The integrated analysis yielded 35 genes that satisfied the selection criteria. Out of the 27 differentially expressed target genes identified for miR 200c, 17 have been shown to influence the migration, invasion, or metastasis of cancer cells both in vitro http://www.selleckchem.com/products/MG132.html and in vivo. Of these genes, LOX, which encodes Lysyl oxidase, is essential for hypoxia induced metastasis and it was reported that breast cancer cell metastasis can be attenuated by lysyl oxidase inhibitors. EMP1 may represent a novel immunohistochemical marker helpful in distinguishing between invasive ductal and lobular carcinomas. Fascin is a key regulator of breast cancer inva sion. CDH11 may play a role in recruiting Trio to the plasma membrane where Trio activates Rac, leading to cell migration.
SEC23A, which mediates the secretion of metastasis suppressive proteins including IGFBP4, has been shown to be a direct Inhibitors,Modulators,Libraries target of miR 200c, and the subse quent down regulation has been correlated to an increase in metastatic colonization. Interestingly, SEC23A was identified as a target of both miR 200c and miR 375, suggesting crosstalk can occur between these two miRNAs. Inhibitors,Modulators,Libraries PRKCA overexpression is strongly associated with a more invasive and metastatic phenotype in breast cancer. Furthermore, it has been shown that PRKCA expres sion is increased in the invasive breast cancer cell lines MDA MB 231 and HS578T, and overexpression can lead to a significant increase in both the migration and invasion ability of the cell lines. Finally, SLC7A11, which Inhibitors,Modulators,Libraries is functional subunit of the cystine glutamate transporter, plays an important role in breast tumor metastasis and maybe a potential target for cancer therapy.
Among the target genes identified, CFL2 was most significantly down regulated by miR 200c. Hurteau et al. first Inhibitors,Modulators,Libraries indicated that CFL2 as a potential target gene of miR 200c, and later re reported by Gregory et al. Korpal et al showed recently that knockdown of Cfl2 in a mouse mammary tumor Inhibitors,Modulators,Libraries cell lines 4TO7 signifi cantly decreased cell migration. In this study, we further revealed that CFL2 plays a crucial role in regulat ing actin turnover and is intimately linked to the cell migration and invasion ability. An increased level of CFL2 would allow for a much higher F actin turnover rate, thus allowing the cell to become much more mobile.
Therefore by slowing the F actin turnover rate, miR 200c helps to maintain the anchoring filaments that tend to hold the cells in place, leading to the decreased migration and invasion ability. CFL2 expression was also noted to increase significantly along with the grade of the tumor. This increase in CFL2 pro duction likely assists the tumor in spreading both locally and metastatically license with Pfizer at a much greater rate. In summary, we have performed the first systematic screening of miRNA mRNA target pairs that are differen tially expressed between invasive and less invasive breast cancer cells.