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

Aging
Zhi-Chao WangWan-Hai Xu

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.

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Citations

Jun 27, 2021·Pharmacology & Therapeutics·Maria Adamaki, Vassilios Zoumpourlis

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Datasets Mentioned

BETA
GDS2545
GSE66187

Methods Mentioned

BETA
co-IP
co-immunoprecipitation
xenografts
dissection
biopsy
Assay
transfection

Software Mentioned

miRmap
Target Scan
Targetscan

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