Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/-) transgenic mice.
Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/-) transgenic mice.
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DOI：
10.1186/1471-2407-12-532
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发表时间：
2012-11-20
期刊：
影响因子：
3.8
通讯作者：
Kakar SS
中科院分区：
文献类型：
--
作者：
Fong MY;Farghaly H;Kakar SS
垂体肿瘤转化基因（PTTG）是一种在多种肿瘤中过度表达并表现出转化基因特征的癌基因。先前利用垂体和卵巢致瘤潜力的转基因小鼠模型导致了发育不良，但没有形成可见的肿瘤，这可能是由于 PTTG 表达不足所致。 PTTG 表达水平对于异种移植模型中卵巢肿瘤的发生至关重要。因此，PTTG在体内的致瘤功能仍不清楚。我们培育了一只在 CMV 启动子驱动下过表达 PTTG 的转基因小鼠，以确定 PTTG 是否作为能够启动肿瘤发生的转化癌基因发挥作用。通过将 PTTG 转基因显微注射到 FVB 0.5 天龄胚胎的雄性原核中来产生转基因动物。使用免疫组织化学分析来分析转基因动物组织中PTTG的表达水平。进行H&E染色和免疫组织染色来检查转基因和PTTG转基因/p53+/-动物中的肿瘤类型。监测 PTTG 转基因后代 (TgPTTG) 在不同年龄的肿瘤发展情况。进行 H&E 分析以确定是否存在癌症和增生状况，并通过增殖标记物 PCNA 和微血管标记物 CD31 进行验证。进行免疫组织化学以确定转基因表达，揭示了输卵管上皮的定位，在肝、肺、肾和脾中的表达更广泛。八个月大时，15 名 TgPTTG 中的 2 名患上卵巢癌，15 名中的 2 名患上良性肿瘤，15 名中的 2 名患上宫颈发育不良，15 名中的 3 名患上子宫腺肌病。十个月大时，十分之二的 TgPTTG 发展为卵巢腺癌，十分之一的人发展为乳头状浆液性腺癌，十分之二的人出现卵巢上皮细胞异型性。肿瘤发生是一个多步骤过程，通常需要多种癌基因和/或抑癌基因失活。因此，为了了解 p53 对 PTTG 诱导的肿瘤发生的贡献，我们将 TgPTTG 与 p53+/- 小鼠杂交并维持 8 至 10 个月。 TgPTTG/p53+/- 动物比单独的 p53+/- 动物更快地形成肉瘤，并且在 17 名雌性动物中，除了原位宫颈癌之外，还有 10 名动物出现不同的肿瘤类型。我们的结论是，虽然 PTTG 是一种功能性转化癌基因，但它需要额外的伙伴才能通过 p53 缺失或功能或调节来有效促进肿瘤发生。
Pituitary tumor-transforming gene (PTTG) is an oncogene that is overexpressed in variety of tumors and exhibits characteristics of a transforming gene. Previous transgenic mouse models to access the tumorigenic potential in the pituitary and ovary have resulted in dysplasia without formation of visible tumors, possibly due to the insufficient expression of PTTG. PTTG expression level is critical for ovarian tumorigenesis in a xenograft model. Therefore, the tumorigenic function of PTTG in vivo remains unclear. We generated a transgenic mouse that overexpresses PTTG driven by the CMV promoter to determine whether PTTG functions as a transforming oncogene that is capable of initiating tumorigenesis. Transgenic animals were generated by microinjection of PTTG transgene into the male pronucleus of FVB 0.5 day old embryos. Expression levels of PTTG in tissues of transgenic animals were analyzed using an immunohistochemical analysis. H&E staining and immunohistostaining were performed to examine the type of tumor in transgenic and PTTG transgenic/p53+/- animals. PTTG transgenic offspring (TgPTTG) were monitored for tumor development at various ages. H&E analysis was performed to identify the presence of cancer and hyperplastic conditions verified with the proliferation marker PCNA and the microvessel marker CD31. Immunohistochemistry was performed to determine transgene expression, revealing localization to the epithelium of the fallopian tube, with more generalized expression in the liver, lung, kidney, and spleen. At eight months of age, 2 out of 15 TgPTTG developed ovarian cancer, 2 out of 15 developed benign tumors, 2 out of 15 developed cervical dysplasia, and 3 out of 15 developed adenomyosis of the uterus. At ten months of age, 2 out of 10 TgPTTG developed adenocarcinoma of the ovary, 1 out of 10 developed a papillary serous adenocarcinoma, and 2 out of 10 presented with atypia of ovarian epithelial cells. Tumorigenesis is a multi-step process, often requiring multiple oncogenes and/or inactivation of tumor suppressor genes. Therefore, to understand the contribution of p53 to PTTG induced tumorigenesis, we crossbred TgPTTG to p53+/− mice and maintained those 8 to 10 months. TgPTTG/p53+/− animals developed sarcomas faster than p53+/− alone as well as different tumor types in addition to cervical carcinomas in situ in 10 out of 17 females. We conclude that while PTTG is a functional transforming oncogene, it requires an additional partner to effectively promote tumorigenesis through the loss of p53 include or between function or modulation.
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