Abstract
High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization capacity of ten hrHPV types relates to DNA damage induction and overall genomic instability in HFKs.Twenty five cell cultures obtained by transduction of ten hrHPV types (i.e. HPV16/18/31/33/35/45/51/59/66/70 E6E7) in two or three HFK donors each were studied.All hrHPV-transduced HFKs showed an increased number of double strand DNA breaks compared to controls, without exhibiting significant differences between types. However, immortal descendants of HPV-transduced HFKs that underwent a prior crisis period (HPV45/51/59/66/70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without crisis (HPV16/18/31/33/35-transduced HFKs). Notably, the hTERT locus at 5p was exclusively gained in cells with a history of crisis and coincided with increased expression. Chromothripsis was detected in one cell line in which multiple rearrangements within chromosome 8 resulted in a gain of MYC.Together we demonstrated that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the viral immortalization capacity. We propose that hrHPV types with reduced immortalization capacity in vitro, reflected by a crisis period, require more genetic host cell aberrations to facilitate immortalization than types that can immortalize without crisis. This may in part explain the observed differences in HPV-type prevalence in cervical cancers and emphasizes that changes in the host cell genome contribute to HPV-induced carcinogenesis.
Highlights
A persistent infection with certain types of the human papillomavirus (HPV) has been causally associated with the development of cervical cancer, as well as a subset of other anogenital and head-and-neck cancers
The induction of DNA damage is a well-established feature of High-risk human papillomavirus (hrHPV) types such as HPV16 and is known to contribute to HPV-induced cellular transformation
In the present study we showed a progressive increase in chromosomal aberrations during hrHPVmediated immortalization
Summary
A persistent infection with certain types of the human papillomavirus (HPV) has been causally associated with the development of cervical cancer, as well as a subset of other anogenital and head-and-neck cancers. M1, or senescence, can be overcome by hrHPV itself, resulting in an extended though still limited lifespan In this phase hrHPV E6 and E7 induce DNA double strand breaks that are prevented from repair by virus-mediated impairment of cell cycle control [4, 5]. Studies on (epi)genetic host cell aberrations associated with hrHPV-mediated immortalization have mostly focused on HPV16 and HPV18 [8,9,10,11] In these studies in vitro immortalization has been associated with chromosomal aberrations that largely overlap with those described in cervical carcinomas and its high-grade precursor lesions (cervical intraepithelial neoplasia grade 3; CIN3), such as gains at 1q and 3q (reviewed by [12, 13])
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