title: Keratinocyte-specific stat3 heterozygosity impairs development of skin tumors in human papillomavirus 8 transgenic mice.
abstract: Human papillomaviruses (HPV) of the genus β are thought to play a role in human skin cancers, but this has been difficult to establish using epidemiologic approaches. To gain insight into the transforming activities of β-HPV, transgenic mouse models have been generated that develop skin tumors. Recent evidence suggests a central role of signal transducer and activator of transcription 3 (Stat3) as a transcriptional node for cancer cell-autonomous initiation of a tumor-promoting gene signature associated with cell proliferation, cell survival, and angiogenesis. Moreover, high levels of phospho-Stat3 have been detected in tumors arising in HPV8-CER transgenic mice. In this study, we investigate the in vivo role of Stat3 in HPV8-induced skin carcinogenesis by combining our established experimental model of HPV8-induced skin cancer with epidermis-restricted Stat3 ablation. Stat3 heterozygous epidermis was less prone to tumorigenesis than wild-type epidermis. Three of the 23 (13%) Stat3(+/-):HPV8 animals developed tumors within 12 weeks of life, whereas 54.3% of Stat3(+/+):HPV8 mice already exhibited tumors in the same observation period (median age for tumor appearance, 10 weeks). The few tumors that arose in the Stat3(+/-):HPV8 mice were benign and never progressed to a more malignant phenotype. Collectively, these results offer direct evidence of a critical role for Stat3 in HPV8-driven epithelial carcinogenesis. Our findings imply that targeting Stat3 activity in keratinocytes may be a viable strategy to prevent and treat HPV-induced skin cancer.
authors.affiliation: Department of Public Health and Microbiology, Medical School of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Andrea
authors.forename: Massimo
authors.initials: M
authors.lastname: Rittà
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Landini
authors.forename: Cinzia
authors.initials: C
authors.lastname: Borgogna
authors.forename: Michele
authors.initials: M
authors.lastname: Mondini
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
authors.forename: Karin
authors.initials: K
authors.lastname: Ehrenreiter
authors.forename: Manuela
authors.initials: M
authors.lastname: Baccarini
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Marcuzzi
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.forename: Santo
authors.initials: S
authors.lastname: Landolfo
authors.forename: Marisa
authors.initials: M
authors.lastname: Gariglio
mesh_terms: D000818:Animals; D002465:Cell Movement; D052816:Foreskin / Q000166:cytology / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D039121:Integrin alpha6beta1; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D039121:Integrin alpha6beta1; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000077022:Survivin