IGF2BP3-mediated microRNA diversity control impacts on the malignancy in early-stage lung adenocarcinoma

The nature of microRNA dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Oncofetal IGF2BP3-mediated miRNA biogenesis is demonstrated to be a key network controlling cancer-specific gene expression profiles by regulating the production of 3'-isoforms of the miR-21-5p and Let-7 family. The D-score, reflecting a miR-21-5p.C expression dominance, clearly discriminates early-stage lung adenocarcinoma cases with high risk of recurrence by grasping molecular features of cell cycle progression, EMT pressure and immune-evasion. IGF2BP3 is demonstrated controlling the production of miR-21-5p.C by formation of the nuclear Drosha complex to select the cleavage site. IGF2BP3 knockdown also induced a selective up-regulation of Let-7 3'-isoforms, leading to increasing cellular Let-7 seed occupancy, resulting in broad repression of Let-7 target genes encoding cell cycle regulators. These results will provide conceptualization that functional abnormalities of miRNAs are dysregulation of isoform organization, fine-tuning the function of cancer-associated miRNAs, rather than their expression levels.