F-box and WD repeat domain-containing7 (Fbxw7), a member of the F-box family of
proteins, which are components of an
E3 ubiquitin ligase complex, plays an important role as a general
tumor suppressor in regulating the effects of various
oncoproteins. Recently, accumulating studies have shown that Fbxw7 plays an important role in
tumor cell motility, invasion and
cancer metastasis. However, little is known about the signaling mechanisms that regulate
tumor apoptosis, growth arrest and the epithelial-to-mesenchymal transition (EMT) in
gastric cancer. In our study, we confirmed that Fbxw7 expression was decreased in
gastric cancer tissues, and that Fbxw7 inhibited
gastric cancer progression by inducing apoptosis and growth arrest. Furthermore,
gastric cancer migration and invasion were decreased or increased following Fbxw7 overexpression or knockdown, respectively, and the expressions of various EMT markers, such as
E-cadherin,
N-cadherin and
vimentin, were altered after Fbxw7 inhibition or overexpression. Furthermore, we demonstrated that Fbxw7 inhibits the EMT via the down-regulation of Snail 1 and ZEB 1, which are upstream
transcription factors that promote this process. Additionally, RhoA showed higher expression in the same
gastric cancer tissues than in normal
tumor-adjacent samples. We found that Fbxw7 expression was negatively correlated with
RhoA protein expression in
gastric cancer tissues based on Pearson's correlation coefficient analysis. Moreover, we found that
RhoA protein abundance was regulated by Fbxw7 via ubiquitination and proteasomal degradation in
gastric cancer. We further demonstrated the effects of RhoA re-expression or inhibition on stable Fbxw7-overexpressing or Fbxw7-silenced cell lines in vitro and in vivo. These results suggest that Fbxw7 induces apoptosis and growth arrest and inhibits the EMT in part by down-regulating the RhoA signaling pathway.