Mutation or loss of p53 differentially modifies TGFβ action in ovarian cancer.
Mutation or loss of p53 differentially modifies TGFβ action in ovarian cancer.
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DOI：
10.1371/journal.pone.0089553
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发表时间：
2014
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：
Ó hAinmhire E;Quartuccio SM;Cheng W;Ahmed RA;King SM;Burdette JE
卵巢癌是影响美国女性的最致命的妇科疾病。癌症基因组图谱网络在96%的高级别浆液性卵巢癌中发现了p53突变，证明了其关键作用。此外，转化生长因子β（TGFβ）通路在各种恶性肿瘤（包括卵巢癌）中功能失调。本研究调查了野生型、突变型或缺乏p53的表达如何改变卵巢癌细胞对TGFβ信号传导的反应，以及卵巢表面上皮和输卵管上皮对TGFβ的反应。只有表达野生型p53的卵巢癌细胞的生长受到TGFβ的抑制，而突变型或无效p53的卵巢癌细胞则不受抑制。TGFβ诱导p53缺失的SKOV 3细胞迁移，而在稳定表达突变型p53 R273 H的SKOV 3细胞中未观察到这种迁移。OVCA 420卵巢癌细胞中野生型p53的敲除增强了对TGFβ的响应的细胞迁移。在p53敲低和无效细胞中观察到DKK 1和TMEPAI（两种在晚期转移性卵巢癌中表达增强的促侵袭基因）的蛋白表达增加，而稳定表达突变型p53的细胞表现出较低的DKK 1和TMEPAI诱导。突变型p53的表达或p53的缺失允许卵巢癌细胞系在TGFβ存在下继续增殖;然而，表达突变型p53的细胞表现出迁移减少和DKK 1和TMEPAI蛋白水平降低。
Ovarian cancer is the most lethal gynecological disease affecting women in the US. The Cancer Genome Atlas Network identified p53 mutations in 96% of high-grade serous ovarian carcinomas, demonstrating its critical role. Additionally, the Transforming Growth Factor Beta (TGFβ) pathway is dysfunctional in various malignancies, including ovarian cancer. This study investigated how expression of wild-type, mutant, or the absence of p53 alters ovarian cancer cell response to TGFβ signaling, as well as the response of the ovarian surface epithelium and the fallopian tube epithelium to TGFβ. Only ovarian cancer cells expressing wild-type p53 were growth inhibited by TGFβ, while ovarian cancer cells that were mutant or null p53 were not. TGFβ induced migration in p53 null SKOV3 cells, which was not observed in SKOV3 cells with stable expression of mutant p53 R273H. Knockdown of wild-type p53 in the OVCA 420 ovarian cancer cells enhanced cell migration in response to TGFβ. Increased protein expression of DKK1 and TMEPAI, two pro-invasive genes with enhanced expression in late stage metastatic ovarian cancer, was observed in p53 knockdown and null cells, while cells stably expressing mutant p53 demonstrated lower DKK1 and TMEPAI induction. Expression of mutant p53 or loss of p53 permit continued proliferation of ovarian cancer cell lines in the presence of TGFβ; however, cells expressing mutant p53 exhibit reduced migration and decreased protein levels of DKK1 and TMEPAI.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1097/pas.0b013e3181cf3d79
发表时间：
2010-03
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Kurman RJ;Shih IeM
通讯作者：
Shih IeM
影响因子：
3.7
作者：
Clark-Knowles, Katherine V.;Garson, Kenneth;Vanderhyden, Barbara C.
通讯作者：
Vanderhyden, Barbara C.
影响因子：
4
作者：
Dong, Peixin;Tada, Mitsuhiro;Sakuragi, Noriaki
通讯作者：
Sakuragi, Noriaki
影响因子：
4.7
作者：
Helleman, Jozien;Smid, Marcel;Berns, Els M. J. J.
通讯作者：
Berns, Els M. J. J.