding tumorigenesis and for the Diphtheria toxin–induced Treg cell ablation restrained gastric cancer development of immunotherapeutic strategies. However, it remains progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, unclear how b-catenin signaling regulates the tumor immune clarifying the tumor-promoting role of Treg cells. Thus, the b-cate- microenvironment in the stomach. Here, we identify CCL28 as a nin–CCL28–Treg cell axis may serve as an important mechanism for direct transcriptional target gene of b-catenin/T-cell factor (TCF). immunosuppression of the stomach tumor microenvironment. Our Protein levels of b-catenin and CCL28 positively correlated in human findings reveal an immunoregulatory role of b-catenin signaling in gastric adenocarcinoma. b-Catenin–activated CCL28 recruited reg- stomach tumors and highlight the therapeutic potential of CCL28 ulatory T (Treg) cells in a transwell migration assay. In a clinically blockade for the treatment of gastric cancer. relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and N-methyl-N-nitrosourea (MNU) treatment, inhi- Significance: These findings demonstrate an immunosuppressive bition of b-catenin/TCF activity by a pharmacologic inhibitor role of tumor-intrinsic b-catenin signaling and the therapeutic iCRT14 suppressed CCL28 expression and Treg cell infiltration in potential of CCL28 blockade in gastric cancer. Introduction Wnt/b-catenin signaling has been identified in more than 70% patients with gastric cancer (6). In addition to genetic mutations, alterations in Gastric cancer is the fifth most common cancers and the third many Wnt pathway components may occur through various mechan- leading cause of cancer-related deaths worldwide (1). The initiation isms either to upregulate the expression of the positive regulators or and progression of gastric cancer is attributable to complex genetic and downregulate the expression of the negative regulators, eventually environmental interactions. Majority of stomach tumors are adeno- leading to an aberrant activation of the canonical Wnt pathway (7). It carcinomas that are traditionally divided into two main histologic has also been shown that H. pylori infection promotes Wnt/b-catenin subtypes: intestinal and diffuse types. Among all the environmental activation in gastric epithelial cells (8, 9). Together, these findings factors, Helicobacter pylori (H. pylori) infection is overwhelmingly the pinpoint a crucial role of Wnt/b-catenin signaling in the pathogenesis greatest risk factor for gastric cancer and is associated with approx- of gastric cancer. imately 90% of cases (2, 3). Recent comprehensive molecular profiling Immune evasion has been recognized as an emerging hallmark of has provided new classifications and highlighted the molecular com- cancer (10). Understanding the tumor immune microenvironment is plexity of gastric adenocarcinoma (4, 5). Canonical Wnt pathway- essential for the discovery of new therapeutic targets as well as prediction related genes including APC and CTNNB1 are among the most and guidance of immunotherapeutic responsiveness. Data from murine significantly mutated genes (4, 5). Importantly, dysregulation of models or patient samples have suggested the involvement of myeloid- derived suppressor cells (MDSC) and M2 macrophages in the immu- 1State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical nosuppression of gastric cancer (11, 12). Regulatory T (Treg) cells are Stem Cell Research Center, Renji Hospital, School of Medicine and School of another group of immunosuppressive cells that accelerate tumor pro- Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. 2Med- gression in a broad range of cancer types (13, 14). However, the X Research Institute, Shanghai Jiao Tong University, Shanghai, China. 3School of prognostic role of Treg cells in gastric cancer is still controversial based Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. on previous clinical studies (15–20) and the tumor-promoting or 4 Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, tumor-inhibiting function of Treg cells in gastric adenocarcinoma is Shanghai Jiao Tong University, Shanghai, China. still not verified. Moreover, tumor immune microenvironment or Note: Supplementary data for this article are available at Cancer Research immunotherapy in gastric cancer is much less well explored than many Online (http://cancerres.aacrjournals.org/). other cancer types such as melanoma and lung cancer (21–23). Corresponding Authors: Wei-Qiang Gao, Shanghai Jiao Tong University, 160 Recent studies have underlined a strong impact of oncogenic Pujian Road, Shanghai 200017, China. Phone: 86-21-62932049; Fax: 86-21- pathways on evasion of antitumor responses (24). For example, in 68383916; E-mail: [email protected]; and