IGF2BP3 Modulates the Interaction of Invasion-Associated Transcripts with RISC

• IGF2BP3 promotes an invasive phenotype in pancreatic ductal adenocarcinoma cells
• IGF2BP3 regulates a malignancy-associated gene expression program in PDAC cells
• IGF2BP3 binding sites in PDAC cell lines are enriched near microRNA target sites
• IGF2BP3 modulates mRNA target association with Ago2

SummaryInsulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression correlates with malignancy, but its role(s) in pathogenesis remains enigmatic. We interrogated the IGF2BP3-RNA interaction network in pancreatic ductal adenocarcinoma (PDAC) cells. Using a combination of genome-wide approaches, we have identified 164 direct mRNA targets of IGF2BP3. These transcripts encode proteins enriched for functions such as cell migration, proliferation, and adhesion. Loss of IGF2BP3 reduced PDAC cell invasiveness and remodeled focal adhesion junctions. Individual nucleotide resolution crosslinking immunoprecipitation (iCLIP) revealed significant overlap of IGF2BP3 and microRNA (miRNA) binding sites. IGF2BP3 promotes association of the RNA-induced silencing complex (RISC) with specific transcripts. Our results show that IGF2BP3 influences a malignancy-associated RNA regulon by modulating miRNA-mRNA interactions.

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