A study on the prevention of oral cancer metastasis by targeting a transcription factor NF-κB and protease

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We examined a validity of NF-κB targeting therapy of oral cancer. Firstly, the involvement of matrix metalloproteinase-9 (MMP-9) in cancer invasion and metastasis was studied in the biopsy specimens of oral cancer patients. Secondly, in order to block the capability of oral cancer cells to produce MMP-9, we attempted to inhibit the activation of a transcription factor NF-κB through various methods.(1) We examined a gelatinolytic activity of MMP-9 in the biopsy specimens of 57 cases of oral squamous cell carcinoma by gelatin zymography. The same specimens were also stained immunohistochemically by anti-MMP-9 antibody. The gelatinolytic activity of MMP-9 in each case correlated with the immunohistochemical staining degree of MMP-9. The gelatin zymographic analysis of 57 cases revealed that the gelatinolytic activity of MMP-9 in biopsy specimens statistically correlated with histopathological invasiveness of oral cancer, suggesting that MMP-9 expression contributes to the invasion and met … More astasis of oral cancer.(2) We found that the MMP-9 expression of cultured oral squamous cell carcinoma cell lines was inhibited by dexamethasone (DEX) and interleukin-4 (IL-4). DEX and IL-4 inhibited the conversion from MMP-9 precursor to active form of MMP-9 by inhibiting the gene expression of urokinase type plasminogen activator (uPA). The activation of a transcription factor NF-κB, which can activate gene expressions of MMP-9 and uPA, was also inhibited by DEX and IL-4. Therefore, DEX and IL-4 are likely to target NF-κB to inhibit the gene expression and activation of MMP-9.(3) Early-passage normal human fibroblasts can express normal size of NF-κB while the molecular size of NF-κB of late-passage fibroblasts was reduced to 70-80 kD.The senescence of normal cells may induce the intracellular NF-κB-degrading protease(s). In contrast, tumor cells can express normal NF-κB molecule stably evev after 100 passage.(4) The expression vectors of superreppressor IκBα and dominant negative IκBα kinases (IKK kinases) have been formed. We are now transtecting the expression vectors into oral cancer cells and examining the effects of these vectors on MMP-9 expression.In conclusion, NF-κB-targeting therapy may be useful to prevent invasion and metastasis of oral cancer. Less