High Frequency Loss of 17q11.2 and Downregulation of the Cancer Metastasis Suppression microRNA miR-193a-3p in...

Background/Objectives: Although 90% of prostate cancer (PCa) metastasis occurs in the bone, there are limited studies and rarely available genome-wide profiles at individual sample level for genomic copy number changes in the literature. Methods: We performed Affymetrix SNP 6.0 high-density microarray analysis to generate the genome-wide copy number change profiles for six cases of PCa bone metastases. A common genomic loss was confirmed by fluorescence in situ hybridization (FISH) in paraffin-embedded PCa bone metastasis samples together with primary PCa and benign prostate hyperplasia samples. We overexpressed the candidate miRNA in PCa cell lines and knocked down its target genes by siRNA transfection and investigated the effect on protein expression and cell viability, migration, and invasion abilities, respectively. Protein expression in PCa tissues was analyzed by immunohistochemical staining. Results: We provided high-resolution PCa bone metastasis profiles of six cases and identified potential bone metastasis-specific common genomic alterations, including a 1.6 mb region on 17q11.2, as well as those shared by non-bone metastatic PCa. The common 17q11.2 loss was confirmed by FISH in further 14/21 PCa bone metastasis samples but was only found in 9/151 primary PCa samples. The well-established tumor-suppressing miRNA located within this small genomic region, miR-193a-3p, was downregulated in both bone metastasis and primary PCa cases, leading to overexpression of cyclin D1 and uPA to promote cancer cell migration and invasion. Cyclin D1 was highly expressed in both localized PCa and bone metastasis samples, and the expression was significantly higher in the latter group (p = 0.013). Conclusions: We generated high-resolution copy number change profiles for bone metastasis samples. This led to the identification of a common, small genomic loss and downregulation of miR-193a-3p, which suppresses PCa bone metastasis through inhibition of its target proteins, providing new insight into bone metastasis development.