|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Viswanathan, SR, Powers, JT, Einhorn, W, Hoshida, Y, Ng, TL, Toffanin, S, O'Sullivan, M, Lu, J, Phillips, LA, Lockhart, VL, Shah, SP, Tanwar, PS, Mermel, CH, Beroukhim, R, Azam, M, Teixeira, J, Meyerson, M, Hughes, TP, Llovet, JM, Radich, J, Mullighan, CG, Golub, TR, Sorensen, PH, Daley, GQ|
Multiple members of the let-7 family of miRNAs are often repressed in human cancers, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc. 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, 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 approximately 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.