PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression programs and have a critical role in both normal biology and disease. We previously identified microRNA-194 (miR-194) as an important driver of prostate cancer metastasis, although the molecular mechanisms by which it mediates these effects are not well understood. This study aimed to identify target genes and pathways that are responsible for miR-194s pro-metastatic activity. By integrating transcriptomics with a cutting-edge molecular technique that delineates miRNA:mRNA interaction sites, HITS-CLIP (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation), we characterised the complete set of miR-194 target genes (its targetome) in prostate cancer cells. MiR-194 targets approximately 160 genes in prostate cancer - predominantly through canonical binding to 3UTR regions - many of which are involved in key metastatic pathways. Interestingly, miR-194 activity was inversely correlated with androgen receptor (AR) activity in clinical metastatic cohorts, an observation explained mechanistically by AR-mediated repression of miR-194 expression. In concordance with these findings, miR-194 activity is significantly elevated in neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC), both of which are aggressive AR-independent subtypes. Interestingly, miR-194 enhanced trans-differentiation of epithelial LNCaP cells to neuroendocrine-like cells, a function mediated at least in part by miR-194 targeting of FoxA1, a critical regulator of AR signalling. Importantly, targeting miR-194 in aggressive models of NEPC effectively inhibited cell growth. Overall, our study provides new insights into miR-194 function in prostate cancer progression, cancer cell plasticity and the emergence of aggressive AR-independent disease subtypes.
17 Mar 2019 - 20 Mar 2019