Department of Basic Medicine and Biomedical Engineering, School of Stomatology and Medicine, Foshan University, Foshan, Guangdong, China.
The Medical college of Jiaying University, Meizhou, Guangdong, China.
Cell Biol Int. 2019 Aug;43(8):863-874. doi: 10.1002/cbin.11154. Epub 2019 May 22.
We had previously identified that the co-expression of transmembrane CXCL16 (TM-CXCL16) and its receptor CXCR6 is an independent risk factor for poor survival in patients with diffuse large B-cell lymphoma (DLBCL). However, the impact of the soluble form of CXCL16 (sCXCL16) on the pathogenesis of DLBCL remains unknown. In the present study, the synergistic effect of sCXCL16 and tumor necrosis factor α (TNF-α) on apoptosis in DLBCL cell lines (OCI-LY8 and OCI-LY10) was investigated in vitro. sCXCL16 reinforced TNF-α-mediated inhibition of DLBCL cell proliferation, as determined by the cell counting kit-8 assay. The results of annexin V staining showed that sCXCL16 enhanced TNF-α-induced apoptosis in OCI-LY8 and OCI-LY10 cells through a death receptor-caspase signaling pathway. The results of gene microarray suggested a significant upregulation of differentially expressed genes in the TNF signaling pathway. sCXCL16 increased the concentration of extracellular TNF-α by binding to CXCR6 to activate the nuclear factor-κB (NF-κB) signaling pathway. TNF-α also induced the secretion of sCXCL16 by increasing the expression of ADAM10, which is known to cleave TM-CXCL16 to yield sCXCL16. Moreover, bioinformatics analysis revealed that elevated TNF-α and ADAM10 expression levels in tumor tissues predicted better survival in patients with DLBCL. Thus, our study suggests that sCXCL16 enhances TNF-α-induced apoptosis of DLBCL cells, which may involve a positive feedback loop consisting of TNF-α, ADAM10, sCXCL16, and members of the NF-κB pathway. sCXCL16 and TNF-α may be used as prognostic markers in the clinic, and their combinational use is a promising approach in the context of DLBCL therapy.
我们之前已经确定，跨膜 CXCL16（TM-CXCL16）及其受体 CXCR6 的共表达是弥漫性大 B 细胞淋巴瘤（DLBCL）患者生存不良的独立危险因素。然而，可溶性 CXCL16（sCXCL16）形式对 DLBCL 发病机制的影响尚不清楚。在本研究中，我们在体外研究了 sCXCL16 和肿瘤坏死因子-α（TNF-α）对 DLBCL 细胞系（OCI-LY8 和 OCI-LY10）凋亡的协同作用。细胞计数试剂盒-8 测定结果表明，sCXCL16 增强了 TNF-α对 DLBCL 细胞增殖的抑制作用。Annexin V 染色结果表明，sCXCL16 通过死亡受体-半胱天冬酶信号通路增强了 TNF-α诱导的 OCI-LY8 和 OCI-LY10 细胞凋亡。基因微阵列的结果表明，TNF 信号通路中差异表达基因显著上调。sCXCL16 通过与 CXCR6 结合增加细胞外 TNF-α的浓度，从而激活核因子-κB（NF-κB）信号通路。TNF-α还通过增加已知切割 TM-CXCL16 产生 sCXCL16 的 ADAM10 的表达诱导 sCXCL16 的分泌。此外，生物信息学分析表明，肿瘤组织中 TNF-α和 ADAM10 表达水平的升高预示着 DLBCL 患者的生存更好。因此，我们的研究表明，sCXCL16 增强了 TNF-α诱导的 DLBCL 细胞凋亡，这可能涉及一个由 TNF-α、ADAM10、sCXCL16 和 NF-κB 通路成员组成的正反馈回路。sCXCL16 和 TNF-α可作为临床预后标志物，联合使用可能是 DLBCL 治疗的一种有前途的方法。
