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miR-5089-5p 通过 miR-5089-5p/SPINK1/MAPK/MMP9 信号通路抑制去势抵抗性前列腺癌对恩扎卢胺的耐药性和转移。

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

机构信息

Heilongjiang Key Laboratory of Scientific Research in Urology, The Forth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.

Department of Anesthesia, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.

出版信息

Aging (Albany NY). 2020 Jul 21;12(14):14418-14433. doi: 10.18632/aging.103485.

DOI:10.18632/aging.103485
PMID:32694237
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7425449/
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.

摘要

丝氨酸蛋白酶抑制剂 Kazal 型 1（SPINK1）是否与恩扎鲁胺（Enz）耐药和去势抵抗性前列腺癌（CRPC）的转移有关尚不清楚。SPINK1 通过上调雄激素受体剪接变异体 7（ARv7）促进 Enz 耐药，并通过 ERK/p38/MMP9 信号增强 Enz 耐药细胞的侵袭/迁移。此外，miR-5089-5p 通过直接结合其 3'UTR 抑制 SPINK1 mRNA，并逆转其促增殖和促转移作用。与携带野生型肿瘤的小鼠相比，携带 SPINK1 敲低的 Enz 耐药 PCa 肿瘤的小鼠生存时间明显延长，而用 miR-5089-5p 抑制剂处理则消除了 SPINK1 敲低的保护作用。总之，SPINK1 可作为恩扎鲁胺耐药的生物标志物，miR-5089-5p/SPINK1/MAPK/MMP9 轴是针对恩扎鲁胺耐药和转移性 CRPC 的合适治疗靶点。

方法

通过下一代测序数据和转移性 PCa 患者检测恩扎鲁胺耐药前列腺癌（PCa）细胞系中 SPINK1 的表达。进行体内和体外实验以研究 SPINK1 在恩扎鲁胺耐药和转移中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e946/7425449/1b001260a917/aging-12-103485-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e946/7425449/1b001260a917/aging-12-103485-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e946/7425449/1b001260a917/aging-12-103485-g005.jpg

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