Abstract
Multiple members of the let-7 family of miRNAs are often repressed in human cancers1,2, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc3,4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature miRNAs5,6,7,8, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.
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Change history
21 June 2009
NOTE: In the version of this article initially published online, there was an error in the Acknowledgments. The fourth sentence should read as follows: “This work was supported by funds from the Canadian Cancer Society (P.H.S.).” The error has been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
We thank C. Kim (Children's Hospital Boston) for providing LKR cells and the MGH Gyn Tissue Repository for ovarian tissue samples. Thanks to D. Fink and N. Melnyk for technical assistance. This work was partially supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (J.M.L.; 1R01DK076986-01), the Samuel Waxman Cancer Research Foundation (J.M.L.), the Spanish National Health Institute (J.M.L.; SAF-2007-61898). This work was supported by funds from the Canadian Cancer Society (P.H.S.). This work was supported by grants from the NIH, the NIH Director's Pioneer Award of the NIH Roadmap for Medical Research, Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society (G.Q.D.), and the Howard Hughes Medical Institute (G.Q.D.). J.T.P. was supported by a Hematology Training Grant from the National Institutes of Health (NIH T32-HL 66987).
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S.R.V. and G.Q.D. conceived experiments and wrote the manuscript. S.R.V., J.T.P., W.E., Y.H., T.N., S.T., M.O., J.L., L.A.P., V.L.L., S.P.S., P.S.T., C.H.M., R.B., M.A., J.T., M.M., T.P.H., J.M.L., J.R., C.G.M., T.R.G. and P.H.S. executed experiments, contributed reagents, analyzed array data and edited the manuscript.
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Viswanathan, S., Powers, J., Einhorn, W. et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41, 843–848 (2009). https://doi.org/10.1038/ng.392
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DOI: https://doi.org/10.1038/ng.392
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