Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
Oncol Rep. 2012 Jan;27(1):198-203. doi: 10.3892/or.2011.1474. Epub 2011 Sep 28.
Extracellular matrix remodeling crucial to tumorigenesis involves proteolytic enzymes, primarily matrix metalloproteinases (MMPs). MMP production is stimulated by multiple factors, including the extracellular matrix metallo-proteinase 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.
细胞外基质重塑对于肿瘤发生至关重要，涉及蛋白水解酶，主要是基质金属蛋白酶（MMPs）。MMP 的产生受到多种因素的刺激，包括细胞外基质金属蛋白酶诱导因子 EMMPRIN/CD147。免疫球蛋白超家族成员 EMMPRIN 的过表达促进恶性细胞的侵袭、转移、生长和存活。亲环蛋白 A（CypA）是一种多功能蛋白，可促进多种癌症类型的癌症进展。CypA 可以与 EMMPRIN 相互作用并激活它；然而，CypA-EMMPRIN 相互作用在致癌性中的作用尚不完全清楚。为了研究 CypA-EMMPRIN 相互作用诱导的肿瘤发生，我们用 CypA 刺激表达 EMMPRIN 的头颈部鳞状细胞癌（HNSCC）细胞。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐染料测定法显示，CypA 刺激细胞后 HNSCC 细胞增殖增加，而顺铂诱导的细胞死亡减少。明胶酶谱法显示 CypA 还诱导 MMP-9 的上调。此外，CypA 刺激细胞后，HNSCC 细胞穿过 Matrigel™包被膜的侵袭能力增加。用 EMMPRIN 功能阻断抗体阻断这种侵袭能力。这些发现表明，CypA 通过与 EMMPRIN 的相互作用，促进 HNSCC 的肿瘤发生。
