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 Radich; Charles G. Mullighan; Todd R. Golub; Poul H. Sorensen; George Q. Daley

doi:10.1038/ng.392

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 Radich

Charles G. Mullighan, Todd R. Golub, Poul H. Sorensen, George Q. Daley

Blood Cancer Program

Research output: Contribution to journal › Article › peer-review

756 Citations (Scopus)

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 language	English
Pages (from-to)	843-848
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	7
DOIs	https://doi.org/10.1038/ng.392
Publication status	Published or Issued - Jul 2009

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

@article{239f3f4ff66d4dc7ba1ca8d2acb4f9ba,

title = "Lin28 promotes transformation and is associated with advanced human malignancies",

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.",

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

note = "Funding Information: We thank C. Kim (Children{\textquoteright}s Hospital Boston) for providing LKR cells and the MGH Gyn Tissue Repository for ovarian tissue samples. Thanks to D. Fink and N. Melnyk for technical assistance. This work was partially supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (J.M.L.; 1R01DK076986-01), the Samuel Waxman Cancer Research Foundation (J.M.L.), the Spanish National Health Institute (J.M.L.; SAF-2007-61898). This work was supported by funds from the Canadian Cancer Society (P.H.S.). This work was supported by grants from the NIH, the NIH Director{\textquoteright}s Pioneer Award of the NIH Roadmap for Medical Research, Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society (G.Q.D.), and the Howard Hughes Medical Institute (G.Q.D.). J.T.P. was supported by a Hematology Training Grant from the National Institutes of Health (NIH T32-HL 66987).",

year = "2009",

month = jul,

doi = "10.1038/ng.392",

language = "English",

volume = "41",

pages = "843--848",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "7",

}

Viswanathan, SR, Powers, JT, Einhorn, W, Hoshida, Y, Ng, TL, Toffanin, S, O'Sullivan, M, Lu, J, Phillips, LA, Lockhart, VL, Shah, SP, Tanwar, PS, Mermel, CH, Beroukhim, R, Azam, M, Teixeira, J, Meyerson, M, Hughes, TP, Llovet, JM, Radich, J, Mullighan, CG, Golub, TR, Sorensen, PH & Daley, GQ 2009, 'Lin28 promotes transformation and is associated with advanced human malignancies', Nature Genetics, vol. 41, no. 7, pp. 843-848. https://doi.org/10.1038/ng.392

TY - JOUR

T1 - Lin28 promotes transformation and is associated with advanced human malignancies

AU - Viswanathan, Srinivas R.

AU - Powers, John T.

AU - Einhorn, William

AU - Hoshida, Yujin

AU - Ng, Tony L.

AU - Toffanin, Sara

AU - O'Sullivan, Maureen

AU - Lu, Jun

AU - Phillips, Letha A.

AU - Lockhart, Victoria L.

AU - Shah, Samar P.

AU - Tanwar, Pradeep S.

AU - Mermel, Craig H.

AU - Beroukhim, Rameen

AU - Azam, Mohammad

AU - Teixeira, Jose

AU - Meyerson, Matthew

AU - Hughes, Timothy P.

AU - Llovet, Josep M.

AU - Radich, Jerald

AU - Mullighan, Charles G.

AU - Golub, Todd R.

AU - Sorensen, Poul H.

AU - Daley, George Q.

N1 - Funding Information: We thank C. Kim (Children’s Hospital Boston) for providing LKR cells and the MGH Gyn Tissue Repository for ovarian tissue samples. Thanks to D. Fink and N. Melnyk for technical assistance. This work was partially supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (J.M.L.; 1R01DK076986-01), the Samuel Waxman Cancer Research Foundation (J.M.L.), the Spanish National Health Institute (J.M.L.; SAF-2007-61898). This work was supported by funds from the Canadian Cancer Society (P.H.S.). This work was supported by grants from the NIH, the NIH Director’s Pioneer Award of the NIH Roadmap for Medical Research, Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society (G.Q.D.), and the Howard Hughes Medical Institute (G.Q.D.). J.T.P. was supported by a Hematology Training Grant from the National Institutes of Health (NIH T32-HL 66987).

PY - 2009/7

Y1 - 2009/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/67649881121

U2 - 10.1038/ng.392

DO - 10.1038/ng.392

M3 - Article

C2 - 19483683

AN - SCOPUS:67649881121

SN - 1061-4036

VL - 41

SP - 843

EP - 848

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Lin28 promotes transformation and is associated with advanced human malignancies

Abstract

ASJC Scopus subject areas

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