Bin Ma, Med-X Research mouse models of live carcinoma, p53 maintains the expression of Institute, 1954 Huashan Road, Shanghai 200030, China. Phone: 86-21- – – 62933631; E-mail: [email protected] natural killer (NK) cell recruiting chemokines and NK cell mediated antitumor responses (25, 26); melanoma-intrinsic b-catenin signaling Cancer Res 2020;80:1–13 reduces dendritic and T-cell infiltration via downregulation of doi: 10.1158/0008-5472.CAN-19-3074 CCL4 (27). However, it remains to be elucidated how oncogenic Ó2020 American Association for Cancer Research. pathways such as Wnt/b-catenin and tumor-derived chemokines AACRJournals.org | OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 10, 2020; DOI: 10.1158/0008-5472.CAN-19-3074 Ji et al. determine the composition of gastric cancer immune microenviron- After washing with PBS, slides were incubated with anti-mouse or anti- ment. The present study was set forth to answer this important rabbit HRP–conjugated secondary antibodies (1:1,000 dilution) and question. Our experiments revealed that activation of b-catenin in visualized using a DAB Peroxidase Substrate Kit (Gene Tech). Staining gastric cancer caused an upregulation of CCL28 expression and was visualized by Olympus BX53 System Microscope. Staining of subsequent Treg cell recruitment. Blockade of CCL28 suppressed Treg b-catenin and CCL28 on human gastric cancer tissue sections was cell infiltration and gastric cancer progression, thus shedding new light analyzed by ImageJ. To quantify the histopathologic score of mouse on the role of b-catenin signaling in shaping the gastric cancer immune stomach, tissue sections were stained with hematoxylin-eosin and was microenvironment. evaluated as described previously (28). Immunofluorescence of gastric cancer cells or mouse stomach tissue Materials and Methods sections was performed using the rabbit anti-b-catenin (clone E247, Abcam, 1:300 dilution) or rabbit polyclonal anti-GFP antibody Cell lines and plasmid transfection (Abcam, 1:300 dilution). Secondary antibody was Alexa Fluor 488– Human gastric cancer cell lines SGC7901, AGS, and BGC823 conjugated polyclonal goat anti-rabbit IgG (Abcam, 1:1,000 dilution). were obtained from the Cell Bank of Chinese Academy of Sciences Immunofluorescence images were acquired using Zeiss LSM 710 (Shanghai, China). MKN28 and MKN45 cell lines were obtained from Confocal Microscope. the Japanese Collection of Research Bioresources (JCRB) Cell Bank. Human normal gastric epithelial cell line GES-1 was a kind gift from Chromatin immunoprecipitation assay Dr. Helen H. Zhu (Renji Hospital, Shanghai Jiao Tong University Chromatin immunoprecipitation (ChIP) assay was performed as School of Medicine, Shanghai, China). Authentication of these cell described previously (29). Relative enrichment was calculated as lines was performed by Shanghai Biowing Applied Biotechnology Co. relative binding of anti-b-catenin over control IgG on the potential Ltd. using the short tandem repeat genetic analysis. All cell lines were DNA binding sites. maintained in RPMI1640 supplemented with 10% FBS and 1% penicillin–streptomycin (Thermo Fisher Scientific), cultured for no Luciferase reporter assay more than 2–3 weeks after thawing, and routinely checked for Myco- Wnt/b-catenin pathway reporter plasmid M50 Super 8X TOP- plasma infection using PlasmoTest Kit (InvivoGen). Transfection of Flash (Addgene plasmid, catalog no. 12456; ref. 30) was a kind gift À þ plasmids into gastric cancer cells was performed using jetPRIME from Randall Moon. A 2.8-kb promoter ( E2576/ 205 relative to CCL28 fi fl transfection reagent (Polybus Transfection) following the manufac- transcription start site) of human gene was cloned into a re y turers’ protocols. luciferase reporter construct pGL4. Mutations on potential T-cell factor/lymphoid enhancer factor (TCF/LEF) biding sites on CCL28 RNA purification and qPCR promoter were introduced
Load more

Recommended publications
  • Induces Homing of Antigen-Specific and Non Chemokine-Adjuvanted
    Chemokine-Adjuvanted Plasmid DNA Induces Homing of Antigen-Specific and Non −Antigen-Specific B and T Cells to the Intestinal and Genital Mucosae This information is current as of September 25, 2021. Yoann Aldon, Sven Kratochvil, Robin J. Shattock and Paul F. McKay J Immunol published online 8 January 2020 http://www.jimmunol.org/content/early/2020/01/07/jimmun ol.1901184 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/01/07/jimmunol.190118 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 8, 2020, doi:10.4049/jimmunol.1901184 The Journal of Immunology Chemokine-Adjuvanted Plasmid DNA Induces Homing of Antigen-Specific and Non–Antigen-Specific B and T Cells to the Intestinal and Genital Mucosae Yoann Aldon, Sven Kratochvil, Robin J.
