Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors.
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.
Schreiber
Karin
K
Department of Pathology, The University of Chicago, 5841 S. Maryland Ave, MC 3008, Chicago, IL 60637, USA. hszz@midway.uchicago.edu
Cannon
Ronald E
RE
Karrison
Theodore
T
Beck-Engeser
Gabriele
G
Huo
Dezheng
D
Tennant
Raymond W
RW
Jensen
Heather
H
Kast
W Martin
WM
Krausz
Thomas
T
Meredith
Stephen C
SC
Chen
Lieping
L
Schreiber
Hans
H
D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D018631:ras Proteins