The Human Papillomavirus E6 Oncogene Dysregulates the Cell Cycle and Contributes to Cervical Carcinogenesis through Two Independent Activities

Abstract

Cervical cancer is a leading cause of death due to cancer among women worldwide. Using transgenic mice to dissect the contributions of the human papillomavirus (HPV) 16 E6 and E7 oncogenes in cervical cancer, E7 was identified previously to be the dominant oncogene. Specifically, when treated with exogenous estrogen for 6 months, E7 transgenic mice developed cancer throughout the reproductive tract, but E6 transgenic mice did not. E6 contributed to carcinogenesis of the reproductive tract, as E6/E7 double transgenic mice treated for 6 months with estrogen developed larger cancers than E7 transgenic mice. In the current study, we investigated whether the E6 oncogene alone could cooperate with estrogen to induce cervical cancer after an extended estrogen treatment period of 9 months. We found that the E6 oncogene synergizes with estrogen to induce cervical cancer after 9 months, indicating that E6 has a weaker but detectable oncogenic potential in the reproductive tract compared with the E7 oncogene. Using transgenic mice that express mutant forms of HPV16 E6, we determined that the interactions of E6 with cellular A-helix and PDZ partners correlate with its ability to induce cervical carcinogenesis. In analyzing the tumors arising in E6 transgenic mice, we learned that E6 induces expression of the E2F-responsive genes, Mcm7 and cyclin E, in the absence of the E7 oncogene. E6 also prevented the expression of p16 in tumors of the reproductive tract through a mechanism mediated by the interaction of E6 with

Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries

“…During adolescence and pregnancy, the cervix is exposed to augmented levels of hormonal changes (Singer and Monaghan, 2000), in which oestrogen stimulation facilitates acidification of the vaginal cavity, a determinant of squamous metaplasia when the endocervical epithelial everts (Elson et al, 2000). When this oestrogen-stimulated metaplastic transformation occurs in the presence of HPV, the probability of cell transformation increases, resulting in neoplastic changes (Elson et al, 2000;Shai et al, 2007Shai et al, , 2008Hwang et al, 2009). This phenomenon is dependent primarily on parity, and is more likely to occur during the first pregnancy rather than subsequent pregnancies (Singer and Monaghan, 2000).…”

Human papillomaviruses, cervical cancer and cell polarity

“…Co-carcinogen studies with chemical carcinogens or with oestrogen in these mice indicated that whereas E7 promotes immortalization, E6 promotes progression into full malignancy (Song et al, 2000;Riley et al, 2003;Brake and Lambert, 2005). In the reproductive tract, E6 has significantly weaker activity than E7 (Riley et al, 2003); however, after prolonged oestrogen treatment, cervical tumours did result, although this activity did not seem to require PDZ-binding capacity (Shai et al, 2007). Most importantly, however, the ability of E6 to cooperate with E7 in increasing tumour size and frequency, both in the cervix and at other tumour sites, was dependent upon the ability of E6 to bind to its PDZ domain-containing substrates (Nguyen et al, 2003;Shai et al, 2007Shai et al, , 2008.…”

“…In the reproductive tract, E6 has significantly weaker activity than E7 (Riley et al, 2003); however, after prolonged oestrogen treatment, cervical tumours did result, although this activity did not seem to require PDZ-binding capacity (Shai et al, 2007). Most importantly, however, the ability of E6 to cooperate with E7 in increasing tumour size and frequency, both in the cervix and at other tumour sites, was dependent upon the ability of E6 to bind to its PDZ domain-containing substrates (Nguyen et al, 2003;Shai et al, 2007Shai et al, , 2008. Obviously, the prime candidates for these activities of E6 are those substrates implicated in the regulation of cell polarity (see below), but the dissection of which target(s) is involved will require further dissection of E6's PDZ-binding capacity, as well as the use of conditional knockout mice in some of the polarity candidates.…”

FOXO1 is a tumor suppressor in cervical cancer

“…However, a previous study suggested that HPV infection alone is insufficient for inducing cervical cancer (Shai et al, 2007) and malignant changes (Kim and Zhao, 2005). There is an urgent need to understand the molecular mechanisms governing cervical tumorigenesis.…”