IMP3 RNP Safe Houses Prevent miRNA-Directed HMGA2mRNA Decay in Cancer and Development

The IMP3 RNA-binding protein is associated with metastasis and poor outcome in human cancer. Using solid cancer transcriptome data, we found that IMP3correlates with HMGA2mRNA expression. Cytoplasmic IMP3 granules contain HMGA2, and IMP3 dose-dependently increases HMGA2mRNA. HMGA2is regulated by let-7, and let-7antagomiRs make HMGA2refractory to IMP3. Removal of let-7target sites eliminates IMP3-dependent stabilization, and IMP3-containing bodies are depleted of Ago1-4 and miRNAs. The relationship between Hmga2mRNA and IMPs also exists in the developing limb bud, where IMP1-deficient embryos show dose-dependent Hmga2mRNA downregulation. Finally, IMP3 ribonucleoproteins (RNPs) contain other let-7target mRNAs, including LIN28B, and a global gene set enrichment analysis demonstrates that miRNA-regulated transcripts in general are upregulated following IMP3 induction. We conclude that IMP3 RNPs may function as cytoplasmic safe houses and prevent miRNA-directed mRNA decay of oncogenes during tumor progression.