Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples

Abstract

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.

Differential Expression of miRNAs Contributes to Tumor Aggressiveness and Racial Disparity in African American Men with Prostate Cancer

“…Previous studies reported that downregulation of miR-135b was associated with the status of tumor and tumor metastasis [ 70 ]. These data suggested that low expression of miR-135b in the primary tumors may be a risk factor for bone metastatic [ 71 ].…”

Developing high-resolution metastasis signatures for improved cancer prognosis using single-cell RNA sequencing data：A case study in lung adenocarcinoma

“…YIPF2 affects migration and invasion of hepatocellular carcinoma cells through endoplasmic reticulum (ER)-Golgi transport processes [33]. VTI1B is a potential mediator for prostate cancer bone metastases and is associated with modification of malignant cells at primary tumor site prior to metastasis [34]. NPC2 inhibits the recruitment of immature macrophages to tumor microenvironment in the early stages of cancer, while knockdown of NPC2 promotes proliferation and migration of malignant cells [35,36].…”

Prostate cancer bone metastases biology and clinical management (Review)

“…Despite miR-205 expression levels being lower in the serum of individuals with PCa relative to healthy controls, it has been shown that miR-205 expression is significantly elevated in patients with bone metastases compared to PCa patients without bone metastases (164). Furthermore, a number of additional miRNAs have been identified as showing promising indications for the ability to distinguish patients with bone metastases, including miR-96, miR-135b, miR-15, miR-16, miR-21 and miR505-3p (169)(170)(171)(172)(173).…”