Human Papillomaviruses (HPVs) are small DNA tumour viruses that are strictly epitheliotropic, infecting keratinocytes at a wide range of body sites. They are classified into several phylogenetic groups. The α lfa-genus HPVs are associated with infections of mucosal epithelia, genital cancer, and are the best characterized. Beta-HPVs are associated with skin infections and development of non-melanoma skin cancer (NMSC). The molecular mechanisms by which the early proteins of these viruses contribute towards NMSC are poorly understood. Signal Transducer and Activator of Transcription 3 (Stat3) is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with cytokines/growth factors. Stat3 plays critical roles in biological activities including cell proliferation, migration, survival, and oncogenesis, and its constitutive activation has been found in a wide spectrum of human malignancies, including skin cancers. A fruitful approach to gain insight into the transforming activities of β-HPV has been development of mouse models. Targeted expression of the entire early region of HPV8 in the basal epithelium from a keratin K14 promoter can give rise to skin tumours without any co-carcinogenic treatment. To elucidate the physiological role of Stat3 in HPV8-induced skin carcinogenesis, we specifically disrupted the Stat3 gene in keratinocytes by constructing Cre transgenes driven by the keratin 5 (K5) promoter and used this transgenic mouse in the established experimental model of HPV8-induced skin carcinogenesis. Soon after birth, both Stat3−/− and Stat3−/−: HPV8 mice displayed an unhealthy phenotype and died prematurely. Surprisingly, development of spontaneous skin lesions was much less frequent in Stat3 haploinsufficient mice (Stat3+/−:HPV8) (80.25% vs 20.74%)and significantly delayed compared with WT mice. To elucidate the biological determinants that are responsible for impaired tumour formation in Stat3+/− mice, possible alteration in the process of proliferation and differentiation were investigated. Overall, our results clearly demonstrated that skin-specific Stat3 haploinsufficiency conferred resistance to HPV-induced transformation.
Disruption of epidermal specific Stat3 expression and delayed skin tumor development in HPV8 transgenic mice
DE ANDREA, Marco;LANDINI, Manuela Miriam;LANDOLFO, Santo Giuseppe
2009-01-01
Abstract
Human Papillomaviruses (HPVs) are small DNA tumour viruses that are strictly epitheliotropic, infecting keratinocytes at a wide range of body sites. They are classified into several phylogenetic groups. The α lfa-genus HPVs are associated with infections of mucosal epithelia, genital cancer, and are the best characterized. Beta-HPVs are associated with skin infections and development of non-melanoma skin cancer (NMSC). The molecular mechanisms by which the early proteins of these viruses contribute towards NMSC are poorly understood. Signal Transducer and Activator of Transcription 3 (Stat3) is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with cytokines/growth factors. Stat3 plays critical roles in biological activities including cell proliferation, migration, survival, and oncogenesis, and its constitutive activation has been found in a wide spectrum of human malignancies, including skin cancers. A fruitful approach to gain insight into the transforming activities of β-HPV has been development of mouse models. Targeted expression of the entire early region of HPV8 in the basal epithelium from a keratin K14 promoter can give rise to skin tumours without any co-carcinogenic treatment. To elucidate the physiological role of Stat3 in HPV8-induced skin carcinogenesis, we specifically disrupted the Stat3 gene in keratinocytes by constructing Cre transgenes driven by the keratin 5 (K5) promoter and used this transgenic mouse in the established experimental model of HPV8-induced skin carcinogenesis. Soon after birth, both Stat3−/− and Stat3−/−: HPV8 mice displayed an unhealthy phenotype and died prematurely. Surprisingly, development of spontaneous skin lesions was much less frequent in Stat3 haploinsufficient mice (Stat3+/−:HPV8) (80.25% vs 20.74%)and significantly delayed compared with WT mice. To elucidate the biological determinants that are responsible for impaired tumour formation in Stat3+/− mice, possible alteration in the process of proliferation and differentiation were investigated. Overall, our results clearly demonstrated that skin-specific Stat3 haploinsufficiency conferred resistance to HPV-induced transformation.
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