Estrogen contributes to non-pRb targeted HPV18 E7-caused cell proliferation and transformation.

Almost all of cervical carcinoma arises as a result of persistent infection with high-risk human papillomaviruses (HPVs) where E7 oncogene plays an important role. In addition, estrogen is a confirmed cofactor in HPV related cervical carcinoma working synergistically with E7. There are two pathways involved in the E7 carcinogenesis of cervical cancer, the pRb-dependent and pRb-independent pathway. In this study we analyzed that whether estrogen contributes to high-risk HPV E7 in cervical carcinogenesis via pRb-independent pathway or not. E7(DeltaRB), which can not bind to and degrade pRb protein, hence no transformation ability, worked synergistically with estrogen in cell proliferation and transformation. Estrogen combined with PTD-HPV18E7(DeltaRB) enhanced cell proliferation rate, induced genomic instability, including abnormal centrosome duplication and chromosomal instability, and exhibited malignant transformation with anchorage-independent growth. We also observed that, PTD-HPV18E7(DeltaRB) can interact with c-Jun and c-Myc proteins, but this interaction was limited to the estrogen-treated cells where c-Jun and c-Myc were expressed highly and no such interaction was observed in estrogen-untreated cells where c-Jun and c-Myc expression levels were low. In conclusion, estrogen can cooperate with E7 through a pRB-independent manner in cervical carcinogenesis. The functional interaction between E7 and c-Jun or between E7 and c-Myc could only be triggered when the c-Jun or c-Myc expression level reaches a certain threshold.