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

Zhichao Wang | Zendy; Yan Li | Zendy; Keliang Wang | Zendy; Lu Wang | Zendy; Bosen You | Zendy; Danfeng Zhao | Zendy; Zhongqing Liu | Zendy; Ruizhe Fang | Zendy; Jiaqi Wang | Zendy; Wei Zhang | Zendy; Jinming Zhang | Zendy; Wanhai Xu | Zendy

Open Access

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

Author(s) -

Zhichao Wang,

Yan Li,

Keliang Wang,

Lu Wang,

Bosen You,

Danfeng Zhao,

Zhongqing Liu,

Ruizhe Fang,

Jiaqi Wang,

Wei Zhang,

Jinming Zhang,

Wanhai Xu

Publication year - 2020

Publication title -

aging

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.473

H-Index - 90

ISSN - 1945-4589

DOI - 10.18632/aging.103485

Subject(s) - enzalutamide , prostate cancer , cancer research , gene knockdown , androgen receptor , metastasis , mapk/erk pathway , biology , medicine , cancer , cell culture , signal transduction , microbiology and biotechnology , genetics

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.

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