MicroRNA - 203 represses selection and expansion of oncogenic 1 Hras transformed tumor initiating cells

23 In many mouse models of skin cancer, only a few tumors typically form even though many cells 24 competent for tumorigenesis receive the same oncogenic stimuli. These observations suggest an 25 active selection process for tumor-initiating cells. Here we use quantitative mRNA-and miR-Seq 26 to determine the impact of Hras G12V on the transcriptome of keratinocytes. We discover that 27 microRNA-203 is downregulated by Hras G12V. Using a knockout mouse model, we demonstrate 28 that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. 29 Conversely, restoration of microRNA-203 using an inducible model potently inhibits 30 proliferation of these cells. We comprehensively identify microRNA-203 targets required for 31 Hras-initiated tumorigenesis. These targets include critical regulators of the Ras pathway and 32 essential genes required for cell division. This study establishes a role for the loss of microRNA-33 203 in promoting selection and expansion of Hras mutated cells and identifies a mechanism 34 through which microRNA-203 antagonizes Hras-mediated tumorigenesis.