Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells
Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells
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DOI：
10.1007/s00441-014-2001-y
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发表时间：
2014-12-01
影响因子：
3.6
通讯作者：
Peng, Xinsheng
中科院分区：
文献类型：
--
作者：
Ren, Dong;Wang, Min;Peng, Xinsheng
肿瘤的侵袭和转移是由上皮细胞向间质细胞转化（EMT）触发的，EMT由microRNA（miRNAs）调节。EMT还促进恶性肿瘤的进展和干细胞特性的维持，这赋予癌细胞自我更新和永生化增殖的能力。转录抑制因子ZEB 2作为EMT激活因子，可能是某些肿瘤转移的重要促进因子。在这里，我们报告ZEB 2直接抑制miR-145的转录，这是EMT的强阻遏物。反过来，ZEB 2也是miR-145的直接靶点。此外，我们的研究结果表明，ZEB 2的下调不仅抑制前列腺癌（PCa）细胞的侵袭，迁移，EMT和干细胞，而且还抑制PC-3细胞在体内侵入骨的能力。重要的是，通过免疫组织化学分析揭示的ZEB 2表达水平与PCa患者的骨转移、血清游离PSA水平、总PSA水平和Gleason评分正相关，并且与原发性PCa标本中的miR-145表达负相关。因此，我们的研究结果证明了ZEB 2和miR-145之间的双负反馈环，并表明ZEB 2/miR-145双负反馈环在PCa细胞骨转移过程中控制EMT和干细胞特性中起着重要作用。这些结果表明，ZEB 2和miR-145之间的双负反馈回路有助于PCa的进展和转移，并且可能对PCa的骨转移具有治疗相关性。
The invasion and metastasis of tumors are triggered by an epithelial to mesenchymal transition (EMT), which is regulated by microRNAs (miRNAs). EMT also promotes malignant tumor progression and the maintenance of the stem cell property, which endows cancer cells with the capabilities of self-renewal and immortalized proliferation. The transcriptional repressor zinc-finger E-box binding homeobox 2 (ZEB2), as an EMT activator, might be an important promoter of metastasis in some tumors. Here, we report that ZEB2 directly represses the transcription of miR-145, which is a strong repressor of EMT. In turn, ZEB2 is also a direct target of miR-145. Further, our findings show that the downregulation of ZEB2 not only represses invasion, migration, EMT, and the stemness of prostate cancer (PCa) cells, but also suppresses the capability of PC-3 cells to invade bone in vivo. Importantly, the expression level of ZEB2 as revealed by immunohistochemical analysis is positively correlated to bone metastasis, the serum free PSA level, the total PSA level, and the Gleason score in PCa patients and is negatively correlated with miR-145 expression in primary PCa specimens. Thus, our findings demonstrate a double-negative feedback loop between ZEB2 and miR-145 and indicate that the ZEB2/miR-145 double-negative feedback loop plays a significant role in the control of EMT and stem cell properties during the bone metastasis of PCa cells. These results suggest that the double-negative feedback loop between ZEB2 and miR-145 contributes to PCa progression and metastasis and might have therapeutic relevance for the bone metastasis of PCa.