MT2-MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression

Objective: Membrane type-matrix metalloproteinases (MT-MMPs) are known as key regulators of cancer pro-gression/metastasis. However, their roles in the growth and progression of multiple myeloma (MM) have not been yet elucidated. Methods and materials: The expression of 6 MT-MMPs in MM, B cell lines, and normal peripheral blood (PB) cells were measured by RT-PCR, qRT-PCR, flow cytometry, western blotting, and immunocytochemistry. B lympho-cytes, CD19-/CD138(-), and CD19-/CD138(+ )cells, known as malignant plasma cells (MPC), were sorted from bone marrow (BM) aspirations of 10 MM patients, and MT2-MMP expression was examined in these cells using qRT-PCR, flow cytometry and immunohistochemistry, and western blotting. Moreover, the expression of MT2-MMP in BM biopsies from 13 normal individuals and 14 MM patients was analyzed by immunohistochem-istry. MT2-MMP was also knocked down in U266 cells using siRNA technology and the adhesion, invasion, migration abilities, and cell proliferation were determined and compared with scrambled ones in both in vitro and in vivo studies. Results: Our results showed that MT2-MMP expression is significantly higher in MM cell lines and MPC cells than B cell lines and other PB-or BM-derived cells. MT2-MMP is expressed in BM biopsies from all 14 patients with MM, and 67.85%+/- 32.38 of BM cells were positive for MT2-MMP. In contrast, only 0.38 +/- 0.76 of BM biopsies from normal individuals were positive for MT2-MMP. Importantly, MT2-MMP was expressed in all the patients' BM biopsies at the diagnosis, but not in the remission phase. MT2-MMP siRNA significantly decreased adhesion, invasion, migration, and 3D cell proliferation of U266 cells. Moreover, in the xenographic model, MT2-MMP siRNA prevented the growth and development of plasmacytoma. Taken together, these data demonstrate that MT2-MMP is strongly expressed in MM cells and plays important role in the growth and progression of these cells, suggesting that MT2-MMP is an appropriate biomarker in diagnosis and therapeutic interventions of MM.