CD147 Increases U937 Tumorigenicity And Cell Invasiveness Through Regulation Of Matrix Metalloproteinases Activities

CD147, extracellular matrix metalloproteinase inducer (EMMPRIN), is a 50 000-60 000 MW glycoprotein of the immunoglobulin superfamily broadly expressed on haemopoietic and non-haemopoietic cell lines. It stimulates peritumoral fibroblasts to produce matrix metalloproteinases (MMPs) thus contributing to tumor invasion and metastasis.In order to clarify the role of CD147 in the progression and invasion of leukemia, U937 monoblastoid cells were treated by lipopolysaccharide (LPS) or anti-CD147 monoclonal antibody, and the expression of CD147 and MMP-2, 9, the invasive potential of the cells in vitro and ex vivo, as well as the growth and invasion of the implanted tumors in nude mice and SCID mice respectively were investigated. The results showed that expression of CD147 was elevated by the induction of LPS, and enhanced expression of CD147 on U937 cells increased the production and secretion of MMP-2 and MMP-9 as measured by reverse transcription-PCR and gel zymography. An increased number of LPS-induced cells invading through a reconstituted basement membrane was observed by invasion assays. These responses were down-regulated by a blocking antibody to CD147. The cell cycle analysis showed that the proportions of S-phase cells were increased by LPS induction, and CD147 antibody can cause the cells arrest at G0/G1 phase and undergo apoptosis. The cell viability decreased by anti-CD147 antibody treatment. Implantation of anti-CD147 antibody pretreated U937 cells to the nude mice s.c. showed a significant delay of tumor appearance, a better animal survival and a remarkable reduction of tumor volume. 30 days after injection of LPS pretreated U937 cells to SCID mice i.v. human U937 cells were found in the bone marrow and lung of the mice, indicating the invasion of the tumor cells. And an overexpression of CD147 and MMP-9 was found in the lung tissue of the mice injected with LPS-treated but not anti-CD147 antibody treated tumor cells.These results suggested that overexpression of CD147 on U937 cells may increase the secretion and activation of MMP-2 and MMP-9 and thus promote the tumorigenicity and invasiveness of the cells.