Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer
Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer
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DOI：
10.1073/pnas.1110977109
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发表时间：
2012-09-18
影响因子：
11.1
通讯作者：
Melino, Gerry
中科院分区：
文献类型：
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作者：
Tucci, Paola;Agostini, Massimiliano;Melino, Gerry
p63抑制转移。在这里，我们发现p63（TAp 63和Delta Np 63亚型）调节前列腺癌（PCa）细胞中miR-205的表达，而miR-205对于p63对上皮-间质转化（EMT）标志物（如ZEB 1和波形蛋白）的抑制作用至关重要。相应地，p63对EMT标志物和细胞迁移的抑制作用被抗miR-205逆转。p53突变体抑制p63和miR-205两者的表达，并且在表达内源性突变的p53的细胞系中，细胞迁移可以通过前-miR-205或突变的p53的沉默来消除。根据该体外数据，Delta Np 63或miR-205在小鼠尾静脉模型中显著抑制体内肺转移的发生率。类似地，在一组218个人前列腺癌样品中，p63/miR-205轴的一个或两个组分在转移或定殖淋巴结中不存在。这在281例患者的独立临床数据集中得到证实。该轴的丢失与较高的Gleason评分、转移和浸润事件的可能性增加以及预后较差相关。这些数据表明，p63/miR-205可能是前列腺癌转移行为的一个有用的临床预测因子。
p63 inhibits metastasis. Here, we show that p63 (both TAp63 and Delta Np63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, Delta Np63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer.