Wild-type p53 suppresses the epithelial-mesenchymal transition and sternness in PC-3 prostate cancer cells by modulating miR-145
Wild-type p53 suppresses the epithelial-mesenchymal transition and sternness in PC-3 prostate cancer cells by modulating miR-145
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野生型 p53 通过调节 miR-145 抑制 PC-3 前列腺癌细胞的上皮间质转化和干性
DOI：
10.3892/ijo.2013.1825
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发表时间：
2013-04-01
影响因子：
5.2
通讯作者：
Peng, Xinsheng
中科院分区：
文献类型：
--
作者：
Ren, Dong;Wang, Min;Peng, Xinsheng
前列腺癌（PCa）的主要问题是其向骨转移的倾向，其机制需要进一步阐明。抑癌基因p53在调节上皮-间质转化（EMT）和癌细胞的干细胞性方面起重要作用，这已被认为在癌症转移中起关键作用。miR-145是p53的直接靶点，抑制PCa的骨转移，并参与调节EMT和癌细胞干性。然而，野生型p53（WT-p53）是否在调节PCa细胞的侵袭、EMT和癌细胞干细胞性中起作用以及miR-145是否介导WT-p53的功能尚不清楚。在本研究中，我们发现WT-p53的异位表达抑制了PCa骨转移来源的p53缺失的PC-3细胞的迁移和侵袭，并增强了粘附。此外，WT-p53抑制PC-3细胞中间充质标志物纤连蛋白、波形蛋白、N-cadherin、ZEB 2的表达，并上调上皮标志物E-cadherin的表达。此外，WT-p53还抑制PC-3细胞中的集落形成、肿瘤球形成以及CSC标志物和干细胞因子（包括CD 44、Oct 4、c-Myc和Klf 4）的表达。重要的是，WT-p53上调miR-145的表达，并且WT-p53对PC-3细胞的迁移、侵袭、EMT和干性的抑制作用被anti-miR-145逆转。总之，我们的研究结果表明，WT-p53抑制PC-3细胞中的迁移，侵袭，EMT和干性至少部分通过调节miR-145。这些结果表明，WT-p53的缺失可能至少部分地通过抑制miR-145来促进PCa的骨转移，从而提高癌细胞的EMT和干性。
The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone and the mechanism(s) need to be further elucidated. The tumor suppressor p53 plays an important role in regulating the epithelial-mesenchymal transition (EMT) and cancer cell stemness, which have been proposed to play critical roles in cancer metastasis. MiR-145, a direct target of p53, represses bone metastasis of PCa and is involved in regulating EMT and cancer cell sternness. However, it is unknown whether wild-type p53 (WT-p53) plays a role in regulating invasion, EMT and cancer cell stemness of PCa cells and whether miR-145 mediates the function of WT-p53. In the present study, we found that ectopic expression of WT-p53 inhibited the migration and invasion, and enhanced the adhesion of p53-null PC-3 cells derived from PCa bone metastasis. Furthermore, WT-p53 suppressed the expression of the mesenchymal markers fibronectin, vimentin, N-cadherin, ZEB2 and upregulated the expression of the epithelial marker E-cadherin in PC-3 cells. Moreover, WT-p53 also suppressed colony formation, tumor sphere formation and expression of CSC markers and sternness factors including CD44, Oct4, c-Myc and Klf4 in PC-3 cells. Importantly, WT-p53 upregulated the expression of miR-145, and the inhibitory effects of WT-p53 on migration, invasion, EMT and stemness of PC-3 cells were reversed by anti-miR-145. Together, our findings demonstrate that WT-p53 suppresses migration, invasion, EMT and sternness in PC-3 cells at least partially through modulating miR-145. These results suggest that loss of WT-p53 may promote the bone metastasis of PCa at least partially through repressing miR-145 to elevate EMT and stemness of cancer cells.