Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies.

[primary effusion lymphoma]

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 .