Identification of Putative Metastasis Suppressor MicroRNA in Human Breast Cancer

摘要

Metastases are responsible for >90% of human cancer deaths; yet, our knowledge regarding the molecular regulation of metastasis remains fragmentary. MicroRNAs are short RNAs that suppress their targets post-transcriptionally, leading to modulation of diverse biological processes. MicroRNAs are well suited to regulate metastasis due to their capacity to concomitantly inhibit numerous target genes. We have identified a microRNA, miR-31, whose levels correlated inversely with metastatic recurrence in human breast cancer patients. Expression of miR-31 in otherwise-aggressive breast tumor cells impeded metastasis. We deployed a novel microRNA sponge strategy to stably inhibit miR-31; this allowed otherwise-non-aggressive breast cancer cells to metastasize. These phenotypes were achieved via pleiotropic modulation of a cohort of clinically relevant metastasis-promoting genes, which were over represented among the >200 mRNAs predicted to be direct targets of miR-31. In fact, we discovered that miR-31-evoked concurrent regulation of three such effectors - integrin alpha5, radixin, and RhoA - was sufficient to explain this microRNA's impacts on metastasis. Together, these findings provide insights into metastasis that may prove useful in the diagnosis and/or treatment of breast cancer.