HPV oncogenes increase viability and nucleararchitecture stability in pretumoral keratinocytesexposed to UVB radiation.

Abstract

Ultraviolet radiation (UVR) is an environmental risk factor and a cofactor in carcinogenesis. UVBradiation (UVBR), mainly from sunlight, is a known risk factor for lip cancer and can also contribute tooral cavity cancer. Besides inducing DNA damage, UVBR can activate dormant HPV infections in the oralcavity, increasing oral carcinogenesis likelihood via HPV oncogenes. In this study, we evaluated theresponses to UVBR in human keratinocytes infected with viral oncogenes of HPV-18. While UVBRinduced similar levels of DNA damage in the HaCaT human keratinocyte parental cell line compared toHaCaT cells containing HPV-18 oncogenes E5, E6 and E7, the latter showed increased viability andreduced levels of apoptotic and necrotic markers in response to UVBR. Both HaCaT parental and HaCaTE5/E6/E7-18 cells showed marked alterations in the actin cytoskeleton upon UVBR, but HaCaT parentalcells retained more stress fi bers, while displaying deep nuclear invaginations, which were much lessfrequent in HaCaT E5/E6/E7-18 cells. Deep nuclear invaginations were lined by highly condensedchromatin, implying alterations in nuclear architecture that profoundly affect normal nuclearcompartmentalization. Furthermore, mechanical modelling suggests that reduced nuclear invaginationsin irradiated HaCaT E5/E6/E7-18 cells is related to decreased tractional stress. Our results show thatHPV oncogenes confer increased viability and nuclear architecture stability to keratinocytes exposed toUVBR, which could contribute to their role in cooperating with UVBR induced carcinogenesis in the oralcavity.