Oral squamous cancer cell carcinoma (OSCC) ranks among the top ten most frequently cancers, and 500 000 people per year are world widely diagnosed . OSCC is highly invasive with bad prognosis; despite the recent advances in cancer therapy, the 5-year survival rate of patients has remained at < 50% . Little is known about of the molecular events that govern OSCC initiation, progression and metastasis. Development of OSCC is a complex and multistep process, with transformation from oral premalignant dysplastic lesion to OSCC. Progression is generally known to involve the intervention of proteinases [3–5]. Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147), a membrane glycoprotein greatly enriched on the surface of tumor cells, is mainly known for its ability to increase the synthesis of MMPs in tumor cells and in the neighbouring stromal cells, such as fibroblasts and endothelial cells [6–10]. EMMPRIN has been implicated in tumor invasion and its elevated levels in cancer tissues have been correlated with tumor progression in numerous malignant tumor models including tumors of the oral cavity and larynx [11, 12].
In addition to increasing invasion through proteinase induction, EMMPRIN induces several other malignant properties associated with cancer. These include, amongst others, the stimulation of cell survival signaling, including Akt, Erk and FAK, through the increased production of the pericellular polysaccharide hyaluronan . Also, EMMPRIN can promote angiogenesis by the upregulation of VEGF expression as well as its main receptor VEGFR-2 in both tumor cells and endothelial cells [14–16]. This effect on VEGF and VEGFR-2 was shown to be mediated by HIF-2α .
The role of EMMPRIN in tumor growth and invasion was illustrated by the accelerated growth and increased invasiveness of EMMPRIN-overexpressing human breast cancer cells [18, 19]. The increased tumor size in the EMMPRIN overexpressing cells was associated with an increase, in the tumors, of not only MMP-2 and MMP-9 [18, 19], but also of urokinase type plasminogen activator (uPA) levels . Indeed, we have previously reported that EMMPRIN is able to upregulate the expression of the plasminogen activation system, including uPA, in mammary tumor cells, further increasing its proteolytic and invasion potential .
Microarray analyses of primary oral tumors have identified uPA and its receptor (uPAR) as key genes associated with human OSCC progression [18, 20, 21]. Human OSCC tumors with high levels of uPA and uPAR are more invasive, exhibit enhanced lymph node metastasis and more frequent tumor relapse .
Increased expression of EMMPRIN in oral squamous cell carcinoma has been shown to correlate with lymphatic metastasis and tumor progression . EMMPRIN overexpression has been previously reported to occur at a very early stage of oral carcinogenesis and to play a contributing role in OSCC tumorogenesis . Its role in facilitating tumor cell motility was attributed to its ability to increase MMP production and tenascin-C matrix deposition [25, 26]. In this study using both invasive and precancerous oral cancer cell models we present evidence suggesting that EMMPRIN promotes oral tumor invasion by inducing uPA expression.