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
Department of Obstetrics & Gynecology, Catholic University Medical College, Catholic Cancer Research Center, Seoul, South Korea.
Gynecol Oncol. 2003 Jun;89(3):360-8. 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 x 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.
本研究旨在探讨雌激素是否可通过直接激活病毒基因的激素作用来诱导宫颈肿瘤进展。
我们检测了雌激素对HPV - 18 URR E6/E7转基因小鼠的体内作用。分析了转基因小鼠鳞柱交界处和阴道上皮细胞的生长刺激情况以及HPV E6/E7的表达。还通过体外瞬时转染试验评估了雌激素处理后HPV - 18 URR的启动子活性。
与对照组相比，HPV - 18 URR E6/E7转基因小鼠和雌激素处理组小鼠下生殖道发育异常病变更为常见（P < 0.05）。经免疫组化染色，雌激素处理的转基因小鼠宫颈和阴道全层上皮中的大多数细胞增殖细胞核抗原呈阳性（PCNA）。在雌激素处理的HPV - 18 URR E6/E7转基因小鼠（21只中有5只）和雌激素处理的非转基因小鼠（10只中有2只）中也发现了增生性腺体病变。在存在雌二醇的情况下，转基因小鼠中E6/E7转录本水平升高。在与雌激素受体表达载体和URR - CAT共转染时，用0.5×10⁻⁶ M雌二醇处理显示CAT活性有相加作用（增加4.8倍）。
在动物模型中，与宫颈癌相关的HPV E6和E7癌基因确实能够增强肿瘤形成。雌激素诱导的持续增殖可能通过体内和体外机制发生，通过这些机制，宫颈和阴道中的鳞状细胞以及腺上皮细胞在HPV - 18 URR E6/E7转基因小鼠及其分子系统中易于发生肿瘤进展。
