The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions
Journal of Cell Science
The importance of non-coding RNA transcripts in regulating microRNA (miRNA) functions, especially the 39-untranslated region (39 UTR), has been revealed in recent years. Genes encoding the extracellular matrix normally produce large mRNA transcripts including the 39 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 39 UTR results in enhanced cell
... ility, invasion and cell adhesion in human breast carcinoma cell line MDA-MB-231. Furthermore, we found that expression of the CD44 39 UTR enhances metastasis in vivo. We hypothesize that increased expression of the CD44 39 UTR affects miRNA binding and modulates synthesis of the extracellular matrix. Computational analysis indicated that miRNAs that interact with the CD44 39 UTR also have binding sites in other matrix-encoding mRNA 39 UTRs, including collagen type 1a1 (Col1a1) 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, Col1a1 and FN1 were synergistically upregulated in vitro and in vivo upon transfection of the CD44 39 UTR. The non-coding 39 UTR of CD44 interacts with multiple miRNAs that target extracellular matrix properties and thus can be used to antagonize miRNA activities.