Regulation of coagulation factor XI expression by microRNAs in the human liver.
High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR-23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK) demonstrated a direct interaction between miR-181a-5p and 3'untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI.
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Salam
S
Salloum-Asfar
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Raúl
R
Teruel-Montoya
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Ana B
AB
Arroyo
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Nuria
N
García-Barberá
Department of Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Amarjit
A
Chaudhry
Department of Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Erin
E
Schuetz
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Ginés
G
Luengo-Gil
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Vicente
V
Vicente
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Rocío
R
González-Conejero
Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.
Constantino
C
Martínez
D001483:Base Sequence; D005172:Factor XI / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D005172:Factor XI