A Yin-Yang balancing act of the lin28/let-7 link in tumorigenesis

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. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.