Research Paper|Volume 12, Issue 14|pp 14418—14433

miR-5089-5p suppresses castration-resistant prostate cancer resistance to enzalutamide and metastasis via miR-5089-5p/SPINK1/ MAPK/MMP9 signaling

Zhi-Chao Wang¹, Yan Li², Ke-Liang Wang¹, Lu Wang¹, Bo-Sen You¹, Dan-Feng Zhao¹, Zhong-Qing Liu¹, Rui-Zhe Fang¹, Jia-Qi Wang¹, Wei Zhang¹, Jin-Ming Zhang¹, Wan-Hai Xu¹

¹Heilongjiang Key Laboratory of Scientific Research in Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
²Department of Anesthesia, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China

* Equal contribution

Received: March 3, 2020Accepted: May 27, 2020Published: July 21, 2020

https://doi.org/10.18632/aging.103485

Copyright: © 2020 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Whether serine protease inhibitor Kazal type 1 (SPINK1) being associated with enzalutamide (Enz) resistance and metastasis of castration-resistant prostate cancer (CRPC) has not been clear. SPINK1 promoted Enz resistance by upregulating Androgen receptor splicing variant 7 (ARv7), and enhanced the invasion/migration of Enz-resistant cells via ERK/p38/ MMP9 signaling. Furthermore, miR-5089-5p suppressed SPINK1 mRNA through direct binding to its 3'UTR, and reversed its pro-proliferative and pro-metastatic effects. Mice bearing SPINK1-knockdown Enz-resistant PCa tumors showed significantly longer survival compared with those bearing wild-type tumors, while treatment with miR-5089-5p inhibitor abrogated the protective effects of SPINK1 knockdown. Taken together, SPINK1 can be used as a biomarker of resistance to Enz, and the miR-5089-5p/SPINK1/MAPK/MMP9 axis is a suitable therapeutic target against Enz-resistant and metastatic CRPC.

Methods: The expression of SPINK1 in Enz-resistant prostate cancer (PCa) cell lines was detected through next-generation sequencing data and metastatic PCa patients. In vivo and in vitro experiments were performed to investigate the role of SPINK1 in Enz-resistance and metastasis.