55294

FBXW7

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.CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: Recently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear. METHODS: The expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. RESULTS: Here, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome. CONCLUSIONS: Overall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC.

Background and Objective: FBXW7, known as a general tumor suppressor, is commonly lowly expressed in metastatic malignancies. We aim to investigate the potential influence of FBXW7 overexpression on renal cell carcinoma (RCC) metastasis. Methods: We employed quantitative real-time PCR (qRT-PCR) and Western blotting (WB) to quantify the FBXW7 expression in RCC cell lines. Upregulation of FBXW7 was performed in vitro on RCC cells using the lentivirus covering coding region FBXW7 cDNA sequence, and functional tests were performed to verify FBXW7 overexpression on migration and invasion of RCC cells. Moreover, WB was employed to determine the expressions of MMP-2, MMP-9, and MMP-13, as well as EMT markers in the transfected RCC cells. Results: FBXW7 was significantly downregulated in RCC cell lines, dominated by 786-O and ACHN, when compared to normal renal cell line HK-2. Moreover, upregulation of FBXW7 in 786-O and ACHN cell lines significantly inhibited cell migration and invasion, as well as EMT. Present study also showed that FBXW7 was involved in the migration and invasion of RCC cells via regulating the expressions of MMP-2, MMP-9, and MMP-13. Conclusion: Our findings demonstrate that upregulation of FBXW7 inhibits RCC metastasis and EMT. FBXW7 is a potential therapeutic target for RCC patients.

The E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7alpha) functions as a putative tumor suppressor in non-small cell lung cancer (NSCLC) due to its regulation of a set of oncogenic proteins associated with cell proliferation and mitosis. Increasing efforts have been focused on the understanding of FBW7 in determining cell cycle progression and apoptosis induction, however, the correlation between FBW7 and tumor metastasis is not fully understood. In this study, we reported a potential anti-metastatic effect of FBW7 in non-small cell lung cancer (NSCLC). In this model, FBW7 inhibited cancer cell metastasis primarily by inducing ubiquitination and proteolysis of the transcriptional factor Snail, which suppressed E-cadherin cell tight junction protein expression. Loss of FBW7 would stabilize the Snail protein, thus, inhibit E-cadherin expression and promote metastasis in vitro and in vivo. Moreover, Snail ubiquitination and degradation were also achieved by pharmacological approach, in which the FBW7 agonist oridonin treatment led to Snail proteolysis. Furthermore, FBW7 silencing stabilized Snail protein and induced epithelial-to mesenchymal transition (EMT), and acquisition of migration and invasion properties in NSCLC. Overall, our study provides new insights into the FBW7-Snail axis in regulating cell migration and invasion, and suggests that targeting FBW7 may be a potent approach to inhibit metastasis in NSCLC.CI - Copyright (c) 2018 The Author(s). Published by Elsevier B.V. All rights reserved.