Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

Karin Schreiber, Ronald E. Cannon, Theodore Karrison, Gabriele Beck-Engeser, Dezheng Huo, Raymond W. Tennant, Heather Jensen, W. Martin Kast, Thomas Krausz, Stephen C. Meredith, Lieping Chen, Hans Schreiber

Research output: Contribution to journalArticlepeer-review

Abstract

E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for V-Ha-ras gene (R+) were crossed with transgenic C57BL/ 6 mice that harbor E6/E7 of HPV16 (E +). Beginning at about 3 months of age, the bitransgenic E +R+(C57BL/ 6 x FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E+R+ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E-R +) and 0, 0 and 0% (E+R-), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E-R+, E+R-). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice.

Original languageEnglish (US)
Pages (from-to)3972-3979
Number of pages8
JournalOncogene
Volume23
Issue number22
DOIs
StatePublished - May 13 2004
Externally publishedYes

Keywords

  • E6/E7
  • HPV 16
  • Human papilloma virus 16
  • Primary tumors
  • Synergy
  • Transgenic mice
  • vHa ras

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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