Medical Research Council, Toxicology Unit, Leicester University, Leicester, United Kingdom.
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15312-7. doi: 10.1073/pnas.1110977109. Epub 2012 Sep 4.
p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 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, ΔNp63 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.
p63 抑制转移。在这里，我们表明 p63（TAp63 和 ΔNp63 同工型）调节前列腺癌（PCa）细胞中 miR-205 的表达，并且 miR-205 对于 p63 对上皮-间充质转化（EMT）标志物的抑制作用至关重要，如 ZEB1 和波形蛋白。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 的表达，并且在表达内源性突变 p53 的细胞系中，细胞迁移可以通过 pre-miR-205 或突变 p53 的沉默来消除。与这些体外数据一致，在小鼠尾静脉模型中，ΔNp63 或 miR-205 显著抑制体内肺转移的发生率。同样，在一组 218 个人类前列腺癌样本中，转移或定植淋巴结中缺失了 p63/miR-205 轴的一个或两个组成部分。在 281 名患者的独立临床数据集得到了证实。该轴的缺失与更高的 Gleason 评分、转移和浸润事件的可能性增加以及预后更差相关。这些数据表明，p63/miR-205 可能是前列腺癌转移行为的有用临床预测因子。
