自分泌IGF-1/IGF-1R环路促进NK/T细胞淋巴瘤细胞株迁移和侵袭

Autocrine IGF-1/IGF-1R signaling promotes cell migration and invasion in NK/T-cell lymphoma cells

目的 探讨IGF-1/IGF-1R信号通路对NK/T细胞淋巴瘤（NK/TCL）细胞株迁移和侵袭的作用及其调控机制.方法 采用反转录聚合酶链反应（RT-PCR）及免疫荧光技术检测IGF-1和IGF-1R的表达,Transwell技术观察NK/TCL细胞迁移和侵袭.酶联免疫吸附实验（ELISA）检测MMP-2、MMP-9及TIMP1水平.结果 NK/TCL细胞株SNK-1和SNK-6均表达IGF-1与IGF-1R,而健康人NK细胞不表达IGF-1R.IGF-1R抑制剂显著抑制SNK-1和SNK-6的迁移和侵袭.外源性IGF-1则促进细胞迁移及侵袭,而IGF-1R抑制剂能阻断该效应.IGF-1R下游相关激酶p38、PI3K及JNK的抑制剂均可降低细胞迁移能力.外源性IGF-1可上调MMP-2、MMP-9的分泌水平,IGF-1R抑制剂则抑制MMP-2、MMP-9的分泌.结论 NK/TCL细胞株中存在IGF-1/IGF-1R自分泌环路,并通过IGF-1/IGF-1R通路促进MMP-2、MMP-9分泌及IGF-1R下游p38、PI3K及JNK等激酶促进肿瘤细胞的迁移和侵袭.

Objective To identify the expression pattern of IGF-1 and IGF-1R in NK/T-cell lymphoma （NK/TCL） cell lines and to investigate the role of IGF-1/IGF-1R signaling in regulation of cell migration and invasion.Methods RT-PCR and immunofluorescence were performed to detect the expression of IGF-1 and IGF-1R.Transwell assay was applied to observe the effects of IGF-1/IGF-1R signaling and downstream kinases activities on cell migration and invasion.Concentrations of MMP-2 and MMP-9 were quantified by ELISA.Results Co-expression of IGF-1 and its receptor IGF-1R were identified in two NK/TCL cell lines,SNK-1 and SNK-6,while normal NK cells lack the IGF-1R expression.IGF-1R inhibitors significantly reduced SNK-1 and SNK-6 cells migration and invasion rates.Exogenous IGF-1 promoted both cell lines migration and invasion,but these effects were both blocked by IGF-1R inhibitors.Inhibition of AKT,p38 and JNK,the possible IGF-1R downstream kinases,reduced cell migration rates.Further more,exogenous IGF-1 significantly increased MMP-2 and MMP-9 secretion,while decreased secretion of MMP-2 and MMP-9 were observed when IGF-1R inhibitors were applied.Conclusion An autocrine IGF-1/IGF-1R signaling loop is aberrantly expressed on NK/TCL cells and the autocrine loop significantly promotes cell migration and invasion through activation of p38,PI3K and JNK signaling and enhances secretion of MMP-2 and MMP-9.