Gao Ge, Wang Liqiang, Li Changfeng
Department of Pathology, The China-Japan Union Hospital of Jilin University, Jilin University Changchun 130022, Jilin, P. R. China.
Department of Endoscopy Center, The China-Japan Union Hospital of Jilin University, Jilin University Changchun 130022, Jilin, P. R. China.
Am J Cancer Res. 2022 May 15;12(5):1934-1959. eCollection 2022.
Extracellular vesicles, particularly exosomes, play a vital role via their cargoes. Their potential in pancreatic ductal adenocarcinoma (PDAC), one of the leading causes of cancer-related mortality worldwide is attracting interests. However, the roles and underlying mechanisms of exosomal circular RNAs (circRNAs) in the development of PDAC remain unclear yet. We aimed to illuminate the mechanisms of exosomal hsa_circ_0006790 (thereafter termed circ_6790) released by exosomes (Exo) derived from bone marrow mesenchymal stem cell (BM-MSC) during immune escape in PDAC in this study. BM-MSC-derived Exo inhibited growth, metastasis, and immune escape in PDAC. Exo enhanced circ_6790 expression in PDAC cells. Knockdown of circ_6790 in Exo significantly attenuated the anti-tumor effect of Exo. Circ_6790 facilitated the nuclear translocation of chromobox 7 (CBX7). CBX7 increased the DNA methylation of S100A11 by recruiting DNA methyltransferases to its promoter region, thereby inhibiting the transcription of S100A11. Inhibition of CBX7 or overexpression of S100A11 annulled the inhibitory effects of Exo on PDAC growth, metastasis, and immune escape. In conclusion, our results suggest that MSC-derived exosomal circ_6790 could downregulate S100A11 in PDAC cells and hamper immune escape via CBX7-catalyzed DNA hypermethylation.
细胞外囊泡，尤其是外泌体，通过其携带的物质发挥着至关重要的作用。它们在胰腺导管腺癌（PDAC）中的潜力，而PDAC是全球癌症相关死亡的主要原因之一，正吸引着人们的关注。然而，外泌体环状RNA（circRNAs）在PDAC发生发展中的作用和潜在机制仍不清楚。在本研究中，我们旨在阐明骨髓间充质干细胞（BM-MSC）来源的外泌体（Exo）在PDAC免疫逃逸过程中释放的外泌体hsa_circ_0006790（以下称为circ_6790）的机制。BM-MSC来源的Exo抑制了PDAC的生长、转移和免疫逃逸。Exo增强了PDAC细胞中circ_6790的表达。敲低Exo中的circ_6790显著减弱了Exo的抗肿瘤作用。Circ_6790促进了染色体框蛋白7（CBX7）的核转位。CBX7通过将DNA甲基转移酶招募到其启动子区域增加了S100A11的DNA甲基化，从而抑制了S100A11的转录。抑制CBX7或过表达S100A11消除了Exo对PDAC生长、转移和免疫逃逸的抑制作用。总之，我们的结果表明，MSC来源的外泌体circ_6790可下调PDAC细胞中的S100A11，并通过CBX7催化的DNA高甲基化阻碍免疫逃逸。
