Lin28 promotes transformation and is associated with advanced human malignancies

Srinivas R. Viswanathan, John T. Powers, William Einhorn, Yujin Hoshida, Tony L. Ng, Sara Toffanin, Maureen O'Sullivan, Jun Lu, Letha A. Phillips, Victoria L. Lockhart, Samar P. Shah, Pradeep S. Tanwar, Craig H. Mermel, Rameen Beroukhim, Mohammad Azam, Jose Teixeira, Matthew Meyerson, Timothy P. Hughes, Josep M. Llovet, Jerald RadichCharles G. Mullighan, Todd R. Golub, Poul H. Sorensen, George Q. Daley

Research output: Contribution to journalArticle

575 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)843-848
Number of pages6
JournalNature genetics
Volume41
Issue number7
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Viswanathan, S. R., Powers, J. T., Einhorn, W., Hoshida, Y., Ng, T. L., Toffanin, S., O'Sullivan, M., Lu, J., Phillips, L. A., Lockhart, V. L., Shah, S. P., Tanwar, P. S., Mermel, C. H., Beroukhim, R., Azam, M., Teixeira, J., Meyerson, M., Hughes, T. P., Llovet, J. M., ... Daley, G. Q. (2009). Lin28 promotes transformation and is associated with advanced human malignancies. Nature genetics, 41(7), 843-848. https://doi.org/10.1038/ng.392