Conditional inactivation of p53 in mouse ovarian surface epithelium does not alter MIS driven Smad2-dominant negative epithelium-lined inclusion cysts or teratomas.
Conditional inactivation of p53 in mouse ovarian surface epithelium does not alter MIS driven Smad2-dominant negative epithelium-lined inclusion cysts or teratomas.
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DOI：
10.1371/journal.pone.0065067
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Burdette JE
中科院分区：
文献类型：
--
作者：
Quartuccio SM;Lantvit DD;Bosland MC;Burdette JE
上皮性卵巢癌是美国女性中最致命的妇科恶性肿瘤。这种疾病的病因虽然鲜为人知，但可能涉及卵巢表面上皮或输卵管伞状上皮作为祖细胞。在化疗耐药的浆液性卵巢肿瘤中，常可发现转化生长因子-β(转化生长因子-β)途径和P53基因的中断。转化生长因子β信号通路下游转录因子Smad2(Smad2Dn)是一种以生殖道组织为靶点的转基因小鼠，表达Smad2的显性阴性形式。这些小鼠出现了上皮样包涵体囊，这是卵巢癌的一种潜在前驱病变，在形态上类似于输卵管上皮，但其蛋白表达更接近于卵巢表面上皮。据预测，另一种p53缺失的基因“命中”会导致卵巢肿瘤。通过将表达Cre重组酶的重组腺病毒(AdCreGFP)注射到P53 FLOX/FLOX小鼠体内，尝试在卵巢和输卵管中单独组织特异性缺失P53。囊内注射6个月后，部分小鼠可见卵巢囊性囊肿。输卵管内注射组小鼠未见病理改变，这可能与腺病毒感染输卵管上皮细胞比卵巢表面上皮细胞的感染性降低有关。同时表达Smad2DN转基因和P53 FLOX/FLOX的双转基因小鼠，然后在法氏囊和输卵管腔内暴露于AdCreGFP。这些小鼠没有发展出任何额外的表型。暴露于AdCreGFP并不是有条件地删除输卵管上皮中的FLOX基因的有效方法，组织特异性启动子应该在未来的小鼠疾病模型中使用。此外，通过qPCR分析证实，在Smad2DN转基因高表达的小鼠中发现了一种新的表型，其特征是畸胎瘤样病变涉及Smad信号在畸胎瘤的发展中。
Epithelial ovarian cancer is the most lethal gynecological malignancy among US women. The etiology of this disease, although poorly understood, may involve the ovarian surface epithelium or the epithelium of the fallopian tube fimbriae as the progenitor cell. Disruptions in the transforming growth factor beta (TGFβ) pathway and p53 are frequently found in chemotherapy-resistant serous ovarian tumors. Transgenic mice expressing a dominant negative form of Smad2 (Smad2DN), a downstream transcription factor of the TGFβ signaling pathway, targeted to tissues of the reproductive tract were created on a FVB background. These mice developed epithelium-lined inclusion cysts, a potential precursor lesion to ovarian cancer, which morphologically resembled oviductal epithelium but exhibited protein expression more closely resembling the ovarian surface epithelium. An additional genetic “hit” of p53 deletion was predicted to result in ovarian tumors. Tissue specific deletion of p53 in the ovaries and oviducts alone was attempted through intrabursal or intraoviductal injection of Cre-recombinase expressing adenovirus (AdCreGFP) into p53 flox/flox mice. Ovarian bursal cysts were detected in some mice 6 months after intrabursal injection. No pathological abnormalities were detected in mice with intraoviductal injections, which may be related to decreased infectivity of the oviductal epithelium with adenovirus as compared to the ovarian surface epithelium. Bitransgenic mice, expressing both the Smad2DN transgene and p53 flox/flox, were then exposed to AdCreGFP in the bursa and oviductal lumen. These mice did not develop any additional phenotypes. Exposure to AdCreGFP is not an effective methodology for conditional deletion of floxed genes in oviductal epithelium and tissue specific promoters should be employed in future mouse models of the disease. In addition, a novel phenotype was observed in mice with high expression of the Smad2DN transgene as validated through qPCR analysis, characterized by teratoma-like lesions implicating Smad signaling in teratoma development.
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