Lin28 promotes transformation and is associated with advanced human malignancies

Abstract

George Daley and colleagues show that Lin28 and Lin28B promote cellular transformation by repressing let-7 family members, leading to derepression of let-7 targets. They also find that LIN28 and LIN28B are overexpressed in ∼15% of primary human tumors and cancer cell lines and that their expression is associated with aggressive disease and poor prognosis across multiple tumor types. 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.