miR-93, miR-98, and miR-197 regulate expression of tumor suppressor gene FUS1.
FUS1 is a tumor suppressor gene located on human chromosome 3p21, and expression of Fus1 protein is highly regulated at various levels, leading to lost or greatly diminished tumor suppressor function in many lung cancers. Here we show that selected microRNAs (miRNA) interact with the 3'-untranslated region (3'UTR) of FUS1, leading to down-regulation of protein expression. Using computational methods, we first predicted that FUS1 is a target of three miRNAs, miR-93, miR-98, and miR-197, and then showed that exogenous overexpression of these miRNAs inhibited Fus1 protein expression. We then confirmed that the three miRNAs target the 3'UTR region of the FUS1 transcript and that individual deletion of the three miRNA target sites in the FUS1 3'UTR restores the expression level of Fus1 protein. We further found that miR-93 and miR-98 are expressed at higher levels in small-cell lung cancer cell lines (SCLC) than in non-small-cell lung cancer cell lines (NSCLC) and immortalized human bronchial epithelial cells (HBEC), and that miR-197 is expressed at higher levels in both SCLCs and NSCLCs than in HBECs. Finally, we found that elevated miR-93 and miR-197 expression is correlated with reduced Fus1 expression in NSCLC tumor specimens. These results suggest that the three miRNAs are negative regulators of Fus1 expression in lung cancers.
Du
Liqin
L
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8591, USA. Liqin.Du@UTSouthwestern.edu
Schageman
Jeoffrey J
JJ
Subauste
Maria C
MC
Saber
Barbara
B
Hammond
Scott M
SM
Prudkin
Ludmila
L
Wistuba
Ignacio I
II
Ji
Lin
L
Roth
Jack A
JA
Minna
John D
JD
Pertsemlidis
Alexander
A
D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D001980:Bronchi / Q000166:cytology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion; D055752:Small Cell Lung Carcinoma / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; C546085:MIRN197 microRNA, human; C543350:MIRN93 microRNA, human; C546084:MIRN98 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; C499993:TUSC2 protein, human; D025521:Tumor Suppressor Proteins