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.
Keywords: Apoptosis; EMT; Fbxw7; Gastric cancer; Proliferation; RhoA.
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