Cadherin-6 type 2, K-cadherin (CDH6) is regulated by mutant p53 in the fallopian tube but is not expressed in the ovarian surface.
Cadherin-6 type 2, K-cadherin (CDH6) is regulated by mutant p53 in the fallopian tube but is not expressed in the ovarian surface.
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DOI：
10.18632/oncotarget.11499
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Burdette JE
中科院分区：
文献类型：
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作者：
Karthikeyan S;Lantvit DD;Chae DH;Burdette JE
高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤，可能发生在输卵管上皮（FTE）或卵巢表面上皮（OSE）。据报道，96%的HGSOC中存在p53突变，最常见于R273和R248。本研究的目的是鉴定FTE中被突变型p53改变的特异性基因靶点，而OSE中没有。基因分析显示，R273和R248突变体p53都降低了输卵管中CDH 6的表达，但在小鼠OSE细胞中未检测到CDH 6。p53 R273 H诱导SLUG和FOXM 1，而p53 R248 W不诱导SLUG，仅适度增加FOXM 1，这与与p53 R273 H相比更少的迁移相关。建立了输卵管特异性PAX 8 Cre/+/p53 R270 H/+小鼠模型，并证实了体内突变型p53抑制CDH 6，但不足以单独稳定p53表达。突变型p53在p53缺失的OVCAR 5细胞中的过表达降低了CDH 6水平，表明这是功能获得。用p53 R273 H敲低鼠输卵管细胞中的SLUG恢复了CDH 6抑制，ChIP分析显示突变型p53在CDH 6启动子上的直接结合。NSC 59984是一种降解突变型p53 R273 H的小分子，可挽救CDH 6的表达。总之，CDH 6在输卵管中表达，但在卵巢中不表达，并且被突变型p53抑制。进一步验证的CDH 6表达可能有助于建立告知高级别浆液性肿瘤起源细胞的标志物。
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy and may arise in either the fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). A mutation in p53 is reported in 96% of HGSOC, most frequently at R273 and R248. The goal of this study was to identify specific gene targets in the FTE that are altered by mutant p53, but not in the OSE. Gene analysis revealed that both R273 and R248 mutant p53 reduces CDH6 expression in the oviduct, but CDH6 was not detected in murine OSE cells. p53R273H induced SLUG and FOXM1 while p53R248W did not induce SLUG and only modestly increased FOXM1, which correlated with less migration as compared to p53R273H. An oviduct specific PAX8Cre/+/p53R270H/+ mouse model was created and confirmed that in vivo mutant p53 repressed CDH6 but was not sufficient to stabilize p53 expression alone. Overexpression of mutant p53 in the p53 null OVCAR5 cells decreased CDH6 levels indicating this was a gain-of-function. SLUG knockdown in murine oviductal cells with p53R273H restored CDH6 repression and a ChIP analysis revealed direct binding of mutant p53 on the CDH6 promoter. NSC59984, a small molecule that degrades mutant p53R273H, rescued CDH6 expression. In summary, CDH6 is expressed in the oviduct, but not the ovary, and is repressed by mutant p53. CDH6 expression with further validations may aide in establishing markers that inform upon the cell of origin of high grade serous tumors.