Analysis of mechanism of carcinogenesis in uterine cervix of c-src transgenic mice

“高危”人乳头瘤病毒（HPV），如HPV-16和-18，在80-90%的宫颈浸润性癌中发现。然而，HPV感染似乎是不足以致癌，因为大多数病变的人宫颈鳞状上皮细胞含有高风险的HPV不进展为浸润性癌。此外，一些研究人员报告说，HPV或E6/E7转基因小鼠发生宫颈上皮内瘤变，但不是浸润性癌症。提示除HPV感染外，其他改变在宫颈癌的发生中也可能起重要作用。近年来，我们利用特异性角蛋白启动子建立了许多转基因小鼠，这些小鼠发生了包括皮肤、前列腺和胆囊在内的各种上皮性肿瘤。在我们最近的研究中，宫颈鳞状上皮表达K1，K5和K14，鳞状-柱状交界处的储备细胞表达K5。这些结果表明，目的基因s可能在转基因小鼠的子宫颈中过表达，使用特定的角蛋白启动子。在本研究中，我们分析了我们的各种小鼠的雌性生殖道，最后我们发现，BK 5.src ^<wt>转基因小鼠发生了子宫颈癌。c-Src以及角蛋白5在来自BK5.src^转基因小鼠的子宫颈鳞状上皮和癌组织中过表达<wt>。在大量BK5.src^<wt>转基因小鼠（18/20，90%）中观察到子宫颈上皮增生。在BK5.src^转基因小鼠中，宫颈上皮内瘤变（CIN）的发生率为30%（6/20）<wt>。未观察到浸润性癌。这些结果表明，c-src在子宫颈上皮的组成性表达可能在该组织的肿瘤发生中起重要作用。

The "high-risk" human papilloma viruses (HPVs), such as HPV-16 and-18, are found in 80-90% of invasive cancers of the uterine cervix. However, HPV-infection appears to be insufficient for carcinogenesis, because most lesions in human cervical squamous epithelium containing high-risk HPVs do not progress to invasive carcinoma. Furthermore, several researchers reported that HPV or E6/E7 transgenic mice developed cervical intraepithelial neoplasias, but not invasive cancers. These evidences suggested that the other alterations in addition to HPV- infection might be also important for cervical carcinogenesis. Recently, we have established a lot of transgenic mice using specific keratin promoters, which developed various epithelial tumors including skin, prostate and gallbladder. In our more recent studies, the squamous epithelium of uterine cervix expressed K1, K5 and K14, and the reserve cells at the squamo-columnar junction had K5 expression. These result suggested that target gene s might be overexpressed in uterine cervix of transgenic mice using specific keratin promoters.In this study, we analyzed female genital tract from our various mice, and finally we found that BK5.src^<wt> transgenic mice developed cancer of the uterine cervix. c-Src, as well as keratin 5, was overexpressed in the squamous epithelium of uterine cervix and cancer tissues from BK5.src^<wt> transgenic mice. Hyperplasia of uterine cervical epithelium was observed in a significant number of BK5.src^<wt> transgenic mice (18/20, 90%). The incidence of cervical intraepithelial neoplasias (CINs) was 30% (6/20) in BK5.src^<wt> transgenic mice. Invasive carcinoma was not observed. These findings suggest that constitutive expression of c-src in epithelium of uterine cervix may play an important role in tumorigenesis in this tissue.