Diaz-Chavez Jose, Hernandez-Pando Rogelio, Lambert Paul F, Gariglio Patricio
Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados, México DF, 07000, México.
Mol Cancer. 2008 Jan 9;7:3. doi: 10.1186/1476-4598-7-3.
Cervical carcinogenesis is a multistep process initiated by "high risk" human papillomaviruses (HR-HPV), most commonly HPV16. The infection per se is, however, not sufficient to induce malignant conversion. Transforming Growth Factor beta (TGF-beta) inhibits epithelial proliferation and altered expression of TGF-beta or its receptors may be important in carcinogenesis. One cofactor candidate to initiate neoplasia in cervical cancer is the prolonged exposure to sex hormones. Interestingly, previous studies demonstrated that estrogens suppress TGF-beta induced gene expression. To examine the expression of TGF-beta2, TGF-betaRII, p15 and c-myc we used in situ RT-PCR, real-time PCR and immunohistochemistry in transgenic mice expressing the oncogene E7 of HPV16 under control of the human Keratin-14 promoter (K14-E7 transgenic mice) and nontransgenic control mice treated for 6 months with slow release pellets of 17beta-estradiol.
Estrogen-induced carcinogenesis was accompanied by an increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-E7 mice. TGF-beta2 mRNA and protein levels increased in K14-E7 transgenic mice as compared with nontransgenic mice and further increased after hormone-treatment in both nontransgenic and transgenic mice. In contrast, TGF-betaRII mRNA and protein levels were decreased in K14-E7 transgenic mice compared to nontransgenic mice and these levels were further decreased after hormone treatment in transgenic mice. We also observed that c-myc mRNA levels were high in K14-E7 mice irrespective of estrogen treatment and were increased in estrogen-treated nontransgenic mice. Finally we found that p15 mRNA levels were not increased in K14-E7 mice.
These results suggest that the synergy between estrogen and E7 in inducing cervical cancer may in part reflect the ability of both factors to modulate TGF-beta signal transduction.
宫颈癌发生是一个多步骤过程，由“高危”人乳头瘤病毒（HR-HPV）引发，最常见的是HPV16。然而，感染本身不足以诱导恶性转化。转化生长因子β（TGF-β）抑制上皮细胞增殖，TGF-β或其受体表达改变在致癌过程中可能很重要。引发宫颈癌瘤形成的一个辅助因子候选物是长期暴露于性激素。有趣的是，先前的研究表明雌激素抑制TGF-β诱导的基因表达。为了检测TGF-β2、TGF-βRII、p15和c-myc的表达，我们在人角蛋白-14启动子（K14-E7转基因小鼠）控制下表达HPV16癌基因E7的转基因小鼠以及用17β-雌二醇缓释微丸处理6个月的非转基因对照小鼠中，使用原位逆转录聚合酶链反应（RT-PCR）、实时PCR和免疫组织化学方法。
雌激素诱导的致癌作用伴随着仅在K14-E7小鼠的宫颈和阴道鳞状上皮内增殖细胞的发生率和分布增加。与非转基因小鼠相比，K14-E7转基因小鼠中TGF-β2 mRNA和蛋白水平升高，在非转基因和转基因小鼠中激素处理后进一步升高。相反，与非转基因小鼠相比，K14-E7转基因小鼠中TGF-βRII mRNA和蛋白水平降低，在转基因小鼠中激素处理后这些水平进一步降低。我们还观察到，无论雌激素处理如何，K14-E7小鼠中c-myc mRNA水平都很高，并且在雌激素处理的非转基因小鼠中升高。最后我们发现K14-E7小鼠中p15 mRNA水平没有升高。
这些结果表明，雌激素和E7在诱导宫颈癌中的协同作用可能部分反映了这两种因素调节TGF-β信号转导的能力。
