title: Loss of E2F1 Extends Survival and Accelerates Oral Tumor Growth in HPV-Positive Mice.
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.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, 900 E. 57th Street, Chicago, IL 60637, USA. rzhong@uchicago.edu.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, 900 E. 57th Street, Chicago, IL 60637, USA. jbechill@uchicago.edu.
authors.forename: John
authors.initials: J
authors.lastname: Bechill
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, 900 E. 57th Street, Chicago, IL 60637, USA. mspiotto@radonc.uchicago.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Spiotto
keywords: E2F1 transcription factor; genes; human papillomavirus 16; lethal; mice; transgenic; tumor suppressor