Lee Ji Young, Ryu Daeun, Lim Sung Won, Ryu Kyung Ju, Choi Myung Eun, Yoon Sang Eun, Kim Kihyun, Park Chaehwa, Kim Seok Jin
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
J Cancer. 2021 Mar 14;12(10):2825-2834. doi: 10.7150/jca.55553. eCollection 2021.
Exosomes have emerged as important mediators of tumor progression, and a prognostic role for serum exosomal miRNAs has been suggested in multiple myeloma (MM). Given the association of hypoxia with tumor aggressiveness, including cancer stem cell-like phenotypes, we explored exosomal miRNAs from MM cells under hypoxic conditions and analyzed their diverse roles both in promoting oncogenic activity and in predicting prognosis. The human MM cell line, RPMI 8226, was cultured under hypoxic conditions and their exosome production and exosomal miRNA profiles were compared with those of normoxic parental cells. The survival outcome of myeloma patients was compared using serum levels of exosomal miRNAs, and the effects of exosomal miRNAs on the target genes of MM cells and adjacent immune cells were analyzed. Increased expression of stem cell markers and exosome production were observed in hypoxic MM cells. Exosome miRNA analysis identified a higher expression of miR-1305 in exosomes isolated from hypoxic MM cells than in those of normoxic parental cells. The overall survival of patients with high exosomal miR-1305 was poorer than it was in patients with low exosomal miR-1305. In hypoxic MM cells, an increase of exosomal miR-1305 led to a decrease of cellular miR-1305 and increased expression of the miR-1305 target genes, and resulted in the promotion of oncogenic activity of MM. Exosomal miR-1305 was also transferred from MM cells to macrophages, and miR-1305-transferred macrophages showed tumor-promoting, M2-macrophage phenotypes. Exosome-mediated secretion of miR-1305 in MM cells promoted oncogenic activity of hypoxic MM cells and high serum levels of exosomal miR-1305.
外泌体已成为肿瘤进展的重要介质，血清外泌体微小RNA（miRNA）在多发性骨髓瘤（MM）中具有预后作用。鉴于缺氧与肿瘤侵袭性（包括癌症干细胞样表型）相关，我们探索了缺氧条件下MM细胞的外泌体miRNA，并分析了它们在促进致癌活性和预测预后方面的多种作用。将人MM细胞系RPMI 8226在缺氧条件下培养，并将其外泌体产生情况和外泌体miRNA谱与常氧亲本细胞进行比较。使用血清中外泌体miRNA水平比较骨髓瘤患者的生存结果，并分析外泌体miRNA对MM细胞和邻近免疫细胞靶基因的影响。在缺氧的MM细胞中观察到干细胞标志物表达增加和外泌体产生增多。外泌体miRNA分析发现，从缺氧MM细胞中分离的外泌体中miR-1305的表达高于常氧亲本细胞。外泌体miR-1305水平高的患者总生存期比外泌体miR-1305水平低的患者差。在缺氧的MM细胞中，外泌体miR-1305的增加导致细胞内miR-1305减少，miR-1305靶基因表达增加，从而促进了MM的致癌活性。外泌体miR-1305也从MM细胞转移至巨噬细胞，而转染了miR-1305的巨噬细胞表现出促肿瘤的M2巨噬细胞表型。MM细胞中外泌体介导的miR-1305分泌促进了缺氧MM细胞的致癌活性以及血清中外泌体miR-1305的高水平表达。
