title: Posttranscriptional control of the chemokine receptor CXCR4 expression in cancer cells.
abstract: CXCR4 is a chemokine receptor that is overexpressed in certain cancer types and involved in migration toward distant organs. The molecular mechanisms underlying CXCR4 expression in invasive cancer, particularly posttranscriptional regulation, are poorly understood. Here, we find that CXCR4 harbors AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR) that bind and respond to the RNA-binding proteins, tristetraprolin (TTP/ZFP36) and HuR (ELAVL1). Different experimental approaches, including RNA immunoprecipitation, 3'-UTR reporter, RNA shift and messenger RNA (mRNA) half-life studies confirmed functionality of the CXCR4 ARE. Wild-type TTP, but not the zinc finger mutant, C124R, was able to bind CXCR4 mRNA and ARE. In the invasive breast cancer phenotype, aberrant expression of CXCR4 is linked to both TTP deficiency and HuR overexpression. HuR silencing led to decreased CXCR4 mRNA stability and expression, and significant reduction in migration of the cells toward the CXCR4 ligand, CXCL12. Derepression of TTP using miR-29a inhibitor led to significant reduction in CXCR4 mRNA stability, expression and migration capability of the cells. The study shows that CXCR4 is regulated by ARE-dependent posttranscriptional mechanisms that involve TTP and HuR, and that aberration in this pathway helps cancer cells migrate toward the CXCR4 ligand. Targeting posttranscriptional control of CXCR4 expression may constitute an alternative approach in cancer therapy.
authors.affiliation: Molecular BioMedicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Norah
authors.initials: N
authors.lastname: Al-Souhibani
authors.affiliation: Molecular BioMedicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Al-Ghamdi
authors.affiliation: Molecular BioMedicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Wijdan
authors.initials: W
authors.lastname: Al-Ahmadi
authors.affiliation: Molecular BioMedicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia khabar@kfshrc.edu.sa.
authors.forename: Khalid S A
authors.initials: KS
authors.lastname: Khabar
mesh_terms: D020413:3' Untranslated Regions; D063307:AU Rich Elements; D054377:Chemokine CXCL12 / Q000378:metabolism; D051959:ELAV Proteins / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006207:Half-Life; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051816:Tristetraprolin / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D051959:ELAV Proteins; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D051816:Tristetraprolin; C497552:ZFP36 protein, human