In the present study, we investi gated the relationship between NF ��B and STAT3 in terms of gastric cancer metastasis. To the best of our knowledge, this is the first study to show the associ ation between NF ��B and STAT3 in gastric selleck chemicals cancer. In the present study, constitutive activation of NF ��B and STAT3 was found in 16% and 24% of 255 gastric cancer specimens, respectively, and they showed a positive correlation. In addition, our in vitro experiments showed that NF ��B inhibition reduced the protein expres sion of total STAT3 and pSTAT3, which was possibly caused by the suppression of STAT3 at the transcriptional or translational level. Since we wondered whether there is a reciprocal regulatory loop between NF ��B and STAT3, we further analyzed the effect of STAT3 silencing on the NF ��B activation.

However, we found that STAT3 did not affect either NF ��B expression or activation. Thus, these results suggest that STAT3 is a downstream mol ecule of NF ��B in NF ��B pathway. Our observations contrast with a report by Yang et al. which showed that STAT3 and RelA can heterodimerize to transcriptionally regulate NF ��B dependent genes. Although Wani et al. reported that NF ��B activa tion induced STAT3 activation mediated by IL 6, the present study did not show whether IL 6 is reduced in the SNU 638 cells overexpressing I��BM, which may account for the reduced STAT3 levels. Thus, fur ther investigations are needed to obtain a better under standing of the mechanism involved in NF ��B induced STAT3 activation. EMT confers acquisition of cell migration and invasion as well as molecular alterations in cancer cells.

Al though the existence of EMT has not been shown in all types of cancers, previous studies have demonstrated that EMT plays a key role in the malignant progression of gastric cancer by using gastric cancer cell lines, ortho topic xenograft tumors and surgical gastric cancer speci mens. In the present study, we showed that I��BM overexpression decreased the migration and in vasion of gastric cancer cells. Moreover, I��BM overepx ression increased E cadherin expression and decreased Snail expression, which indicates the change toward the mesenchymal phenotype. Thus, these results indicate that NF ��B might contribute to malignant progression through promotion of EMT. Regarding the role of STAT3 in gastric cancer cells, Okamoto et al.

found that STAT3 activation induced cancer cell motility through the Janus kinase pathway, whereas it enhanced survival of MET activated gastric cancer cells. Thus, they concluded that STAT3 plays differential roles depending on the upstream regulator of STAT3 activation in gastric cancer cells. In the present study, STAT3 silencing decreased the migration and inva sion in SNU 638 gastric cancer cells with high GSK-3 NF ��B activity.