Certain types of cutaneous HPVs (beta HPV types) are implicated in the development of non-melanoma skin cancer (NMSC) although the mechanisms have not been established. The E6 and E7 proteins of some cutaneous HPV types were shown to be able to immortalize primary human keratinocytes (PHKs) and protect keratinocytes from UVB induced apoptosis. The latter activity is believed to enhance the carcinogenic effect of UVB. It is not known which other transforming activities are expressed by cutaneous HPVs in PHKs and whether low and high risk HPVs, detected in skin warts and cancers, respectively, differ in these activities. In the present study, E6E7 and E6 proteins of different HPVs were compared for transforming and carcinogenic abilities in PHKs including several cancer associated cutaneous HPV types, 8, 14, 24, 36, 38, 49, a wart associated skin type, HPV 10, and a mucosal high risk type, HPV16. The HPV proteins were stably expressed in PHKs via retroviral transduction. We show that E6E7 of none of the cutaneous HPV types were able to prolong the life span of PHKs after exposure to serum- and calcium differentiation trigger. E6E7 of several of the cancer associated cutaneous HPVs, notably 49 and 24, were able to extend the life span and enhance the clonogenic efficiency of PHKs when maintained in serum free/low calcium medium. Activities of the cutaneous HPV E6E7 were lower than16E6E7. In contrast, E6 proteins of low and high risk cutaneous HPVs, notably 10, 49 and 38 attenuated UVB induced protective responses in PHKs including cell death, proliferation- arrest and accumulation of the proapoptotic proteins, p53, bax and bak. Together, this investigation revealed functional differences and commonalities between low and high risk cutaneous HPVs which allowed the identification of distinctive properties by which high risk cutaneous HPVs may contribute to skin carcinogenesis.
