Lin28 promotes transformation and is associated with advanced human malignancies.
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.
Viswanathan
Srinivas R
SR
Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA.
Powers
John T
JT
Einhorn
William
W
Hoshida
Yujin
Y
Ng
Tony L
TL
Toffanin
Sara
S
O'Sullivan
Maureen
M
Lu
Jun
J
Phillips
Letha A
LA
Lockhart
Victoria L
VL
Shah
Samar P
SP
Tanwar
Pradeep S
PS
Mermel
Craig H
CH
Beroukhim
Rameen
R
Azam
Mohammad
M
Teixeira
Jose
J
Meyerson
Matthew
M
Hughes
Timothy P
TP
Llovet
Josep M
JM
Radich
Jerald
J
Mullighan
Charles G
CG
Golub
Todd R
TR
Sorensen
Poul H
PH
Daley
George Q
GQ
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human