Induction of promyelocytic leukemia zinc finger protein by miR-200c-3p restores sensitivity to anti-androgen therapy in androgen-refractory prostate cancer and inhibits the cancer progression via down-regulation of integrin α3β4

Abstract

Purpose 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. Methods 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. Results 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. Conclusion 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.

Megakaryocyte-Derived IL-8 Acts as a Paracrine Factor for Prostate Cancer Aggressiveness through CXCR2 Activation and Antagonistic AR Downregulation

“…The present study demonstrates that IL-8 is the most highly expressed cytokine in ARPC cells, confirming our previous transcriptome analysis of hormone-responsive and hormone-refractory PC cells ( Dahal et al ., 2022 ). Previously, it was reported that IL-8 is a tumor-intrinsic factor that contributes to PC progression as well as resistance to ADT and immune checkpoint inhibitors ( Lopez-Bujanda et al ., 2021 ).…”