KSHV MicroRNAs Mediate Cellular Transformation and Tumorigenesis by Redundantly Targeting Cell Growth and Survival Pathways

PLoS Pathogens

Xiaodong Cui¹  Tiffany Jones¹  Ying Zhu²  Roble Bedolla³  Yufei Huang³  Rosalie Moody⁴  Shou-Jiang Gao⁴  Xiufen Lei⁴  Zhiqiang Bai⁴ 

[1] Department of Electrical and Computer Engineering, University of Texas 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;Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America

关键词: Cell cycle;    cell division;    Transcription factors;    Apoptosis;    Kaposi's sarcoma-associated herpesvirus;    Carcinogenesis;    Cell cycle inhibitors;    Gene expression;    Small interfering RNAs;   

DOI  :  10.1371/journal.ppat.1003857

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY