Attenuated miR-203b-3p is critical for ovarian cancer progression and aptamer/miR-203b-3p chimera can be explored as a therapeutic

Abstract

MicroRNAs (miRNAs) are actively involved in the progression and metastasis of ovarian cancer. Here we show that miR-203b–3p is one of the miRNAs whose expression is diminished in advanced ovarian cancer (Stage III/IV). Introducing miR-203b-3p into ovarian cancer cells suppressed cell migration, in vitro invasion and peritoneal metastatic colonization. With the aid of cytokine array and modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH), we identified C-X-C motif chemokine ligand 1 (CXCL1) mRNA as a target of miR-203b-3p. Recombinant CXCL1 largely restored cell migration/invasion and CXCL1 neutralizing antibody blocked cell migration/invasion. Intriguingly, miR-203b-3p targets CXCL1 in an unconventional manner: 1) miR-203b-3p targets the 5′-untranslated region (UTR) and protein coding region of CXCL1 mRNA and 2) seed sequences in miR-203b-3p are not the conventional nucleotides 2 to 8 observed for most of miRNA/target complementation. Finally, we show that epithelial cell adhesion molecule (EpCAM) aptamer can effectively deliver miR-203b-3p into ovarian cancer cells and EpCAM aptamer-delivered miR-203b-3p impeded peritoneal metastatic colonization and prolonged lifespan of tumor-bearing mice. In summary, our findings provide a novel mechanism in which attenuated miR-203b-3p expression sustains CXCL1 abundance and hence ovarian cancer progression. Importantly, we suggest that EpCAM aptamer-delivered miR-203b-3p may be exploited for therapeutic purpose against advanced ovarian cancer.