IMP3 RNP safe houses prevent miRNA-directed HMGA2 mRNA 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 IMP3 correlates with HMGA2 mRNA expression. Cytoplasmic IMP3 granules contain HMGA2, and IMP3 dose-dependently increases HMGA2 mRNA. HMGA2 is regulated by let-7, and let-7 antagomiRs make HMGA2 refractory to IMP3. Removal of let-7 target sites eliminates IMP3-dependent stabilization, and IMP3-containing bodies are depleted of Ago1-4 and miRNAs. The relationship between Hmga2 mRNA and IMPs also exists in the developing limb bud, where IMP1-deficient embryos show dose-dependent Hmga2 mRNA downregulation. Finally, IMP3 ribonucleoproteins (RNPs) contain other let-7 target 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.
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Lars
L
Jønson
Center for Computational and Applied Transcriptomics, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
Jan
J
Christiansen
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Thomas V O
TVO
Hansen
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Jonas
J
Vikeså
Department of Molecular Pathology and Tumor Pathology, Akita University, 1-1-1 Hondo, Japan.
Yohei
Y
Yamamoto
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark. Electronic address: fcn@rh.dk.
Finn C
FC
Nielsen
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D025743:HMGA2 Protein; C498780:IGF2BP3 protein, human; C516326:LIN28B protein, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human