雄激素难治性前列腺癌（ARPC）是一种具有转移能力和对雄激素剥夺治疗（ADT）具有抵抗力的侵略性人类癌症之一。本研究调查了ARPC进展和ADT抵抗的基因以及它们的调节机制。进行转录组分析、共免疫沉淀、共聚焦显微镜和FACS分析以确定不同表达基因、整合素α3β4异二聚体和癌干细胞（CSC）种群。用miRNA阵列、3'-UTR报告基因测试、ChIP测试、qPCR和免疫印迹来确定不同表达的microRNA、它们与整合素转录本的结合以及基因表达。采用异种移植肿瘤模型来评估肿瘤生长和转移。表现出ZBTB16和AR显著下调的转移性ARPC细胞系（PC-3和DU145）显示显著上调ITGA3和ITGB4。沉默其中一个整合素α3β4异二聚体可显著抑制ARPC生存和CSC群体。miRNA阵列和3'-UTR报告试验揭示miR-200c-3p是ARPCs最强烈下调的miRNA，直接结合到ITGA3和ITGB4的3'-UTR上以抑制基因表达。同时，miR-200c-3p还增加了PLZF的表达，从而抑制整合素α3β4的表达。miR-200c-3p模拟剂和AR抑制剂恩扎鲁胺的联合治疗在体外对ARPC细胞存活和在体内对ARPC异种移植肿瘤的生长和转移显示出协同抑制效应，而联合作用优于仅使用模拟剂。本研究表明，miR-200c-3p治疗ARPC是一种有前途的治疗方法，可以恢复对抗雄激素治疗的敏感性并抑制肿瘤生长和转移。©2023. Springer Nature Switzerland AG。

Androgen-refractory prostate cancer (ARPC) is one of the aggressive human cancers with metastatic capacity and resistance to androgen deprivation therapy (ADT). The present study investigated the genes responsible for ARPC progression and ADT resistance, and their regulatory mechanisms.Transcriptome analysis, co-immunoprecipitation, confocal microscopy, and FACS analysis were performed to determine differentially-expressed genes, integrin α3β4 heterodimer, and cancer stem cell (CSC) population. miRNA array, 3'-UTR reporter assay, ChIP assay, qPCR, and immunoblotting were used to determine differentially-expressed microRNAs, their binding to integrin transcripts, and gene expressions. A xenograft tumor model was used to assess tumor growth and metastasis.Metastatic ARPC cell lines (PC-3 and DU145) exhibiting significant downregulation of ZBTB16 and AR showed significantly upregulated ITGA3 and ITGB4. Silencing either one of the integrin α3β4 heterodimer significantly suppressed ARPC survival and CSC population. miRNA array and 3'-UTR reporter assay revealed that miR-200c-3p, the most strongly downregulated miRNA in ARPCs, directly bound to 3'-UTR of ITGA3 and ITGB4 to inhibit the gene expression. Concurrently, miR-200c-3p also increased PLZF expression, which, in turn, inhibited integrin α3β4 expression. Combination treatment with miR-200c-3p mimic and AR inhibitor enzalutamide showed synergistic inhibitory effects on ARPC cell survival in vitro and tumour growth and metastasis of ARPC xenografts in vivo, and the combination effect was greater than the mimic alone.This study demonstrated that miR-200c-3p treatment of ARPC is a promising therapeutic approach to restore the sensitivity to anti-androgen therapy and inhibit tumor growth and metastasis.© 2023. Springer Nature Switzerland AG.