Dataset Information

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

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.

SUBMITTER: Wang ZC

PROVIDER: S-EPMC7425449 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Wang Zhi-Chao ZC Li Yan Y Wang Ke-Liang KL Wang Lu L You Bo-Sen BS Zhao Dan-Feng DF Liu Zhong-Qing ZQ Fang Rui-Zhe RZ Wang Jia-Qi JQ Zhang Wei W Zhang Jin-Ming JM Xu Wan-Hai WH

Aging 20200721 14

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-me ...[more]

PMID: 32694237

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Project description:BackgroundThe investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.MethodsThe current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.ResultsWe demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3'-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.ConclusionsOur study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

Project description:BackgroundMen with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.MethodsIn this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).ResultsA total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.ConclusionsAmong men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).

Dataset Information

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

Publications

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

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