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• W3198104265 abstract "Abstract Background: Prostate cancer (PCa) is currently the most commonly diagnosed type of cancer. The incidence and mortality of PCa worldwide correlate with increasing age and bad dietary habits. Previously, we investigated the mRNA/miRNA role on PCa development and progression using high fat diet (HFD) chronically fed mice models. Here our main goal was to investigate the effect of HFD on the expression of prostate cancer-related miRNAs and their relevance in PCa patients. Methods: Using microarray data from mice prostate tumors generated by TRAMP-C1 cell inoculation, we focused on the role of three candidate miRNAs (miR-133a-3p/133b/1-3p) and their target genes. Based on data from public databases, we examined the expression levels of hsa-miR-133a-3p/133b/1-3p and their correlation with clinicopathological features in PCa patients. The biological roles of hsa-miR-133a-3p/133b/1-3p and their relevant target genes were investigated by bioinformatics approaches. The promoter methylation of hsa-miR-133a-3p/133b/1-3p host genes and their correlation with mature miRNA expression was further evaluated. Results: We identified 6 up- and 18 down-regulated miRNAs in TRAMP-C1 mice prostate tumors under HFD conditions using miRNA microarrays. Target genes (1,278) of down-regulated miRNAs involved in cancer-related biological processes were identified using DIANA-TarBase and STRING databases. Three down-regulated miRNAs: hsa-miR-133a-3p, 133b and 1a-3p showed nine common target genes that negatively correlated with miRNA expression in prostate tumors from patients. Hsa-miR-133a-3p/133b/1-3p expression levels were significantly decreased in PCa compared to normal tissues and their low expression correlated with bad clinicopathological features in patients. We also examined the promoter region of hsa-miR-133a-3p/133b/1-3p encoding genes in PCa patients and then compared methylation at these loci with mature miRNA expression. This analysis revealed that hsa-miR-1-2/miR-133a-1 cluster promoter hypermethylation decreased hsa-miR-133a-3p/1-3p expression in prostate tumors. Furthermore, CENPF and WHSC1 , two common hsa-miR-133a-3p/133b/1-3p target genes, were found significantly up-regulated in PCa and positively correlated with advanced clinicopathological characteristics in PCa patients. Conclusion: Our results provide an explanation for the aggressiveness of PCa and link it mechanistically to the attenuation of hsa-miR-133a-3p/133b/1-3p expression by promoter hypermethylation. Hsa-miR-133a-3p/133b/1-3p downregulation may enhance PCa aggressiveness in part by targeting CENPF and WHSC1 . Therefore, hsa-miR-133a-3p/133b/1-3p might be potential therapeutic targets for lethal PCa." @default.
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• W3198104265 date "2021-08-31" @default.
• W3198104265 modified "2023-10-16" @default.
• W3198104265 title "Hsa-miR-1-2/miR-133a-1 Cluster Expression Silencing by DNA Hypermethylation Triggers Oncogenes Contributing to Prostate Cancer Aggressiveness" @default.
• W3198104265 doi "https://doi.org/10.21203/rs.3.rs-800913/v1" @default.
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