Short loop-targeting oligoribonucleotides antagonize Lin28 and enable pre-let-7 processing and suppression of cell growth in let-7-deficient cancer cells.
MicroRNAs (miRNAs) originate from stem-loop-containing precursors (pre-miRNAs, pri-miRNAs) and mature by means of the Drosha and Dicer endonucleases and their associated factors. The let-7 miRNAs have prominent roles in developmental differentiation and in regulating cell proliferation. In cancer, the tumor suppressor function of let-7 is abrogated by overexpression of Lin28, one of several RNA-binding proteins that regulate let-7 biogenesis by interacting with conserved motifs in let-7 precursors close to the Dicer cleavage site. Using in vitro assays, we have identified a binding site for short modified oligoribonucleotides ('looptomirs') overlapping that of Lin28 in pre-let-7a-2. These looptomirs selectively antagonize the docking of Lin28, but still permit processing of pre-let-7a-2 by Dicer. Looptomirs restored synthesis of mature let-7 and inhibited growth and clonogenic potential in Lin28 overexpressing hepatocarcinoma cells, thereby demonstrating a promising new means to rescue defective miRNA biogenesis in Lin28-dependent cancers.
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
Martina
M
Roos
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
Mario A E
MA
Rebhan
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
Matije
M
Lucic
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
David
D
Pavlicek
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
Ugo
U
Pradere
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
Harry
H
Towbin
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research, Via Vela 6, Bellinzona CH-6500, Switzerland.
Gianluca
G
Civenni
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research, Via Vela 6, Bellinzona CH-6500, Switzerland.
Carlo V
CV
Catapano
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland jonathan.hall@pharma.ethz.ch.
Jonathan
J
Hall
D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009843:Oligoribonucleotides / Q000737:chemistry / Q000378:metabolism*; D012322:RNA Precursors / Q000737:chemistry / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism
C516326:LIN28B protein, human; D035683:MicroRNAs; D009843:Oligoribonucleotides; D012322:RNA Precursors; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; D043244:Ribonuclease III