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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 HPV16tg mouse 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.

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Acknowledgements

We thank members of the Coulombe laboratory for support, Dr Michelle Kerns for critical reading of the manuscript and Drs Janice Evans, Hyo Lee and TC Wu for advice and assistance. These studies were supported by NIH research grants CA160255 and AR44232 (to PAC) and NIH training grant CA009110 (to RH) from the National Institutes of Health.

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Correspondence to P A Coulombe.

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Hobbs, R., Batazzi, A., Han, M. et al. Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo. Oncogene 35, 5653–5662 (2016). https://doi.org/10.1038/onc.2016.102

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