    [Show full text]
  • Human B Cells Expression in Terminally Differentiating Induces
    1,25-Dihydroxyvitamin D3 Induces CCR10 Expression in Terminally Differentiating Human B Cells This information is current as Aiko-Konno Shirakawa, Daisuke Nagakubo, Kunio of September 28, 2021. Hieshima, Takashi Nakayama, Zhe Jin and Osamu Yoshie J Immunol 2008; 180:2786-2795; ; doi: 10.4049/jimmunol.180.5.2786 http://www.jimmunol.org/content/180/5/2786 Downloaded from References This article cites 55 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/180/5/2786.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology 1,25-Dihydroxyvitamin D3 Induces CCR10 Expression in Terminally Differentiating Human B Cells1 Aiko-Konno Shirakawa,2 Daisuke Nagakubo,2 Kunio Hieshima, Takashi Nakayama, Zhe Jin, and Osamu Yoshie3 In the B cell lineage, CCR10 is known to be selectively expressed by plasma cells, especially those secreting IgA.
    [Show full text]
  • Antimicrobial Activity As a Chemokine with Broad-Spectrum CCL28 Has
    CCL28 Has Dual Roles in Mucosal Immunity as a Chemokine with Broad-Spectrum Antimicrobial Activity This information is current as Kunio Hieshima, Haruo Ohtani, Michiko Shibano, Dai of September 26, 2021. Izawa, Takashi Nakayama, Yuri Kawasaki, Fumio Shiba, Mitsuru Shiota, Fuminori Katou, Takuya Saito and Osamu Yoshie J Immunol 2003; 170:1452-1461; ; doi: 10.4049/jimmunol.170.3.1452 Downloaded from http://www.jimmunol.org/content/170/3/1452 References This article cites 36 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/170/3/1452.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CCL28 Has Dual Roles in Mucosal Immunity as a Chemokine with Broad-Spectrum Antimicrobial Activity1 Kunio Hieshima,* Haruo Ohtani,2‡ Michiko Shibano,* Dai Izawa,* Takashi Nakayama,* Yuri Kawasaki,* Fumio Shiba,* Mitsuru Shiota,† Fuminori Katou,§ Takuya Saito,¶ and Osamu Yoshie3* CCL28 is a CC chemokine signaling via CCR10 and CCR3 that is selectively expressed in certain mucosal tissues such as exocrine glands, trachea, and colon.
    [Show full text]
  • The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature
    International Journal of Molecular Sciences Review The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature Jan Korbecki 1 , Klaudyna Kojder 2, Patrycja Kapczuk 1, Patrycja Kupnicka 1 , Barbara Gawro ´nska-Szklarz 3 , Izabela Gutowska 4 , Dariusz Chlubek 1 and Irena Baranowska-Bosiacka 1,* 1 Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powsta´nców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; [email protected] (J.K.); [email protected] (P.K.); [email protected] (P.K.); [email protected] (D.C.) 2 Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-281 Szczecin, Poland; [email protected] 3 Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University in Szczecin, Powsta´nców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; [email protected] 4 Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-914661515 Abstract: Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influ- ence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 Citation: Korbecki, J.; Kojder, K.; Kapczuk, P.; Kupnicka, P.; (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors— Gawro´nska-Szklarz,B.; Gutowska, I.; CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8.
    [Show full text]
  • The Chemokine System in Innate Immunity
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Chemokine System in Innate Immunity Caroline L. Sokol and Andrew D. Luster Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 Correspondence: [email protected] Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. Theyalso recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses. hemokines are chemotactic cytokines that with emphasis placed on its role in the innate Ccontrol cell migration and cell positioning immune system. throughout development, homeostasis, and in- flammation. The immune system, which is de- pendent on the coordinated migration of cells, CHEMOKINES AND CHEMOKINE RECEPTORS is particularly dependent on chemokines for its function.
