Extracellular vesicles in oral squamous carcinoma carry oncogenic miRNA profile and reprogram monocytes via NF-kappaB pathway

Abstract

Extracellular vesicles (EVs) are carriers of different biomacromolecules that participate in cellular signaling and disease pathogenesis. Although it has been shown that EVs can play an active role in cellular communication and different stages of cancer progression, the role of EVs in oral squamous cell carcinoma (OSCC) cancer pathogenesis, especially in the crosstalk of cancer cells with immune cells is unknown. Here, we present a detailed analysis of findings regarding the profile of EVs in OSCC and the role of EVs and associated miRNAs in the crosstalk of malignant cells with monocytes. We demonstrate that EVs are detectable in significantly higher quantities in the plasma of patients with OSCC. Oncogenic miRNAs (such as miR-21, miR-27) were detectable in high quantities in the circulating EVs and plasma of patients with OSCC. EVs isolated from the circulation of OSCC patients and OSCC cell lines showed comparable miRNA signature, indicating the tumor origin of EVs in the circulation of patients with OSCC. Danger signals such as LPS and ethanol increased the production of EVs. EVs were taken up by monocytes after co-culture. Mechanistically, uptake of EVs derived from oral cancer cells by monocytes caused activation of the inflammatory pathway, NF-kappaB activation, and establishment of a pro-inflammatory and pro-tumorigenic milieu marked by increased levels of IL-6, CCL2, PEG2 and MMP9 levels. Series of experiments involving the introduction of exogenous oncogenic miR-21 mimic induced a similar pro-inflammatory and pro-tumorigenic profile in monocytes. Inhibiting miR-21 function in monocytes attenuated the pro-inflammatory phenotype of monocytes after EV challenge. These results indicate the role of EV-associated miR-21 in modulating the immune response in monocytes.