Lyu Tianxin, Wang Yinuo, Li Ding, Yang Hui, Qin Bin, Zhang Wenli, Li Zhiyue, Cheng Cheng, Zhang Binglei, Guo Rongqun, Song Yongping
Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China.
Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China.
Exp Hematol Oncol. 2021 Mar 31;10(1):24. doi: 10.1186/s40164-021-00220-7.
BM-MSCs play an important role in cancer development through the release of cytokines or exosomes. Studies have shown that extracellular exosomes derived from BM-MSCs are a key pro-invasive factor. However, how BM-MSC-exos influence AML cell proliferation, invasion and chemoresistance remains poorly understood.
We isolated exosomes from BM-MSCs and used electron microscopy, particle size separation and western blots to identify the exosomes. The invasion of leukemia cells was observed with a transwell assay. The stemness traits and chemoresistance of the leukemia cells were detected by FCM, colony formation and CCK-8 assays. TCGA database was used to investigate the prognostic relevance of S100A4 and its potential role in AML.
In this study, we found that BM-MSC-exos increased the metastatic potential, maintained the stemness and contributed to the chemoresistance of leukemia cells. Mechanistically, BM-MSC-exos promoted the proliferation, invasion and chemoresistance of leukemia cells via upregulation of S100A4. Downregulating S100A4 clearly suppressed the proliferation, invasion, and chemoresistance of leukemia cells after treatment with BM-MSC-exos. Bioinformatic analysis with data in TCGA database showed that S100A4 was associated with poor prognosis in AML patients, and functional enrichment revealed its involvement in the processes of cell-cell adhesion and cytokine regulation.
S100A4 is vital in the BM-MSC-exo-driven proliferation, invasion and chemoresistance of leukemia cells and may serve as a potential target for leukemia therapy.
骨髓间充质干细胞（BM-MSCs）通过释放细胞因子或外泌体在癌症发展中发挥重要作用。研究表明，源自BM-MSCs的细胞外外泌体是关键的促侵袭因子。然而，BM-MSC-外泌体如何影响急性髓系白血病（AML）细胞的增殖、侵袭和化疗耐药性仍知之甚少。
我们从BM-MSCs中分离出外泌体，并使用电子显微镜、粒度分离和蛋白质免疫印迹法对外泌体进行鉴定。采用Transwell实验观察白血病细胞的侵袭情况。通过流式细胞术（FCM）、集落形成实验和CCK-8实验检测白血病细胞的干性特征和化疗耐药性。利用癌症基因组图谱（TCGA）数据库研究S100A4的预后相关性及其在AML中的潜在作用。
在本研究中，我们发现BM-MSC-外泌体增加了白血病细胞的转移潜能，维持了其干性，并促进了化疗耐药性。机制上，BM-MSC-外泌体通过上调S100A4促进白血病细胞的增殖、侵袭和化疗耐药性。下调S100A4明显抑制了BM-MSC-外泌体处理后白血病细胞的增殖、侵袭和化疗耐药性。对TCGA数据库数据进行的生物信息学分析表明，S100A4与AML患者的不良预后相关，功能富集分析显示其参与细胞间粘附和细胞因子调节过程。
S100A4在BM-MSC-外泌体驱动的白血病细胞增殖、侵袭和化疗耐药性中至关重要，可能成为白血病治疗的潜在靶点。
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