Doxorubicin sensitization effect of exosomal miR-16 derived from epigallocatechin gallate treated mesenchymal stem cells in diffuse large B-cell lymphoma

Abstract

The anti-cancer activity of epigallocatechin gallate (EGCG) is well known but the effect of EGCG on other cells in the tumor microenvironment, such as mesenchymal stem cells (MSCs), is unclear. Exosomes are microvesicles released by various cell types. They mediate cell-to-cell communication by transferring genetic material including micro-RNA (miRNA), mRNA, and protein. MSCs have been associated with tumor progression. However, whether MSCs induce the tumor growth or not is controversial. MSCs may mediate the influence of paracrine on communication between MSCs and the tumor microenvironment. In this study, we investigated the effect of EGCG on miRNAs derived from MSC exosomes and the effect of EGCG-treated, MSC-derived exosomes on diffuse large B-cell lymphoma (DLBCL) cells in vitro, ex vivo, and in vivo. The level of miR-16 increased markedly in EGCG-treated, MSC-derived exosomes. When DLBCL cells were treated with EGCG treated MSC-derived exosomes, the levels of Bcl-2, Bcl-w and Smad7 decreased, while the level of Smad3 increased because of regulation of up-regulated miR-16 in exosomes. The expression of anti-apoptotic molecule was also decreased at the protein level. These results indicate that apoptosis of DLBCL cells is induced by EGCG-treated, MSC-derived exosomes. Doxorubin sensitization was also increased in EGCG-treated, MSC-derived exosomes compared to normal MSC-derived exosomes. EGCG-treated, MSC-derived exosomes also induced apoptotic effects ex vivo. Tumor growth was inhibited in vivo because of EGCG-treated, MSC-derived exosomes by transferring up-regulated miR-16. Anti-apoptotic molecules were decreased and apoptotic molecules were increased. FAS and Bax mRNA levels were increased, and protein level of Bcl-2 and FAS was decreased and increased, respectively, following the injection of EGCG-treated, MSC-derived exosomes. Taken together, the results indicate the existence of a novel, exosome-mediated cell-to-cell communication between EGCG treated MSCs and DLBCL cells in the tumor microenvironment, and drug sensitization of EGCG-treated, MSC-exosomal miR-16.