GATA3 Inhibits the Expression of Viral E6/E7 Genes, and Its Expression Is Compromised During HPV‐Mediated Cervical Carcinogenesis

ABSTRACT

High‐risk human papillomaviruses (HPV) are the main etiological agents of cervical cancer. The viral early promoter regulates the expression of E6/E7 oncoproteins, and its transcriptional activity is positively or negatively regulated by host transcription factors (TFs) that are able to bind to the viral long control region (LCR). In this study, we assessed the impact of a TF library on the early transcriptional activity of high‐risk HPV‐16 and −18, and among these TF, we selected and investigated the impact of GATA3, as well as its potential role as a prognostic biomarker for the development of cervical cancer. Luciferase reporter assays demonstrated that GATA3 negatively influences the transcriptional activity of HPV‐16 and −18, downregulating E6 and E7 mRNA levels, with in silico and in vivo assays indicating that this effect is due to GATA3 direct binding to the viral LCR. Subsequently, we evaluated GATA3 levels in normal and HPV‐immortalized epithelial raft cultures and cervical cancer samples by immunohistochemistry, also accessing the TF presence in pre‐neoplastic intraepithelial cervical lesions (CIN) by immunofluorescence assays, further correlating GATA3 protein expression with the presence of HPV E6/E7 mRNA. This approach revealed an apparent inverse correlation between GATA3 expression and the grade of CIN lesions, as well as with the presence of viral oncogene transcripts. When accessing GATA3 expression in cancer samples, we observed a significant correlation between the absence of GATA3 and higher stages of cancer. Thus, our data indicates that the loss of GATA3 expression contributes to high‐risk HPV‐mediated cervical carcinogenesis, with the TF possibility acting as a protective factor whose absence enables sustained viral oncogene expression and disease progression in the cervical tissue.