    [Show full text]
  • Immune Evasion by Murine Melanoma Mediated Through CC Chemokine
    Immune Evasion by Murine Melanoma Mediated through CC Chemokine Receptor-10 Takashi Murakami,1 Adela R. Cardones,1 Steven E. Finkelstein,2 Nicholas P. Restifo,2 Brenda A. Klaunberg,5 Frank O. Nestle,4 S. Sianna Castillo,3 Phillip A. Dennis,3 and Sam T. Hwang1 1Dermatology, 2Surgery, and 3Cancer Therapeutics Branches, CCR, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892 4National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892 5Department of Dermatology, University of Zürich Hospital, CH-8091 Zürich, Switzerland Abstract Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3- kinase (PI3K)–dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression. Key words: metastasis • chemokine receptor • cancer • cell signaling Introduction Malignant melanoma is a potentially fatal skin cancer that is In this paper, we explore the role of chemokine recep- increasing in incidence (1). The ability of tumor cells to tors in the context of tumor escape from immune cell avoid immune surveillance is likely to be central to the clearance mechanisms.
    [Show full text]
  • Chloride Channels Regulate Differentiation and Barrier Functions
    RESEARCH ARTICLE Chloride channels regulate differentiation and barrier functions of the mammalian airway Mu He1†*, Bing Wu2†, Wenlei Ye1, Daniel D Le2, Adriane W Sinclair3,4, Valeria Padovano5, Yuzhang Chen6, Ke-Xin Li1, Rene Sit2, Michelle Tan2, Michael J Caplan5, Norma Neff2, Yuh Nung Jan1,7,8, Spyros Darmanis2*, Lily Yeh Jan1,7,8* 1Department of Physiology, University of California, San Francisco, San Francisco, United States; 2Chan Zuckerberg Biohub, San Francisco, United States; 3Department of Urology, University of California, San Francisco, San Francisco, United States; 4Division of Pediatric Urology, University of California, San Francisco, Benioff Children’s Hospital, San Francisco, United States; 5Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Heaven, United States; 6Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, United States; 7Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; 8Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States *For correspondence: Abstract The conducting airway forms a protective mucosal barrier and is the primary target of [email protected] (MH); [email protected] airway disorders. The molecular events required for the formation and function of the airway (SD); mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway [email protected] (LYJ) diseases,
    [Show full text]
  • CCL28 a Mucosal Chemokine That Has a Protective Role in the MALT
    UC Irvine UC Irvine Electronic Theses and Dissertations Title Functional Characterization of IL-40 a novel B cell cytokine and Physiological implications of CCL28 ablation Permalink https://escholarship.org/uc/item/2m7018vx Author Vazquez, Monica Ivonne Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, IRVINE Functional Characterization of IL-40 a novel B cell cytokine and Physiological Implications of CCL28 ablation DISSERTATION Submitted in Partial Satisfaction of the Requirements for the Degree of DOCTOR OF PHILOSOPHY In Biomedical Sciences By Monica Ivonne Vazquez Dissertation Committee: Professor Albert Zlotnik, Chair Professor Kenneth J. Longmuir Professor Craig M. Walsh 2015 Portions of Chapter 1 © 2015 Elselvier Ltd. All other chapters © 2015 Monica Ivonne Vazquez DEDICATION TO My husband Brian Vazquez And son Isaiah Vazquez They have been part of my entire life as a student from my undergraduate years to my graduate career. They both provided a much needed sense of balance and always brought me back to what matters the most: Family. My little girl, Penelope, who always brings a smile to face and has given me the strength to continue. Getsemani, expected April 7, 2015, who I cannot wait to meet. Thank you for your unending love and support. ii TABLE OF CONTENTS Page LIST OF FIGURES iv-vi LIST OF TABLES vii ACKNOWLEDGMENTS viii CURRICULUM VITAE ix-x LIST OF ABBREVIATIONS xi-xiv ABSTRACT OF THE DISSERTATION xv-xvi Chapter
    [Show full text]
  • Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1
    pathogens Article Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1 Acacia F. Dishman 1,2,†, Jie He 3,†, Brian F. Volkman 1,* and Anna R. Huppler 3,* 1 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] 2 Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA 3 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] * Correspondence: [email protected] (B.F.V.); [email protected] (A.R.H.) † These authors contributed equally. Abstract: Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, antimicrobial chemokine that interconverts between the conserved chemokine fold (an α–β monomer) and an alternate fold (an all-β dimer). Previous work has shown that human XCL1 kills C. albicans but has not assessed whether one or both XCL1 folds perform this activity. Here, we use structurally locked engineered XCL1 variants and Candida killing assays, adenylate kinase release assays, and propidium iodide uptake assays to demonstrate that both XCL1 folds kill Candida, but they do so via different mechanisms. Our results suggest that the alternate fold kills via membrane disruption, consistent with previous work, and the chemokine fold does not. XCL1 fold-switching thus provides a mechanism to regulate Citation: Dishman, A.F.; He, J.; the XCL1 mode of antifungal killing, which could protect surrounding tissue from damage associ- Volkman, B.F.; Huppler, A.R.
