Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis

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Abstract

Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database. We focused on high-mobility group box 3 (HMGB3) because it was the most downregulated by ectopic expression of miR-205-5p in PC3 cells and its expression was involved in PCa pathogenesis. Luciferase reporter assays showed that HMGB3 was directly regulated by miR-205-5p in PCa cells. Knockdown studies using si-HMGB3 showed that expression of HMGB3 enhanced PCa cell aggressiveness. Overexpression of HMGB3/HMGB3 was confirmed in naive PCa and castration-resistant PCa (CRPC) clinical specimens. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in PCa cells may provide new insights into the pathogenic mechanisms of the disease.

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Acknowledgements

This study was supported by JSPS KAKENHI (grant numbers; 16H05462, 17K16777, 16K20125, 17K11160, and 15K10801).

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Correspondence to Naohiko Seki.

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The authors declare no conflict of interest.

Electronic supplementary material

Flow chart illustrates the analytic strategy to identify miR-205-5p targets in PC3 cells

Evaluation of differences in expression of HMGB3 in T stage, N stage and Gleason Score (GS) using TCGA database

Kaplan-Meier survival curves showing disease-free survival rates for minichromosome maintenance complex component (MCM) family, genes that are downstream from HMGB3

Clinical features of patients with naive PCa and CRPC in expression analyses of miR-205-5p and HBGB3

Clinical features of patients with naive PCa and CRPC in expression of HMGB3 by immunohistochemistry

Upregulated genes by silencing HMGB3 in PCa cells

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