Elucidating the role of Keratin 17 in cervical carcinogenesis
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Cervical malignancies develop when viral genes from high-risk strains of the Human Papilloma Virus (HPV) such as HPV type 16 and 18 are expressed in the cervical epithelium. Expression of Keratin 17 (K17), an intermediate filament cytoskeletal protein that is robustly upregulated in a variety of epithelial-derived tumors, is positively correlated with the progression of cervical lesions and is considered a reliable prognostic biomarker for cervical cancer. We previously reported that the genetic loss of Krt17 attenuates skin tumorigenesis in a mouse model for spontaneous basaloid tumor formation, correlating with a modulation of T helper 1/ T helper 17 (Th1/Th17) and T helper 2 (Th2) inflammatory cytokine expression, and resulting in dampened recruitment of immune cells to the site of tumor formation. The present study aims to understand the role of K17 in cervical carcinogenesis using the HPV16tg mouse model, which spontaneously forms squamous cell carcinoma-like lesions in cervical epithelia when females are treated with estrogen. We hypothesized that onset and progression of HPV16tg-induced cervical lesions would be delayed in the absence of K17, and that K17’s immunomodulatory role extends to the cervical epithelium. Compared to wildtype controls, HPV16tg/+ mice exhibit robust hyperplasia of cervical epithelia, as well as increased cervical epithelial proliferation and vasculature 3 months after receiving an estrogen implant. All of these trademarks of cancer were found to be attenuated with the genetic loss of Krt17. Whereas several Th1 pro-inflammatory cytokines are upregulated in HPV16tg/+ cervical tissue relative to wildtype control, these are further upregulated in the Krt17 null background, a finding that is consistent with the literature on cervical carcinogenesis, but opposite to what prevails in the ear skin tumors occurring in the same mice. Collectively, these findings support the notion that K17 expression is positively correlated with the progression of tumors and extends the idea that K17 functions as an immune response modulator in both cervical and skin carcinogenesis. The observed differences in inflammatory readouts between ear and cervical epithelia suggest that K17’s impact on signaling pathways and gene expression occurs in a tissue and/or context-dependent manner.