Neoplastic change of squamo-columnar junction in uterine cervix and vaginal epithelium by exogenous estrogen in hpv-18 URR E6/E7 transgenic mice

• Published in: Gynecologic oncology 2003-06, Vol.89 (3), p.360-368
• Main Authors: Park, Jong Sup, Rhyu, Jae Woong, Kim, Chan Joo, Kim, Hy Sook, Lee, Sun Young, Kwon, Yong Ill, Namkoong, Sung Eun, Sin, Hong Sig, Um, Soo Jong
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Transformation, Viral - drug effects; Cervical cancer; DNA-Binding Proteins; Epithelium - drug effects; Epithelium - virology; Estradiol - toxicity; Estrogen; Female; Female genital diseases; Gene Expression Regulation, Viral - drug effects; Gynecology. Andrology. Obstetrics; Human papillomavirus (HPV); Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Oncogene Proteins, Viral - genetics; Papillomaviridae - genetics; Regulatory Sequences, Nucleic Acid - drug effects; Regulatory Sequences, Nucleic Acid - genetics; Transcriptional Activation - drug effects; Tumors; Up-Regulation - drug effects; URR; Uterine Cervical Neoplasms - chemically induced; Uterine Cervical Neoplasms - etiology; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Vaginal Neoplasms - chemically induced; Vaginal Neoplasms - etiology; Vaginal Neoplasms - pathology; Vaginal Neoplasms - virology
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/S0090-8258(02)00106-3

The goal of this study was to study whether estrogen could induce progression of cervical neoplasia by the influence of direct hormonal transactivation of the viral genes. We examined the in vivo effect of estrogen on HPV-18 URR E6/E7 transgenic mice. We analyzed the growth stimulation of epithelial cells at squamo-columnar junction and vagina and the expression of HPV E6/E7 in transgenic mice. The promoter activity of HPV-18 URR after treatment of estrogen was also evaluated by in vitro transient transfection assay. The dysplastic lesions of lower genital tract were more frequently seen in the HPV-18 URR E6/E7 transgenic mice and estrogen-treated mice, when compared to those of control group ( P < 0.05). The majority of cells in whole epithelial layer of cervix and vagina were proliferating cell nuclear antigen-positive (PCNA) by immunohistochemical staining in the estrogen-treated transgenic mice. Hyperplastic glandular lesions were also identified in estrogen-treated HPV-18 URR E6/E7 transgenic mice (5 of 21) and estrogen-treated nontransgenic mice (2 of 10). The level of E6/E7 transcripts in transgenic mouse was increased in the presence of estradiol. Treatment with 0.5 × 10 −6 M estradiol in the presence of cotransfection with the estrogen receptor expression vector and URR-CAT showed an additive effect of CAT activity (4.8-fold increase). The HPV E6 and E7 oncogenes implicated in cervical cancer are indeed capable of potentiating tumor formation in animal model. Continual estrogen-induced proliferation might be viewed by in vivo and in vitro mechanisms by which squamous cells as well as glandular cells in cervix and vagina became permissive for neoplastic progression in HPV-18 URR E6/E7 transgenic mice and their molecular systems.