The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions.

The importance of non-coding RNA transcripts in regulating microRNA (miRNA) functions, especially the 3'-untranslated region (3' UTR), has been revealed in recent years. Genes encoding the extracellular matrix normally produce large mRNA transcripts including the 3' UTR. How these large transcripts affect miRNA functions and how miRNAs modulate extracellular matrix protein expression are largely unknown. Here, we demonstrate that the overexpression of the CD44 3' UTR results in enhanced cell motility, invasion and cell adhesion in human breast carcinoma cell line MDA-MB-231. Furthermore, we found that expression of the CD44 3' UTR enhances metastasis in vivo. We hypothesize that increased expression of the CD44 3' UTR affects miRNA binding and modulates synthesis of the extracellular matrix. Computational analysis indicated that miRNAs that interact with the CD44 3' UTR also have binding sites in other matrix-encoding mRNA 3' UTRs, including collagen type 1α1 (Col1α1) repressed by miR-328 and fibronectin type 1 (FN1) repressed by miR-512-3p, miR-491 and miR-671. Protein analysis demonstrated that expression of CD44, Col1α1 and FN1 were synergistically upregulated in vitro and in vivo upon transfection of the CD44 3' UTR. The non-coding 3' UTR of CD44 interacts with multiple miRNAs that target extracellular matrix properties and thus can be used to antagonize miRNA activities.