Thus, we supposed that MT1G may play a role in the migration and invasion of thyroid cancer cells. kinase inhibitor Regorafenib Delight edly, our data showed that MT1G restoration increased E cadherin expression, resulting in the inhibition of mi gration and invasion in thyroid cancer cells. Decreased expression of E cadherin is a critical molecular event of epithelial mesenchymal transition, which endows the epithelial cells with fibroblast like properties and shows reduced intercellular adhesion and increased mo of p53 and the expression of its downstream targets, in cluding p21, Bak, and Smac, in K1 cells, but not in FTC133 cells. Of the genes transcriptionally regulated by p53, p21WAF CIP1 acts as a necessary mediator for the p53 mediated G1 arrest.
Bak, involving in p53 mediated mitochondrial apoptosis, is a pro apoptotic Bcl 2 family protein which induces the release of apoptogenic factors, such as cytochrome c or Smac DIABLO. These data demonstrated that the effect of MT1G on cell cycle and cell death might be at least partially attributed to p53 mediated cell cycle arrest and apoptosis. With the consid eration of decreased expression of Mdm2 induced by MT1G, the up regulation of p53 is most likely caused by the reduced ubiquitination of Mdm2. Mdm2 functions as an E3 ubiquitin ligase, involving in eukaryotic protein deg radation via ubiquitin proteasome system. It de creases the stability of p53 by binding to its N terminal transactivation domain, and therefore, stimulating its polyubiquinated degradation. The previous studies provide strong evidences that active Akt binds to and phosphorylates Mdm2 at Ser166 and Ser186 to enhance protein stability.
Furthermore, phosphorylated Mdm2 translocates more efficiently to the nucleus, where it can bind p53, resulting in enhanced p53 degradation. tility. In oncogenic process, multiple signal trans duction pathways may induce EMT. MAPK pathway, for example, has been shown to activate two transcription factors Snail and Slug, both of which are transcriptional repressors of E cadherin. Twist, another tran scription factor, also induces loss of E cadherin mediated cell cell adhesion and EMT. However, our data showed that MT1G restoration did not affect the expres sion of these genes, suggesting MT1G mediated E cadherin up regulation at a posttranscriptional level.
A previous study revealed a novel role of Mdm2 in inter action with E cadherin leading to its ubiquitination and degradation, which promotes cell motility and invasive ness, as supported by our findings that MT1G inhibited phosphorylation of Akt and the expression of Mdm2, ultimately contributing to increased stability of E cadherin. It is now clear that the Rb E2F pathway is critical in regulating the initiation of DNA replication and plays a key citation role in controlling cell growth in human carcino genesis.