The role of restored expression of RECK gene in regulating carcinogenesis and invasion by demethylation agent in oral squamous cell carcinoma cell lines

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We have previously reported that MMP-2active form correlated with lymph node metastasis. RECK, a novel tumor suppressor gene, was recently found to regulate the activity of MMPs and MT1-MMP. Down regulation of RECK gene plays an important role in malignant progress of cancer cells. Furthermore, hypermethylation is known as the epigenetic change that is associated with cancer development. Therefore determination of hypermethylation is important in carcinogenesis process. However, study on methylation status of RECK gene in oral squamous cell carcinoma has not yet been reported. We investigate that reversal of hypermethylation of RECK gene may relate to inhibition of MMPs activity and cancer invasive ability.The present results showed that hypermethylation occurred in RECK gene promoter in oral squamous cell carcinoma cell lines. In addition, enhanced expression of RECK mRNA was confirmed by RT-PCR and mRNA levels were clearly associated with reversal of hypermethylation of RECK in these cell lines after treatment with 5-aza-2'-deoxycytidine. Furthermore, the inhibition of MMP-2 and MMP-9 activities was also observed in cancer cells after treatment with demethylation agent. Interestingly, 5-aza-2'-deoxycytidine significantly suppressed cancer cell invasive ability by decreasing the number of invasive foci in three-dimensional collagen invasion model.Our findings support the conclusion that demethylation agent plays a crucial role in inhibiting MMPs activities and cell invasive ability possibly by demethylation effect of MMPs inhibitors such as RECK.