Letter abstract
Nature Genetics 41, 843 - 848 (2009)
Published online: 31 May 2009 | Corrected online: 21 June 2009 | doi:10.1038/ng.392
Lin28 promotes transformation and is associated with advanced human malignancies
Srinivas R Viswanathan1, John T Powers1, William Einhorn1, Yujin Hoshida2,3, Tony L Ng4,5, Sara Toffanin6,7, Maureen O'Sullivan8,9, Jun Lu2,3, Letha A Phillips10, Victoria L Lockhart11, Samar P Shah1, Pradeep S Tanwar12, Craig H Mermel3, Rameen Beroukhim3, Mohammad Azam1, Jose Teixeira12, Matthew Meyerson3, Timothy P Hughes13, Josep M Llovet6,14,15, Jerald Radich11, Charles G Mullighan10, Todd R Golub2,3,16, Poul H Sorensen4,5 & George Q Daley1,2,16,17,18
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.
- Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts, USA.
- Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts, USA.
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA and Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
- Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
- Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA.
- Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, IRCSS Foundation, Milan, Italy.
- Department of Pathology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
- Department of Pathology, Trinity College Dublin, Dublin, Ireland.
- Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Massachusetts General Hospital, Vincent Center for Reproductive Biology, Boston, Massachusetts, USA.
- Division of Haematology, The Institute for Medical and Veterinary Science, Adelaide, South Australia, Australia.
- 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.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
- Howard Hughes Medical Institute, Boston, Massachusetts, USA.
- Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
- Manton Center for Orphan Disease Research, Boston, Massachusetts, USA.
Correspondence to: George Q Daley1,2,16,17,18 e-mail: george.daley@childrens.harvard.edu
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