Lin28 promotes transformation and is associated with advanced human malignancies

Nat Genet. 2009 Jul;41(7):843-8. doi: 10.1038/ng.392. Epub 2009 May 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Liver Neoplasms / genetics
  • Mice
  • MicroRNAs / genetics
  • Neoplasms / genetics*
  • RNA-Binding Proteins / genetics*

Substances

  • DNA-Binding Proteins
  • LIN-28 protein, human
  • LIN28B protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • mirnlet7 microRNA, human

Associated data

  • GEO/GSE11024
  • GEO/GSE4170
  • GEO/GSE6222
  • GEO/GSE9843
  • GEO/GSE9891