MiR-296 regulation of a cell polarity-cell plasticity module controls tumor progression.

Abstract

The expression of small, non-coding RNA, or microRNAs (miR), is frequently deregulated in human cancer, but how these pathways affect disease progression is still largely elusive. Here, we report on a microRNA, miR-296, which is progressively lost during tumor progression, and correlates with metastatic disease in colorectal, breast, lung, gastric, parathyroid, liver and bile ducts cancers. Functionally, miR-296 controls a global cell motility gene signature in epithelial cells by transcriptionally repressing the cell polarity-cell plasticity module, Scrib. In turn, loss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration, and tumor cell invasiveness. Re-expression of miR-296 in MDA-MB231 cells inhibits tumor growth, in vivo. Finally, miR-296 or Scrib levels predict tumor relapse in hepatocellular carcinoma patients.These data identify miR-296 as a global repressor of tumorigenicity, and uncover a previously unexplored exploitation of Scrib in tumor progression in humans.