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Identification of Let-7–Regulated Oncofetal Genes

¹ The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois; ² Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; ³ Molecular Evolution Group, Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark; ⁴ Center for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark; and ⁵ The Toyota Technological Institute at Chicago, Chicago, Illinois

Requests for reprints: Marcus E. Peter, The Ben May Department for Cancer Research, The University of Chicago, 924 East 57th Street, R112, Chicago, IL 60637. Phone: 773-702-4728; Fax: 773-702-3701; E-mail: mpeter{at}uchicago.edu.

Key Words: cancer progression • IMP-1 • miRNA

MicroRNAs (miRNA) are small RNA molecules of 20 to 22 nucleotides that reduce expression of proteins through mRNA degradation and/or translational silencing. Each known miRNA has a large number of predicted targets. Members of the let-7/miR-98 family of miRNAs are up-regulated at the end of embryonic development. Let-7 is often down-regulated early during cancer development, suggesting that let-7–regulated oncofetal genes (LOG) may become reexpressed in cancer cells. Using comparative bioinformatics, we have identified 12 conserved LOGs that include HMGA2 and IMP-1/CRD-BP. IMP-1 has growth-promoting activities through stabilization of c-myc mRNA. We experimentally confirmed that IMP-1 is a direct let-7 target that promotes cell growth and motility of tumor cells, and we confirmed by proteomics analysis that IMP-1 and HMGA2 are major miRNA targets. Our data suggest that a substantial part of the growth inhibitory activities of let-7 comes from suppressing the expression of IMP-1. LOGs could be novel therapeutic targets and potential biomarkers for cancer treatment. [Cancer Res 2008;68(8):2587–91]