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miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance

Oncogene volume 36, pages 6336–6347 (2017)Cite this article

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Abstract

Clinical intervention for patients with advanced prostate cancer (PCa) remains challenging due to the inevitable recurrence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Cancer stem cells (CSCs) with serial tumor-propagating capacity are considered to be the driving force for PCa progression and recurrence. In this study, we report that the miR-302/367 cluster, a previously identified potent pluripotency regulator, is upregulated in prostate tumors. Specifically, the forced expression of the miR-302/367 cluster accelerates the in vitro and in vivo growth of PCa cells and their resistance to androgen ablation, whereas the knockdown of the miR-302/367 cluster using anti-sense RNA suppresses the incidence of formation, growth rate and endpoint weight of PCa cell tumors. Mechanistically, we find that LATS2, a key component of the tumor-suppressive Hippo signaling pathway, acts as a direct target of the miR-302/367 cluster in PCa cells. The downregulation of LATS2 by the miR-302/367 cluster reduces the phosphorylation and enhances the nuclear translocation of the YAP oncoprotein. Conversely, the restoration of LATS2 expression abrogates the tumor-promoting effects of forced miR-302/367 cluster expression. Collectively, the potent pluripotency regulator-triggered miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes castration resistance. Thus, targeting this signaling axis may represent a promising therapeutic strategy for CRPC.

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Acknowledgements

The study is supported by grants from the Chinese Ministry of Science and Technology (2017YFA0102900), the National Natural Science Foundation of China (81372189 and 81630073), the Science and Technology Commission of Shanghai Municipality (16JC1405700), the KC Wong foundation, and the Shanghai Eastern Hospital Stem Cell Research Base Fund to Wei-Qiang Gao, and Helen He Zhu received support from the State Key Laboratory of Oncogenes and Related Genes (90-16-03), Shanghai Rising-Star Program (17QA1402100), Shanghai Institutions of Higher Learning (The Program for Professor of Special Appointment (Young Eastern Scholar) QD2015002), School of Medicine at Shanghai Jiao Tong University (Excellent Youth Scholar Initiation Grant 16XJ11003) and Ren Ji Hospital (Seed Project RJZZ14-010).

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  1. Y Guo and J Cui: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Ren ji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Y Guo, J Cui, C Zhang, M Chu, Y-X Fang, W-Q Gao & H H Zhu

  2. School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China

    Z Ji, C Cheng, K Zhang & W-Q Gao

  3. Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

    Q Zhao, Z Yu & Y Zhang

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Guo, Y., Cui, J., Ji, Z. et al. miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance. Oncogene 36, 6336–6347 (2017). https://doi.org/10.1038/onc.2017.240

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