title: Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies.
abstract: MicroRNAs (miRNAs) are stable, small non-coding RNAs that modulate many downstream target genes. Recently, circulating miRNAs have been detected in various body fluids and within exosomes, prompting their evaluation as candidate biomarkers of diseases, especially cancer. Kaposi's sarcoma (KS) is the most common AIDS-associated cancer and remains prevalent despite Highly Active Anti-Retroviral Therapy (HAART). KS is caused by KS-associated herpesvirus (KSHV), a gamma herpesvirus also associated with Primary Effusion Lymphoma (PEL). We sought to determine the host and viral circulating miRNAs in plasma, pleural fluid or serum from patients with the KSHV-associated malignancies KS and PEL and from two mouse models of KS. Both KSHV-encoded miRNAs and host miRNAs, including members of the miR-17-92 cluster, were detectable within patient exosomes and circulating miRNA profiles from KSHV mouse models. Further characterization revealed a subset of miRNAs that seemed to be preferentially incorporated into exosomes. Gene ontology analysis of signature exosomal miRNA targets revealed several signaling pathways that are known to be important in KSHV pathogenesis. Functional analysis of endothelial cells exposed to patient-derived exosomes demonstrated enhanced cell migration and IL-6 secretion. This suggests that exosomes derived from KSHV-associated malignancies are functional and contain a distinct subset of miRNAs. These could represent candidate biomarkers of disease and may contribute to the paracrine phenotypes that are a characteristic of KS.
authors.affiliation: Lineberger Comprehensive Cancer Center, Program in Global Oncology, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Pauline E
authors.initials: PE
authors.lastname: Chugh
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Sin
authors.forename: Sezgin
authors.initials: S
authors.lastname: Ozgur
authors.forename: David H
authors.initials: DH
authors.lastname: Henry
authors.forename: Prema
authors.initials: P
authors.lastname: Menezes
authors.forename: Jack
authors.initials: J
authors.lastname: Griffith
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.forename: Dirk P
authors.initials: DP
authors.lastname: Dittmer
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001826:Body Fluids / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D055354:Exosomes / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human / Q000302:isolation & purification* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000097:blood* / Q000378:metabolism; D035422:Pleural Cavity; D016066:Pleural Effusion, Malignant / Q000209:etiology; D012334:RNA, Neoplasm / Q000097:blood* / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood* / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D015854:Up-Regulation; D019562:Viral Load
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D035683:MicroRNAs; D012334:RNA, Neoplasm; D012367:RNA, Viral