title: KSHV microRNAs mediate cellular transformation and tumorigenesis by redundantly targeting cell growth and survival pathways.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several human cancers, including Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease, malignancies commonly found in HIV-infected patients. While KSHV encodes diverse functional products, its mechanism of oncogenesis remains unknown. In this study, we determined the roles KSHV microRNAs (miRs) in cellular transformation and tumorigenesis using a recently developed KSHV-induced cellular transformation system of primary rat mesenchymal precursor cells. A mutant with a cluster of 10 precursor miRs (pre-miRs) deleted failed to transform primary cells, and instead, caused cell cycle arrest and apoptosis. Remarkably, the oncogenicity of the mutant virus was fully restored by genetic complementation with the miR cluster or several individual pre-miRs, which rescued cell cycle progression and inhibited apoptosis in part by redundantly targeting IκBα and the NF-κB pathway. Genomic analysis identified common targets of KSHV miRs in diverse pathways with several cancer-related pathways preferentially targeted. These works define for the first time an essential viral determinant for KSHV-induced oncogenesis and identify NF-κB as a critical pathway targeted by the viral miRs. Our results illustrate a common theme of shared functions with hierarchical order among the KSHV miRs.
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Moody
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Jones
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Roble
authors.initials: R
authors.lastname: Bedolla
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Bai
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics*; D002478:Cells, Cultured; D053263:Gene Regulatory Networks; D018390:Gene Targeting; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D046228:Microarray Analysis; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome
chemical_list: D035683:MicroRNAs