Direct cell–cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts: involvement of EMMPRIN and MT1-MMP

Abstract. Coordinate cell-surface expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) on cancer cells, tumor-infiltrating lymphocytes (TIL) and cancer-associated myofibroblasts has been shown to play an important role in tumor invasion and metastasis in organ tissues. However, precise localization of tumor cell lines in vitro has remained obscure. The aim of this study was to investigate the spatial localization of these proteolytic enzymes in 21 tumor cell lines consisting of 8 gastric, 4 pancreatic, 2 gallbladder, 1 extrahepatic bile duct cancer and 6 T-or B-cell tumors. The cell-surface and/or intracellular localization of MMP-2, -7, and -9, membrane type-1 (MT1)-MMP and TIMP-2 and -4 was quantitatively determined by flow cytometry in living (non-permeabilized) and permeabilized tumor cell lines. As a result, all of the tumor cell lines showed a high level of intracellular expression, but a low or undetectable level of cell-surface expression of MMPs and TIMPs. The findings revealed that intracellular MMPs and TIMPs in tumor cell lines were preserved as latent pro-enzymes.

Section: Discussionmentioning

confidence: 57%

Intracellular localization of matrix metalloproteinases and their inhibitors in cultured tumor cell lines: Flow cytometric analysis

Koyama

2006

“…The importance of EMMPRIN in the steps of cancer progression such as tumor growth and lymphatic metastasis is widely known based on recent studies including HNSCC (12)(13)(14)(15)24,25). Several studies reported that EMMPRIN blocking or silencing is efficient for cancer suppression (26-30).…”

Section: Discussionmentioning

confidence: 99%

“…EMMPRIN is highly expressed in head and neck squamous cell carcinoma (HNSCC) cells (13). We previously showed that EMMPRIN plays an important role in HNSCC progression through MMP production and activation (14,15).…”

Section: Introductionmentioning

confidence: 99%

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

Takahashi

Suzuki

Ishikawa³

2011

Self Cite

Abstract. 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 EMMPRINexpressing 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.

“…CD147 (EMMPRIN) is a highly glycosylated cell surface transmembrane protein that belongs to the immunoglobulin superfamily (5), and it is thought to be involved in inflammation, neural-glial interaction, and virus infection (6)(7)(8)(9). CD147 is found to be highly expressed in a variety of malignant human cancers, including malignancies of the pancreas (6,10,11), and it induces tumor cell invasion by stimulating the production of matrix metalloproteinases (MMPs), resulting in tumor invasion and metastasis (12).…”

Section: Introductionmentioning

confidence: 99%

CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells

Pan

Song

et al. 2012

Abstract. CD147, which belongs to the immunoglobulin superfamily, is a multifunctional glycoprotein that has been shown to increase tumor invasion, metastasis and multidrug resistance. To define the role of CD147 in invasion and metastasis more precisely, we utilized gene silencing to inhibit the expression of CD147 in pancreatic cancer cells. We observed that CD147 expression was significantly impeded at both the mRNA and protein levels and resulted in a decrease of MMP-2 and MMP-9 activities. There was also a decrease of MCT1 expression in the invasion and metastasis potential of pancreatic cancer cells, as well as increased chemosensitivity to gemcitabine in Panc-1 cells. Overall, these results suggest that CD147 plays an important role in the invasion, metastasis and chemosensitivity of the human pancreatic cancer cell line Panc-1, indicating that CD147 may be a promising therapeutic target for pancreatic cancer. IntroductionPancreatic cancer is a malignancy with an extremely poor prognosis and is refractory to conventional chemotherapy and radiotherapy. Despite efforts in the past years, conventional treatment approaches, such as surgery, radiation, chemotherapy, or combinations of these, the mortality rate of pancreatic cancer still remains high (1-4). Therefore, it can be effectively diagnosed, prevented, and treated only by developing a detailed understanding of the molecular biology of underlying pancreatic cancer formation and progression.CD147 (EMMPRIN) is a highly glycosylated cell surface transmembrane protein that belongs to the immunoglobulin superfamily (5), and it is thought to be involved in inflammation, neural-glial interaction, and virus infection (6-9). CD147 is found to be highly expressed in a variety of malignant human cancers, including malignancies of the pancreas (6,10,11), and it induces tumor cell invasion by stimulating the production of matrix metalloproteinases (MMPs), resulting in tumor invasion and metastasis (12). In addition, CD147 plays a pivotal role as a chaperone for the proper plasma membrane expression and the activity of monocarboxylate transporters (MCTs), particularly MCT1 and MCT4 (13-15). MCTs are among the most important cellular pH regulators likely involved in cancer pH homeostasis (16-18). The MCT family has fourteen members (19), six of which have been functionally characterized, but only MCT1-MCT4 have been shown to catalyze the proton-coupled transport of lactate (20)(21)(22)(23)(24). Many studies have demonstrated that CD147 acts as an essential chaperone to take MCT1 and MCT4 to the plasma membrane where the MCTs and CD147 are tightly associated (13,25).CD147 is also involved in multidrug resistance of cancer cells via hyaluronan-mediated activation of ErbB2 signaling and cell survival pathway activities, but the mechanism of CD147 in multidrug resistance of pancreatic cancer remains elusive (26-28). We demonstrate here that CD147 silencing inhibits pancreatic cancer cell invasion and metastasis and increases chemosensitivity to gemcitabine. Our results su...