Exosomes derived from chronic lymphocytic leukaemia cells transfer miR-146a to induce the transition of mesenchymal stromal cells into cancer-associated fibroblasts.

Abstract

Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia and remains incurable. Mesenchymal stem cells (MSCs) can promote tumour progression by differentiating into cancer-associated fibroblasts (CAFs). However, the mechanisms by which tumour cells induce the transition of MSCs to CAFs are still largely undefined. Exosomes can regulate recipient cellular function by mediating intracellular communication. This study aimed to investigate whether CLL cells regulate the transition of bone marrow-derived MSCs (BM-MSCs) to CAFs via exosomal miR-146a delivery. The exosomes were isolated from CLL cell line MEC-1 (CLL-Exo) and then co-cultured with BM-MSCs. The expression of α-smooth muscle actin (α-SMA) and fibroblast-activated protein (FAP) were determined by immunofluorescence, quantitative real-time polymerase chain reaction and western blot. A luciferase reporter assay was performed to verify whether ubiquitin-specific peptidase 16 (USP16) was a target of miR-146a. CLL-Exo treatment up-regulated miR-146a and down-regulated expression of CAF markers (α-SMA and FAP) and USP16. The inducing effect of CLL-Exo on CAF marker expression was compromised when miR-146a expression was inhibited in CLL-Exo. USP16 was confirmed as a direct target of miR-146a and USP16 overexpression in BM-MSCs abrogated the CLL-Exo-mediated up-regulation of CAF markers. Collectively, CLL-Exo delivered miR-146a into BM-MSCs where miR-146a mediated transition of BM-MSCs into CAFs by targeting USP16.