Abstract
Epidemiological evidence supports that infection with high-risk types of human papillomavirus (HPV) can interact with host and environmental risk factors to contribute to the development of cervical, oropharyngeal, and other anogenital cancers. In this study, we established a mouse epithelial cancer cell line, designated as Chinese University Papillomavirus-1 (CUP-1), from C57BL/KsJ mice through persistent expression of HPV-16 E7 oncogene. After continuous culturing of up to 200 days with over 60 passages, we showed that CUP-1 became an immortalized and transformed epithelial cell line with continuous E7 expression and persistent reduction of retinoblastoma protein (a known target of E7). This model allowed in-vivo study of interaction between HPV and co-factors of tumorigenesis in syngeneic mice. Diabetes has been shown to increase HPV pathogenicity in different pathological context. Herein, with this newly-established cell line, we uncovered that diabetes promoted CUP-1 xenograft growth in syngeneic db/db mice. In sum, we successfully established a HPV-16 E7 transformed mouse epithelial cell line, which allowed subsequent studies of co-factors in multistep HPV carcinogenesis in an immunocompetent host. More importantly, this study is the very first to demonstrate the promoting effect of diabetes on HPV-associated carcinogenesis in vivo, implicating the importance of cancer surveillance in diabetic environment.
Highlights
Persistent infection with high-risk types of human papillomavirus (HPV) is strongly associated with the development of a wide range of malignancies, including cervical, oropharyngeal, anal, PLOS ONE | DOI:10.1371/journal.pone.0164490 October 17, 2016Diabetes Promotes Chinese University Papillomavirus-1 (CUP-1) Xenograft Growth vaginal, vulvar and penile cancers
A continuous mouse epithelial cell line, designated as CUP-1 was formed by introducing HPV-16 E7 oncogene into primary baby mouse kidney cells
Stable and continuous E7 expression from early to late passages was confirmed by Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot
Summary
Persistent infection with high-risk types of human papillomavirus (HPV) is strongly associated with the development of a wide range of malignancies, including cervical, oropharyngeal, anal, PLOS ONE | DOI:10.1371/journal.pone.0164490 October 17, 2016Diabetes Promotes CUP-1 Xenograft Growth vaginal, vulvar and penile cancers. Persistent infection with high-risk types of human papillomavirus (HPV) is strongly associated with the development of a wide range of malignancies, including cervical, oropharyngeal, anal, PLOS ONE | DOI:10.1371/journal.pone.0164490. Diabetes Promotes CUP-1 Xenograft Growth vaginal, vulvar and penile cancers. The pathogenic mechanism of HPV has been extensively studied and it is well established that E6 and E7 are its major oncogenes. Though infection of high risk HPV types is common, only a small proportion of infected subjects eventually develop cancer [1]. Interaction of HPV with host risk factors and other environmental factors play an important role in the multistep HPV carcinogenesis. Our knowledge on the correlation between HPV and these co-factors is still very limited
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