Srinivas R. Viswanathan 1 , John T. Powers 1 , William Einhorn 1 , Yujin Hoshida 2 , 5 , Tony Ng 15 , Sara Toffanin 8 , 9 , Maureen O'Sullivan 16 , Jun Lu 2 , 3 , 5 , Letha A. Philips 13 , Victoria L. Lockhart 12 , Samar P. Shah 1 , Pradeep S. Tanwar 7 , Craig H. Mermel 5 , Rameen Beroukhim 5 , Mohammad Azam 1 , Jose Teixeira 7 , Matthew Meyerson , Timothy P. Hughes 14 , Josep M Llovet 8 , 10 , 11 , Jerald Radich 12 , Charles G. Mullighan 13 , Todd R. Golub 2 , 5 , Poul H. Sorensen 15 , George Q. Daley 1 , 2 , 3 , 4 , *
31 May 2009
Multiple members of the let-7 family of miRNAs are often repressed in human cancers 1, 2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3, 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 miRNAs 5– 8, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression 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/LIN28B with poor clinical prognosis.