Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family. Mus musculus

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression critical for organismal viability. Changesin miRNA activity are common in cancer, but how these changes relate to subsequent alterations in transcription andthe process of tumorigenesis is not well understood. Here, we report a deep transcriptional, oncogenic network reg-ulated by miRNAs. We present analysis of the gene expression and phenotypic changes associated with global miRNA restoration in miRNA-deficient fibroblasts. This analysis uncovers a miRNA-repressed network containing oncofetalgenes Imp1, Imp2, and Imp3 (Imp1–3) that is up-regulated primarily transcriptionally >100-fold upon Dicer loss and isresistant to resilencing by complete restoration of miRNA activity. This Dicer-resistant epigenetic switch confers tumorigenicity to these cells. Let-7 targets Imp1–3 are required for this tumorigenicity and feed back to reinforceand sustain expression of the oncogenic network. Together, these Dicer-resistant genes constitute an mRNA expression signature that is present in numerous human cancers and is associated with poor survival.