Cyclophilin A-EMMPRIN interaction induces invasion of head and neck squamous cell carcinoma

Extracellular matrix remodeling crucial to tumorigenesis involves proteolytic enzymes, primarily matrix metalloproteinases (MMPs). MMP production is stimulated by multiple factors, including the extracellular matrix metallo­proteinase inducer EMMPRIN/CD147. Overexpression of EMMPRIN, a member of the immunoglobulin superfamily, promotes invasion, metastasis, growth and survival of malignant cells. Cyclophilin A (CypA) is a multifunctional protein that promotes cancer progression in various cancer types. CypA can interact with and activate EMMPRIN; however, the role of CypA-EMMPRIN interaction in oncogenicity is not completely understood. To investigate tumorigenicity induced by the CypA-EMMPRIN interaction, we stimulated EMMPRIN-expressing head and neck squamous cell carcinoma (HNSCC) cells with CypA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay revealed that HNSCC cell proliferation increased upon stimulation of the cells with CypA, whereas cisplatin-induced cell death decreased after stimulation. Gelatin zymography showed that CypA also induced MMP-9 up-regulation. Moreover, HNSCC cell invasion through Matrigel™-coated membranes was increased upon stimulation of cells with CypA. This elevated invasive potential was abrogated by an EMMPRIN function-blocking antibody. These findings suggest that CypA, through its interaction with EMMPRIN, contributes to HNSCC tumorigenesis.