TY - JOUR
T1 - Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors
AU - Schreiber, Karin
AU - Cannon, Ronald E.
AU - Karrison, Theodore
AU - Beck-Engeser, Gabriele
AU - Huo, Dezheng
AU - Tennant, Raymond W.
AU - Jensen, Heather
AU - Kast, W. Martin
AU - Krausz, Thomas
AU - Meredith, Stephen C.
AU - Chen, Lieping
AU - Schreiber, Hans
PY - 2004/5/13
Y1 - 2004/5/13
N2 - 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.
AB - 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.
KW - E6/E7
KW - HPV 16
KW - Human papilloma virus 16
KW - Primary tumors
KW - Synergy
KW - Transgenic mice
KW - vHa ras
UR - http://www.scopus.com/inward/record.url?scp=2542583106&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2542583106&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1207507
DO - 10.1038/sj.onc.1207507
M3 - Article
C2 - 15077191
AN - SCOPUS:2542583106
SN - 0950-9232
VL - 23
SP - 3972
EP - 3979
JO - Oncogene
JF - Oncogene
IS - 22
ER -