CUX1/Wnt signaling regulates epithelial mesenchymal transition in EBV infected epithelial cells.
Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGFbeta1-mediated lytic phase. EBV lytic reactivation by TGFbeta1 drives a selective alteration in CUX1 variant (a) (NCBI accession number NM_181552) expression, inducing activation of non-canonical Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition (EMT), the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids (ATRA). Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via CUX1 signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.
Clinical Research Centre, School of Medicine and Medical Science, University College Dublin. 21, Nelson Street. Dublin, 7. Ireland.
Andrea P
AP
Malizia
Noreen
N
Lacey
Dermot
D
Walls
Jim J
JJ
Egan
Peter P
PP
Doran
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000150:complications; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000472:pathogenicity*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000998:Antiviral Agents; C080632:CUX1 protein, human; D017931:DNA Primers; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C435831:WNT5B protein, human; D051153:Wnt Proteins