title: Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo.
abstract: Despite preventive human papilloma virus (HPV) vaccination efforts, cervical cancer remains a leading cause of death in women worldwide. Development of therapeutic approaches for cervical cancer are hampered by a lack of mechanistic insight during tumorigenesis. The cytoskeletal protein Keratin 17 (KRT17;K17) is robustly expressed in a broad array of carcinomas, including in cervical tumors, where it has both diagnostic and prognostic value. In this study, we have established multiple functional roles for K17 in the promotion of cervical tumorigenesis in vivo using the established HPV16tgmouse model for cervical squamous cell carcinoma. In HPV16tg/+;Krt17-/-relative to HPV16tg/+reference female mice, onset of cervical lesions is delayed and closely paralleled by marked reductions in hyperplasia, dysplasia and vascularization. In addition, loss of Krt17 is associated with a cytokine polarization and recruitment of effector immune cells to lesion-prone cervical epithelia. Further, we observed marked enhancement of terminal differentiation in HPV16tg/+;Krt17-/-cervical epithelium accompanied by a stimulation and expansion in the expression of p63, a known basal/reserve cell marker in this tissue. Altogether, the data suggest that the loss of Krt17 may foster an overall protective environment for lesion-prone cervical tissue. In addition to providing new insights into the immunomodulatory and cellular mechanisms of cervical tumorigenesis, these findings may help guide the development of future therapies including vaccines.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Hobbs
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Batazzi
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.|Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.|Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.|Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.|The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore MD, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Coulombe
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053537:Keratin-17 / Q000172:deficiency*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D030361:Papillomavirus Infections / Q000150:complications* / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D048948:14-3-3 Proteins; D015415:Biomarkers; D016207:Cytokines; D053537:Keratin-17