    [Show full text]
  • Role of Chemokines in Hepatocellular Carcinoma (Review)
    ONCOLOGY REPORTS 45: 809-823, 2021 Role of chemokines in hepatocellular carcinoma (Review) DONGDONG XUE1*, YA ZHENG2*, JUNYE WEN1, JINGZHAO HAN1, HONGFANG TUO1, YIFAN LIU1 and YANHUI PENG1 1Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051; 2Medical Center Laboratory, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, P.R. China Received September 5, 2020; Accepted December 4, 2020 DOI: 10.3892/or.2020.7906 Abstract. Hepatocellular carcinoma (HCC) is a prevalent 1. Introduction malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges Hepatocellular carcinoma (HCC) is the sixth most common for the treatment of HCC is the prevention or management type of cancer worldwide and the third leading cause of of recurrence and metastasis of HCC. It has been found that cancer-associated death (1). Most patients cannot undergo chemokines and their receptors serve a pivotal role in HCC radical surgery due to the presence of intrahepatic or distant progression. In the present review, the literature on the multi- organ metastases, and at present, the primary treatment methods factorial roles of exosomes in HCC from PubMed, Cochrane for HCC include surgery, local ablation therapy and radiation library and Embase were obtained, with a specific focus on intervention (2). These methods allow for effective treatment the functions and mechanisms of chemokines in HCC. To and management of patients with HCC during the early stages, date, >50 chemokines have been found, which can be divided with 5-year survival rates as high as 70% (3). Despite the into four families: CXC, CX3C, CC and XC, according to the continuous development of traditional treatment methods, the different positions of the conserved N-terminal cysteine resi- issue of recurrence and metastasis of HCC, causing adverse dues.
    [Show full text]
  • Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing CCR10
    Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing CCR10 This information is current as Bertus Eksteen, Alice Miles, Stuart M. Curbishley, Chris of September 26, 2021. Tselepis, Allister J. Grant, Lucy S. K. Walker and David H. Adams J Immunol 2006; 177:593-603; ; doi: 10.4049/jimmunol.177.1.593 http://www.jimmunol.org/content/177/1/593 Downloaded from References This article cites 51 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/177/1/593.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing CCR101 Bertus Eksteen,* Alice Miles,* Stuart M. Curbishley,* Chris Tselepis,‡ Allister J.
    [Show full text]
  • Ccl27/Ccl2 Ccl28
    UNIVERSITY OF CALIFORNIA, SAN DIEGO Structural and Functional Analysis of the Chemokine CCL27 and the Expression and Purification of Silent Chemokine Receptors D6 and DARC A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry and Biochemistry by Ariane L. Jansma Committee in charge: Professor Tracy M. Handel, Chair Professor Patricia Jennings, Co-Chair Professor William Gerwick Professor Susan Taylor Asst. Professor Faik A. Tezcan 2009 This Dissertation of Ariane L. Jansma is approved, and it is acceptable in quality and form for publication on microfilm and electronically: ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ Co-Chair ________________________________________________________ Chair iv TABLE OF CONTENTS Signature Page ................................................................................................................ iii Table of Contents............................................................................................................. iv List of Figures.................................................................................................................... x List of Tables...................................................................................................................xiii List of Abbreviations........................................................................................................xiv
    [Show full text]