Keratinocyte-Specific Stat3 Heterozygosity Impairs Development of Skin Tumors in Human Papillomavirus 8 Transgenic Mice

M. De Andrea, M. Ritta, M. M. Landini, C. Borgogna, M. Mondini, F. Kern, K. Ehrenreiter, M. Baccarini, G. P. Marcuzzi, S. Smola, H. Pfister, S. Landolfo (+1 others)
2010 Cancer Research  
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
more » ... sociated 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. Cancer Res; 70(20); 7938-48.
doi:10.1158/0008-5472.can-10-1128 pmid:20876801 fatcat:pftwtzsw65b2fgnvlbntw6f2rm