title: The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis.
abstract: The productive human papillomavirus (HPV) life cycle is tightly linked to the differentiation and cycling of keratinocytes. Deregulation of these processes and stimulation of cell proliferation by the action of viral oncoproteins and host cell factors underlies HPV-mediated carcinogenesis. Severe HPV infections characterize the wart, hypogammaglobulinemia, infection, and myelokathexis (WHIM) immunodeficiency syndrome, which is caused by gain-of-function mutations in the CXCR4 receptor for the CXCL12 chemokine, one of which is CXCR41013. We investigated whether CXCR41013 interferes in the HPV18 life cycle in epithelial organotypic cultures. Expression of CXCR41013 promoted stabilization of HPV oncoproteins, thus disturbing cell cycle progression and proliferation at the expense of the ordered expression of the viral genes required for virus production. Conversely, blocking CXCR41013 function restored virus production and limited HPV-induced carcinogenesis. Thus, CXCR4 and its potential activation by genetic alterations in the course of the carcinogenic process can be considered as an important host factor for HPV carcinogenesis.
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Meuris
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Carthagena
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jaracz-Ros
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.|US31-UMS3679 -Plateforme PHIC, Institut Paris-Saclay d'Innovation Thérapeutique (IPSIT), Inserm, CNRS, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Gaudin
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Cutolo
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Claire
authors.identifier: http://orcid.org/0000-0001-9465-2381
authors.initials: C
authors.lastname: Deback
authors.affiliation: Papillomavirus Regulation and Cancer, Institute of Medical Biology, A*STAR, Singapore.
authors.forename: Yuezhen
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Papillomavirus Regulation and Cancer, Institute of Medical Biology, A*STAR, Singapore.
authors.forename: Françoise
authors.initials: F
authors.lastname: Thierry
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Doorbar
authors.affiliation: Inflammation Chemokines and Immunopathology, INSERM, Fac. de médecine-Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D064593:Heterografts; D052161:Human papillomavirus 18; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D030361:Papillomavirus Infections / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000821:virology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4