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

“高风险”人乳头瘤病毒（hpv），如HPV-16和18，在80-90%的宫颈浸润性癌症中发现。然而，hpv感染似乎不足以致癌，因为人类宫颈鳞状上皮中含有高危hpv的大多数病变不会进展为浸润性癌。此外，一些研究人员报道，HPV或E6/E7转基因小鼠发生宫颈上皮内瘤变，但未发生浸润性癌症。这些证据表明，除了HPV感染外，其他的改变可能对宫颈癌的发生也很重要。近年来，我们建立了许多使用特异性角蛋白启动子的转基因小鼠，这些小鼠发生了包括皮肤、前列腺和胆囊在内的各种上皮肿瘤。在我们最近的研究中，子宫颈鳞状上皮表达K1、K5和K14，鳞状-柱状交界处的储备细胞表达K5。这些结果提示，利用特异性角蛋白启动子的转基因小鼠子宫颈中靶基因s可能过表达。在这项研究中，我们分析了来自不同小鼠的雌性生殖道，最终我们发现BK5。Src ^<wt>转基因小鼠发生子宫颈癌。c-Src以及角蛋白5在BK5的子宫颈鳞状上皮和癌组织中过表达。Src ^<wt>转基因小鼠。BK5大量出现宫颈上皮增生。Src ^<wt>转基因小鼠（18/ 20,90 %）。BK5中宫颈上皮内瘤变（CINs）的发生率为30%（6/20）。Src ^<wt>转基因小鼠。未见浸润性癌。这些结果提示，c-src在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.