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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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Abstract

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.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, 510080, Guangzhou, Guangdong Province, People’s Republic of China

    Dong Ren, Min Wang, Wei Guo, Shuai Huang, Zeyu Wang & Xinsheng Peng

  2. State Key Laboratory of Oncology in Southern China/Department of Experimental Research, Sun Yat-sen University Cancer Center, 510060, Guangzhou, People’s Republic of China

    Xiaohui Zhao & Libing Song

  3. Department of Pathology, The First People’s Hospital of Guangzhou City, 510180, Guangzhou, Guangdong Province, People’s Republic of China

    Hong Du

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  1. Dong Ren
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  2. Min Wang
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  3. Wei Guo
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Correspondence to Xinsheng Peng.

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Dong Ren and Min Wang contributed equally to this work.

This work was supported by grants from the National Natural Science Foundation of China (no. 81272938) and the Science and Technology Planning Project of Guangzhou, China (no. 11C22060772).

No potential conflicts of interest are declared.

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Ren, D., Wang, M., Guo, W. et al. Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells. Cell Tissue Res 358, 763–778 (2014). https://doi.org/10.1007/s00441-014-2001-y

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