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Lin28 promotes transformation and is associated with advanced human malignancies

Nature Genetics volume 41, pages 843–848 (2009)Cite this article

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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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Figure 1: Lin28 transforms NIH/3T3 cells.
Figure 2: LIN28B knockdown impairs growth and triggers differentiation of K562 cells.
Figure 3: LIN28B is associated with poor outcome in hepatocellular carcinoma.

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  • 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).

Author information

Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Children's Hospital Boston, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts, USA

    Srinivas R Viswanathan, John T Powers, William Einhorn, Samar P Shah, Mohammad Azam & George Q Daley

  2. Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts, USA

    Yujin Hoshida, Jun Lu, Todd R Golub & George Q Daley

  3. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Yujin Hoshida, Jun Lu, Craig H Mermel, Rameen Beroukhim, Matthew Meyerson & Todd R Golub

  4. Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Yujin Hoshida, Jun Lu, Craig H Mermel, Rameen Beroukhim, Matthew Meyerson & Todd R Golub

  5. Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

    Tony L Ng & Poul H Sorensen

  6. Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada

    Tony L Ng & Poul H Sorensen

  7. Division of Liver Diseases, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, New York, USA

    Sara Toffanin & Josep M Llovet

  8. Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, IRCSS Foundation, Milan, Italy

    Sara Toffanin

  9. Department of Pathology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland

    Maureen O'Sullivan

  10. Department of Pathology, Trinity College Dublin, Dublin, Ireland

    Maureen O'Sullivan

  11. Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA

    Letha A Phillips & Charles G Mullighan

  12. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Victoria L Lockhart & Jerald Radich

  13. Massachusetts General Hospital, Vincent Center for Reproductive Biology, Boston, Massachusetts, USA

    Pradeep S Tanwar & Jose Teixeira

  14. Division of Haematology, The Institute for Medical and Veterinary Science, Adelaide, South Australia, Australia

    Timothy P Hughes

  15. HCC Translational Research Lab, Barcelona Clinic Liver Cancer group (BCLC), Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clinic Barcelona, Catalonia, Spain

    Josep M Llovet

  16. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain

    Josep M Llovet

  17. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    Todd R Golub & George Q Daley

  18. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    George Q Daley

  19. Manton Center for Orphan Disease Research, Boston, Massachusetts, USA

    George Q Daley

Authors
  1. Srinivas R Viswanathan
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  2. John T Powers
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Contributions

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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Correspondence to George Q Daley.

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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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