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

## TL;DR

This study identifies a genomic loss and reduced microRNA activity linked to prostate cancer spreading to bones, offering new insights into how this deadly process occurs.

## Contribution

The study reveals a bone metastasis-specific genomic loss and downregulation of miR-193a-3p in prostate cancer.

## Key findings

- Loss of the 17q11.2 region was found in 14/21 bone metastasis samples but only 9/151 primary tumors.
- Downregulation of miR-193a-3p in bone metastasis leads to overexpression of cyclin D1 and uPA, promoting cancer spread.
- Cyclin D1 expression was significantly higher in bone metastasis compared to localized prostate cancer (p = 0.013).

## Abstract

Metastasis is the main cause of death from prostate cancer (PCa), a common malignant disease. A total of 90% of PCa metastases occur in bone, and thus understanding the genetic changes underlying bone preference is critical. However, due to challenges in obtaining bone samples, limited bone metastasis-specific genomic alteration profiles, particularly at individual sample level, have been published. We generated individual genomic change profiles from six PCa bone metastasis samples and identified bone metastasis-specific genomic changes. One of them, loss of the 17q11.2 genomic region, was further confirmed by another method in further 14/21 PCa bone metastasis samples but only in 9/151 primary PCa. The function of a well-established tumor suppressor, miR-193a-3p, located in this lost genomic region, was reduced in bone metastasis, leading to overaction of two well-established genes to promote cancer metastasis. This paper provides new insight into bone metastasis development.

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.