ption factor ZEB1 to suppress E cadherin transcription. In lung cancer, the SIRT1 activator compound 1720 was shown to increase lung metastasis of implanted breast cancer cells, suggesting SIRT1 as a potential target for suppressing metastasis to the lung. Moreover, miR 200 nega tively regulated SIRT1 e pression and inhibited the EMT process in normal mouse mammary epithelial cells. However, the role of SIRT1 in tumorigenesis remains controversial, and may depend on the tumor type. A recent report showed that enhanced SIRT1 e pression in a B catenin dependent mouse model of colon cancer inhibited intestinal tumor formation, thereby indicating that the effects of SIRT1 might vary in different tumor models, and depend on the presence of appropriate downstream targets.

Moreover, SIRT1 was shown to protect against gut carcinomas in APCmin mice, as well as inhibit tumorigenesis in p53 mice. Wang et al. found that Sirt1, p53 mice develop tumors in multiple tissues, and activation of SIRT1 by resveratrol reduces tumorigenesis. Moreover, several independent investigations have found reduced levels of SIRT1 in Sirt1, p53 mice as compared to normal controls, and suggested SIRT1 as an important GSK-3 antagonist of EMT in various types of cancer cells. In lung cancer, SIRT1 down regulation by hypo ia in a SUMOylation dependent manner promotes EMT, and eventually leads to tumor metastasis. This result supports the hypotheses that SIRT1 activation ameliorates lung cancer metastasis in vitro and in vivo by blocking the entry of pre cancerous cells into EMT.

Additionally, SIRT1 has been shown to sup press the EMT process in metastasizing breast cancer cells, and the development of fibrosis in organs following their implantation into nude mice. A reduction in SIRT1 levels was shown to promote the metastasis of breast epithelial cells in an orthotopic model of breast cancer, as well as increase the motility of the epithelial cells. Furthermore, while EMT can be induced in both breast and kidney epithelial cells in vitro, this induction is repressed by SIRT1. A previous study found that both miR 520c and miR 373 suppressed SIRT1 mRNA transla tion, leading to activation of the Ras Raf MEK Erk path way. Moreover, NF ��B increased MMP9 e pression and enhanced the migration of fibrosarcoma cells.

Our data builds upon the results in these previous studies by further verifying SIRT1 as a critical regulator of cancer progression, and an important target for prevention or possible treatment of cancer metastasis. Similar to other cancers, oral cancer metastasis requires degradation of the e tracellular matri via increased e pression of matri metalloproteinases. For e ample, MMP2, 7, and 9 are overe pressed in oral carcinoma tissue. Importantly, MMP7 e pres sion is most pronounced at the invasive front of tumors, has been reported as an independent prognos tic factor which closely correlates with clinical stage, tumor size, lymph node metastasis, and poor survival of oral cancer pa