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Induction of Uterine Cervical Neoplasias in Mice by Human Papillomavirus Type 16 E6/E7 Genes¹

Department of Obstetrics and Gynecology, Osaka University Medical School, 1-1-50 Fukushima, Fukushima-ku, Osaka 553 [T. S., M. I., O. T.], and Department of Tumor Virology, Research Institute for Microbial Diseases, 3-1 Yamadaoka, Suita 565 [H. I., M. Y., A. H.], Japan

We constructed a recombinant retrovirus containing the E6/E7 genes of human papillomavirus (HPV) 16 (ZE67) and examined the morphological changes in the cervicovaginal epithelium induced by inoculation of this virus into the vagina of mice. The ZNeo virus without HPV genes was used as a negative control. Moreover, cotreatment with phorbo-13-myristate-12-acetate or N-methyl-N'-nitro-N-nitrosoguanidine and these viruses was carried out.

At the end of the observation period (9 months for CD-1 nu/nu and 15 months for C57BL/6J), of 31 CD-1 nude mice treated with ZE67, 7 and 19 had low-grade and high-grade dysplasia, respectively, while 5 of 22 mice treated with ZNeo had low-grade dysplasia (rank sum test, P < 0.001). Similarly, 4 and 3 of 8 C57BL mice treated with ZE67 had low-grade and high-grade dysplasias, respectively, whereas 3 of the 8 control mice had low-grade dysplasias (P = 0.049). ZE67 plus phorbol-13-myristate-12-acetate and ZE67 plus N-methyl-N'-nitro-N-nitrosoguanidine cotreatments induced cervical cancers in 2 of 13 CD-1 nude mice and 6 of 15 C57BL mice, respectively. On the contrary, none of 6 CD-1 and 2 of 10 C57BL mice had cancer in the control groups (P = 0.0142 for phorbol-13-myristate-12-acetate treatment; P = 0.0173 for N-methyl-N'-nitro-N-nitrosoguanidine treatment). In addition, the existence and expression of HPV 16 E6/E7 genes were detected in the lesions induced by ZE67 but not in the lesions of the control mice by analysis by polymerase chain reaction and mRNA in situ hybridization.

The present results suggest that HPV 16 E6/E7 genes induce dysplastic changes but require additional promoting or mutagenic stimulation for the development of cancer.

¹ This work was supported in part by grants-in-aid for Special Project Research Cancer/Bioscience from the Ministry of Education, Science and Culture and for cancer research (2-1) from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed, at the Department of Obstetrics and Gynecology, Osaka University Medical School, 1-1-50 Fukushima, Fukushima-ku, Osaka 553, Japan.

Received 1/28/92. Accepted 6/ 2/92.