title: MicroRNA-203 represses selection and expansion of oncogenic Hras transformed tumor initiating cells.
abstract: In many mouse models of skin cancer, only a few tumors typically form even though many cells competent for tumorigenesis receive the same oncogenic stimuli. These observations suggest an active selection process for tumor-initiating cells. Here, we use quantitative mRNA- and miR-Seq to determine the impact of Hras(G12V) on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by Hras(G12V). Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 using an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for Hras-initiated tumorigenesis. These targets include critical regulators of the Ras pathway and essential genes required for cell division. This study establishes a role for the loss of microRNA-203 in promoting selection and expansion of Hras mutated cells and identifies a mechanism through which microRNA-203 antagonizes Hras-mediated tumorigenesis.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States.
authors.forename: Kent
authors.initials: K
authors.lastname: Riemondy
authors.affiliation: Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Denver, United States.
authors.forename: Xiao-jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Denver, United States.
authors.forename: Enrique C
authors.initials: EC
authors.lastname: Torchia
authors.affiliation: Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Denver, United States.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Yi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015603:Keratinocytes / Q000502:physiology*; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012878:Skin Neoplasms / Q000473:pathology
chemical_list: C575934:MIRN203 microRNA, mouse; D035683:MicroRNAs; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Hras; developmental biology; human biology; medicine; microRNA; mouse; skin cancer; stem cells; tumor suppressor