Schreiber Karin, Cannon Ronald E, Karrison Theodore, Beck-Engeser Gabriele, Huo Dezheng, Tennant Raymond W, Jensen Heather, Kast W Martin, Krausz Thomas, Meredith Stephen C, Chen Lieping, Schreiber Hans
Department of Pathology, The University of Chicago, 5841 S. Maryland Ave, MC 3008, Chicago, IL 60637, USA.
Oncogene. 2004 May 13;23(22):3972-9. doi: 10.1038/sj.onc.1207507.
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.
高危型人乳头瘤病毒（HPV）亚型的E6/E7癌基因对于某些类型癌症的发生发展至关重要。然而，这些癌基因不足以将正常细胞转化为永生化或恶性状态。突变型Ha-ras在体外细胞转化过程中与HPV 16亚型的E6/E7协同作用，可能在人类某些HPV相关癌症中发挥作用。本研究调查HPV16 E6/E7和v-Ha-ras在体内是否具有协同作用。将携带v-Ha-ras基因的FVB/n转基因小鼠（R+）与携带HPV16 E6/E7的C57BL/6转基因小鼠（E+）进行杂交。从大约3月龄开始，双转基因E(+)R(+)(C57BL/6×FVB/n)F1小鼠出现口腔、眼睛和耳部肿瘤。到6个月时，E(+)R+小鼠中这些类型的口腔、眼睛和耳部肿瘤的发生率分别为100%、71%和79%。大多数肿瘤逐渐生长，直至小鼠不得不被处死。首次出现口腔、眼睛和耳部肿瘤的中位时间分别为3.6个月、4.3个月和4.2个月。对于两组单转基因小鼠，口腔、眼睛和耳部肿瘤的发生率分别为0、0和6%（E(-)R+）以及0、0和0%（E(+)R-），单转基因小鼠（E(-)R+，E(+)R-）首次出现肿瘤的中位时间大于12个月。因此，v-Ha-ras和HPV16 E
