Lin28 promotes transformation and is associated with advanced human malignancies

被引：683

作者：

Viswanathan, Srinivas R. ^{[1
]}

Powers, John T. ^{[1
]}

Einhorn, William ^{[1
]}

Hoshida, Yujin ^{[2
,3
,4
,5
,6
]}

Ng, Tony L. ^{[7
,8
]}

Toffanin, Sara ^{[9
,10
]}

O'Sullivan, Maureen ^{[11
,12
]}

Lu, Jun ^{[4
,5
,6
]}

Phillips, Letha A. ^{[13
]}

Lockhart, Victoria L. ^{[14
]}

Shah, Samar P. ^{[1
]}

Tanwar, Pradeep S. ^{[15
]}

Mermel, Craig H. ^{[4
,5
,6
]}

Beroukhim, Rameen ^{[4
,5
,6
]}

Azam, Mohammad ^{[1
]}

Teixeira, Jose ^{[15
]}

Meyerson, Matthew ^{[4
,5
,6
]}

Hughes, Timothy P. ^{[16
]}

Llovet, Josep M. ^{[9
,17
,18
]}

Radich, Jerald ^{[14
]}

Mullighan, Charles G. ^{[13
]}

Golub, Todd R. ^{[2
,3
,4
,5
,6
,19
]}

Sorensen, Poul H. ^{[7
,8
]}

Daley, George Q. ^{[1
,2
,3
,19
,20
,21
]}

机构：

[1] Harvard Univ, Childrens Hosp, Dept Biol Chem & Mol Pharmacol, Med Sch,Harvard Stem Cell Inst, Boston, MA 02115 USA

[2] Childrens Hosp Boston, Div Pediat Hematol Oncol, Cambridge, MA USA

[3] Dana Farber Canc Inst, Cambridge, MA USA

[4] MIT & Harvard, Broad Inst, Canc Program, Cambridge, MA USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[7] Univ British Columbia, Dept Pathol, Vancouver, BC V5Z 1M9, Canada

[8] BC Canc Res Ctr, Dept Mol Oncol, Vancouver, BC, Canada

[9] Mt Sinai Sch Med, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY USA

[10] IRCSS Fdn, Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, Milan, Italy

[11] Our Ladys Childrens Hosp, Dept Pathol, Dublin, Ireland

[12] Trinity Coll Dublin, Dept Pathol, Dublin, Ireland

[13] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[14] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA

[15] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA

[16] Inst Med & Vet Sci, Div Haematol, Adelaide, SA 5000, Australia

[17] Hosp Clin Barcelona, HCC Translat Res Lab, Barcelona Clin Liver Canc Grp,CIBERehd, Liver Unit,Inst Invest Biomed August Pi & Sunyer, Catalonia, Spain

[18] Inst Catalana Recerca & Estudis Avancats, Catalonia, Spain

[19] Howard Hughes Med Inst, Boston, MA 02115 USA

[20] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[21] Manton Ctr Orphan Dis Res, Boston, MA USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 07期

关键词：

MICRORNA EXPRESSION; GENE-EXPRESSION; LUNG-CANCER; LET-7; TUMOR; LIN-28; REGION; MYC; DIFFERENTIATION; T(5/6)(Q21; Q21);

D O I：

10.1038/ng.392

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：843 / U109

页数：7

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