Abstract
The Human Papillomavirus (HPV) is associated with several human cancers, including head and neck squamous cell carcinomas (HNSCCs). HPV expresses the viral oncogene E7 that binds to the retinoblastoma protein (RB1) in order to activate the E2F pathway. RB1 can mediate contradictory pathways—cell growth and cell death via E2F family members. Here, we assessed the extent to which E2F1 mediates lethality of HPV oncogenes. Ubiquitous expression of the HPV oncogenes E6 and E7 caused lethality in mice that was associated with focal necrosis in hepatocytes and pancreatic tissues. Furthermore, all organs expressing HPV oncogenes displayed up-regulation of several E2F1 target genes. The E2F1 pathway mediated lethality in HPV-positive mice because deletion of E2F1 increased survival of mice ubiquitously expressing HPV oncogenes. E2F1 similarly functioned as a tumor suppressor in HPV-positive oral tumors as tumors grew faster with homozygous loss of E2F1 compared to tumors with heterozygous loss of E2F1. Re-expression of E2F1 caused decreased clonogenicity in HPV-positive cancer cells. Our results indicate that HPV oncogenes activated the E2F1 pathway to cause lethality in normal mice and to suppress oral tumor growth. These results suggest that selective modulation of the E2F1 pathway, which is activated in HPV tumors, may facilitate tumor regression.
Highlights
The Human Papillomavirus is associated with many epithelial cancers, including those afflicting the oropharynx and anogenital regions [1,2,3]
Our results indicated that the E2F1 pathway, which is controlled by the Human Papillomavirus (HPV) E7 oncogene, inhibits cell proliferation causing lethality in HPV-positive mice and suppressing HPV-positive oral tumor growth
Since the HPV oncogene E7 targets the RB1, we tested if ubiquitous expression of HPV oncogenes results in embryonic lethality
Summary
The Human Papillomavirus is associated with many epithelial cancers, including those afflicting the oropharynx and anogenital regions [1,2,3]. The viral oncogenes of HPV, namely E7, promote DNA synthesis in the maturing epithelial layer in order to facilitate viral replication [4,5]. To facilitate proliferation in differentiated cells, E6 and E7 target canonical tumor suppressor pathways including the proteins TP53 and the retinoblastoma protein (RB1), respectively. Abnormal activation of the cell cycle initiates cell death pathways that safeguard against malignant transformation. E6, by targeting p53 and other anti-apoptotic pathways, inhibits these cell death pathways, thereby predisposing abnormally-proliferating cells to malignant transformation. The malignant transition of HPV-infected cells to cancer coincides with the integration of the HPV viral genome that disrupts E2 expression resulting in E6 and E7 overexpression and the activation and/or inhibition of downstream oncogenic and tumor suppressor pathways, respectively
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