Interleukin-6 Drives Multiple Myeloma Progression By up-Regulating of CD147/Emmprin Expression

Multiple myeloma (MM) is a B-cell malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM). CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a type I transmembrane glycoprotein that belongs to the immunoglobulin superfamily. CD147 is expressed in a variety of tissues, and is involved in a number of physiological and pathological processes. With regard to MM, it was recently documented that the aberrantly elevated expression of CD147 has been tightly correlated with MM cell colonization and proliferation. However, it is still unclear what mechanism is involved in the dysregulation of CD147 expression in MM. In this study, we found that CD147 can be up-regulated by interleukin-6 (IL-6), which is derived from either autocrine or paracrine sources and plays an essential role in the malignant progression of MM. When serum-starved MM cell lines RPMI8226, MM1.S and NCIH929 were stimulated with 20ng/mL of IL-6 for 24 hours, we found that the expression of CD147 on MM cell membrane was significantly up-regulated, as determined by flow cytometric analysis. Moreover, when using the IL-6 autocrine MM cell line U266, CD147 level was found to be continuously increased in serum-starved MM cells in a time-dependent manner. Interestingly, the increase of CD147 in U266 cells was found to be abrogated when using neutralizing antibody to block the secreted IL-6. Next, we investigated the molecular mechanisms involved in the IL-6-mediated upregulation of CD147 in MM cells. We confirmed that IL-6 can activate the JAK/STAT3 signaling pathway, inducing the phosphorylation of STAT3 at Tyrosine 705 in RPMI8226 and MM1.S cells. Further studies using ChIP analysis demonstrated that there is a STAT3 binding site at the position −659 to −650 in the promoter of the CD147 gene. In addition, when inhibiting of STAT3 phosphorylation with a specific inhibitor S3I-201, the CD147 expression in MM cells was accordingly decreased. Finally, we found that siRNA mediated knock-down of CD147 in RPMI8226 and MM1.S cells can decrease the proliferation and migration of MM cells induced by IL-6 and Cyclophilin A (CypA). In conclusion, our data provide evidence that IL-6 can up-regulate CD147 expression in a STAT3-dependent manner, and offer a compelling rationale for exploring this axis as a therapeutic target for MM.