piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment

Extracellular vesicles (EVs) can carry a wide array of RNAs in the tumor microenvironment, and are crucial for communication between tumor and surrounding stromal cells, including endothelial cells. Piwi-interacting RNAs (piRNAs) are important regulators implicated in the pathogenesis of multiple myeloma (MM). However, little is understood about the role of piRNA-823 in intercellular communication between MM and endothelial cells. In this study, we found that piRNA-823 mainly accumulated in EVs from peripheral blood of MM patients and EVs derived from MM cells (MM-derived-EVs). Increased piRNA-823 expression was associated with late stages and poor prognosis of MM. The MM-derived-EVs effectively transferred piRNA-823 to EA.hy926 endothelial cells. The piRNA-823 mimic and inhibitor were designed to upregulate or to suppress the endogenous function of piRNA-823. Transfection with piRNA-823 mimic or treatment with MM-derived-EVs significantly promoted the proliferation, tube formation, and invasion of EA.hy926 cells by enhancing the expression of VEGF, IL-6, and ICAM-1 and attenuating apoptosis. EA.hy926 cells transfected with piRNA-823 mimic or pre-treated with MM-derived-EVs promoted the growth of xenograft MM in mice. In contrast, the transfection with piRNA-823 inhibitor or treatment with EVs from piRNA-823 inhibitor-transfected-MM cells had diametrically opposite effects. Our findings demonstrated that piRNA-823 carried by MM-derived-EVs is essential for the re-education of ECs toward a unique environment amenable to the growth of MM cells by altering its biological characteristics. Our findings may pave the way for the development of new piRNA-mediated prognostic stratification and therapeutic strategies for MM.