Department of Geriatrics, Hematology & Oncology ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
Institute of Immunology and Molecular Medicine, Jining Medical University, Jinan, 272067, Shandong, China.
J Exp Clin Cancer Res. 2019 Feb 12;38(1):73. doi: 10.1186/s13046-019-1081-7.
The drug-resistance and relapse of diffuse large B-cell lymphoma (DLBCL), which are related to mesenchymal stem cells (MSCs), have become increasingly common. However, the underlying mechanisms remain elusive.
CCK 8 assay, colony formation assay, and xenograft mouse model were used to investigate the effects of hBMSCs on DLBCL growth. Immunohistochemistry, qRT-PCR, and ELISA were used to study the expressions of IL-6 and IL-17A. Flow cytometry was used to analyze Th17 cells and Treg cells expressions. Western blot analysis, microarray analysis, and bioinformatics analysis were used to analyze the pathways of IL-6 or IL-17A mediated DLBCL growth.
HBMSCs promoted DLBCL growth by secreting IL-6 in vitro and in vivo and simultaneously upregulating IL-17A in vitro. IL-6 and IL-17A synergistically promoted the growth and drug-resistance of DLBCL cells by protecting them from spontaneous or drug-induced apoptosis in vitro. IL-6 or IL-17A activated the JAK2/STAT3 pathway or upregulated cyclin D2 via activation of PI3K/Akt signaling in vitro, respectively.
The present results indicated that hBMSCs might have a "dual effect" on promoting DLBCL progression and drug-resistance by secreting IL-6 and upregulating IL-17A. IL-6, IL-17A, p-STAT3, p-Akt or cyclin D2 may be potential molecular targets for overcoming drug-resistance in patients with relapsed or refractory DLBCL.
弥漫性大 B 细胞淋巴瘤（DLBCL）的耐药性和复发与间充质干细胞（MSCs）有关，这一问题日益普遍，但潜在机制仍不清楚。
使用 CCK8 检测、集落形成检测和异种移植小鼠模型来研究 hBMSCs 对 DLBCL 生长的影响。免疫组化、qRT-PCR 和 ELISA 用于研究 IL-6 和 IL-17A 的表达。流式细胞术用于分析 Th17 细胞和 Treg 细胞的表达。Western blot 分析、微阵列分析和生物信息学分析用于分析 IL-6 或 IL-17A 介导的 DLBCL 生长的途径。
HBMSCs 在体外和体内通过分泌 IL-6 促进 DLBCL 生长，同时在体外上调 IL-17A。IL-6 和 IL-17A 协同促进 DLBCL 细胞的生长和耐药性，在体外通过保护它们免受自发或药物诱导的细胞凋亡。IL-6 或 IL-17A 通过激活 PI3K/Akt 信号通路分别在体外激活 JAK2/STAT3 通路或上调细胞周期蛋白 D2。
本研究结果表明，hBMSCs 通过分泌 IL-6 和上调 IL-17A 可能对促进 DLBCL 进展和耐药性具有“双重作用”。IL-6、IL-17A、p-STAT3、p-Akt 或细胞周期蛋白 D2 可能是克服复发性或难治性 DLBCL 患者耐药性的潜在分子靶点。
