Nature Genetics, 2009 Jul;41(7):843-8. Published: 2009.05.30
Srinivas R Viswanathan, John T Powers, William Einhor, Yujin Hoshida, Tony L Ng, Sara Toffanin, Maureen O'Sullivan, Jun Lu, Letha A Phillips, Victoria L Lockhart, Samar P Shah, Pradeep S Tanwar, Craig H Mermel, Rameen Beroukhim, Mohammad Azam, Jose Teixeira, Matthew Meyerson, Timothy P Hughes, Josep M Llovet, Jerald Radich, Charles G Mullighan, Todd R Golub, Poul H Sorensen, George Q DaleyRead Manuscript
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 approx15%), 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.