title: Oncogenic IRFs provide a survival advantage for Epstein-Barr virus- or human T-cell leukemia virus type 1-transformed cells through induction of BIC expression.
abstract: miR-155, processed from the B-cell integration cluster (BIC), is one of the few well-studied microRNAs (miRNAs) and is involved in both innate immunity and tumorigenesis. BIC/miR-155 is induced by distinct signaling pathways, but little is known about the underlying mechanisms. We have identified two conserved potential interferon (IFN) regulatory factor (IRF)-binding/interferon-stimulated response element motifs in the Bic gene promoter. Two oncogenic IRFs, IRF4 and -7, in addition to some other members of the family, bind to and significantly transactivate the Bic promoter. Correspondingly, the endogenous levels of IRF4 and -7 are correlated with that of the BIC transcript in Epstein-Barr virus (EBV)-transformed cells. However, RNA interference studies have shown that depletion of IRF4, rather than of IRF7, dramatically decreases the endogenous level of BIC by up to 70% in EBV- or human T-cell leukemia virus type 1 (HTLV1)-transformed cell lines and results in apoptosis and reduction of proliferation rates that are restored by transient expression of miR-155. Moreover, the endogenous levels of the miR-155 target, SHIP1, are consistently elevated in EBV- and HTLV1-transformed cell lines stably expressing shIRF4. In contrast, transient expression of IRF4 decreases the SHIP1 level in EBV-negative B cells. Furthermore, the level of IRF4 mRNA is significantly correlated with that of BIC in adult T-cell lymphoma/leukemia (ATLL) tumors. These results show that IRF4 plays an important role in the regulation of BIC in the context of EBV and HTLV1 infection. Our findings have identified Bic as the first miRNA-encoding gene for IRFs and provide evidence for a novel molecular mechanism underlying the IRF/BIC pathway in viral oncogenesis.
authors.affiliation: Division of Hematology/Oncology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. sning@med.miami.edu
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Ngoc L
authors.initials: NL
authors.lastname: Toomey
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Gail
authors.initials: G
authors.lastname: Walker
authors.forename: Juan C
authors.initials: JC
authors.lastname: Ramos
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Shunbin
authors.initials: S
authors.lastname: Ning
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000099218:Interferon Regulatory Factor-4
chemical_list: D000072181:Inositol Polyphosphate 5-Phosphatases; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D035683:MicroRNAs; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000099218:Interferon Regulatory Factor-4; C524942:MIRN155 microRNA, human; C000606430:INPP5D protein, human