Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice
Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice
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DOI：
10.1073/pnas.93.7.2930
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发表时间：
1996-04-02
影响因子：
11.1
通讯作者：
Hanahan, D
中科院分区：
文献类型：
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作者：
Arbeit, JM;Howley, PM;Hanahan, D
高风险的人乳头瘤病毒（hpv），包括16型，已被确定为宫颈癌发生的因素，然而，病毒本身的存在和表达似乎不足以致癌。相反，除了病毒基因表达之外，辅助因子很可能是引发肿瘤的必要因素，一个候选的辅助因子是长期暴露于性激素。为了研究雌激素对hpv相关肿瘤的可能影响，我们用人类角蛋白14启动子控制表达HPV16癌基因的转基因小鼠（K14-HPV16转基因小鼠）和用17 β -雌二醇缓释微丸治疗非转基因小鼠，K14-HPV16转基因小鼠的阴道和宫颈鳞状癌以多阶段途径发展。雌激素诱导的癌变伴随着增殖细胞在K14-HPV16小鼠宫颈和阴道鳞状上皮内的发生率和分布的增加，未经处理的转基因小鼠仅在发情期检测到HPV转基因的表达；这些数据表明，在K14-HPV16转基因小鼠的雌性生殖道中，慢性雌激素暴露与HPV16致癌基因之间存在一种协同合作的新机制，该机制协调了HPV16转基因小鼠的鳞状癌的发生。
High-risk human papillomaviruses (HPVs), including type 16, have been identified as factors in cervical carcinogenesis, However, the presence and expression of the virus per se appear to be insufficient for carcinogenesis. Rather, cofactors most likely are necessary in addition to viral gene expression to initiate neoplasia, One candidate cofactor is prolonged exposure to sex hormones. To examine the possible effects of estrogen on HPV-associated neoplasia, we treated transgenic mice expressing the oncogenes of HPV16 under control of the human keratin-14 promoter (K14-HPV16 transgenic mice) and nontransgenic control mice with slow-release pellets of 17 beta-estradiol, Squamous carcinomas developed in a multistage pathway exclusively in the vagina and cervix of K14-HPV16 transgenic mice, Estrogen-induced carcinogenesis was accompanied by an incremental increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-HPV16 mice, Expression of the HPV transgenes in untreated transgenic mice was detectable only during estrus; estrogen treatment resulted in transgene expression that was persistent but not further upregulated, remaining at low levels at all stages of carcinogenesis, The data demonstrate a novel mechanism of synergistic cooperation between chronic estrogen exposure and the oncogenes of HPV16 that coordinates squamous carcinogenesis in the female reproductive tract of K14-HPV16 transgenic mice.