Journal
NATURE GENETICS
Volume 41, Issue 7, Pages 843-U109Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.392
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NHLBI NIH HHS [T32-HL 66987] Funding Source: Medline
- NICHD NIH HHS [R01 HD052701, R01 HD052701-02] Funding Source: Medline
- NIDDK NIH HHS [R01 DK076986, 1 R01 DK076986-01] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007753] Funding Source: Medline
- NIH HHS [DP1 OD000256-01, DP1 OD000256] Funding Source: Medline
- ICREA Funding Source: Custom
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Multiple members of the let-7 family of miRNAs are often repressed in human cancers(1,2), thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc(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 nmiRNAs(5-8), 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 B15%), 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.
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