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

Abstract

Extracellular vesicles (EVs) are carriers of different biomacromolecules thatparticipate in cellular signaling and disease pathogenesis. Although it has been shownthat EVs can play an active role in cellular communication and different stages ofcancer progression, the role of EVs in oral squamous cell carcinoma (OSCC) cancerpathogenesis, 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 OSCCand the role of EVs and associated miRNAs in the crosstalk of malignant cells withmonocytes. We demonstrate that EVs are detectable in significantly higher quantitiesin 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 withOSCC. EVs isolated from the circulation of OSCC patients and OSCC cell lines showedcomparable miRNA signature, indicating the tumor origin of EVs in the circulation ofpatients with OSCC. Danger signals such as LPS and ethanol increased the productionof EVs. EVs were taken up by monocytes after co-culture. Mechanistically, uptake ofEVs derived from oral cancer cells by monocytes caused activation of the inflammatorypathway, NF-κB activation, and establishment of a pro-inflammatory and protumorigenic milieu marked by increased levels of IL-6, CCL2, PEG2 and MMP9 levels.Series of experiments involving the introduction of exogenous oncogenic miR-21mimic induced a similar pro-inflammatory and pro-tumorigenic profile in monocytesafter miR-21 mimic. Inhibiting miR-21 function in monocytes attenuated the proinflammatory phenotype of monocytes after EV challenge. These results indicate therole of EV-associated miR-21 in modulating the immune response in monocytes.