Autocrine Loop Of IGF-1/IGF-1R Signaling Pathway Promotes Cell Migration And Invasion In Natural Killler/T-cell Lymphoma Cells

Objective The aim of this study is to detect the expression pattern of IGF-1/IGF-1R autocrine loop in NK/T-cell lymphoma(NK/TCL) cells and to investigate the function and potential mechanism of IGF-1/IGF-1R signaling in the regulation of cell migration and invasion.Methods RT-PCR and immunofluorescence were performed to identify the expression of IGF-1 and IGF-1R. Western blot was conducted to detect the levels of phosphorylation of IGF-1R and downstream kinases ERK1/2, AKT, JNK and p38. Transwell assay was applied to observe the effects of IGF-1/IGF-1R signaling and downstream kinases on cell migration and invasion. Concentrations of MMP-2, MMP-9, and TIMP1 were quantified by ELISA.Results Co-expression of IGF-1 with its receptor IGF-1R was identified in two NK/TCL cell lines, SNK-1 and SNK-6. SNT-8 cells expressed IGF-1 without co-expression of IGF-1R. Significant increase in phosphorylation levels of IGF-1R and downstream kinases ERK1/2 and AKT werec detected in SNK-1 and SNK-6 cell with additional IGF-1 stimulation. Upon activating AKT signaling pathway by exogenous IGF-1, cell migratory and invasive activities were significantly enhanced. Secreted levels of MMP-2 and MMP-9, not TIMP1, were regulated by IGF-1R axis, which are supposed to contribute to cell invasion through initiating degradation of extracellular matrix(ECM). Small molecular inhibitors of IGF-1R can suppress migration and invasion of SNK-1 and SNK-6 by blocking the activation of IGF-1R and its downstream kinases. Exogenous IGF-1 or IGF-1R inhibitors showed no significant effect on cell migration and invasion in SNT-8 cells.Conclusion An autocrine IGF-1/IGF-1R loop was aberrantly expressed on some NK/TCL lymphoma cells. The autocrine IGF-1R axis promotes cell migration and invasion, which appears to be a potential therapeutic target in NK/TCL.