Background In epithelial cells, tyrosine kinases induce tyrosine phosphorylation and ubiquitination of the E-cadherin complex, which is responsible for the epithelial-mesenchymal transition (EMT). However, the precise mechanisms remain unclear. Methods Protein antibody microarray analysis and E3 ligase profiling were performed to detect the unique E3 ligase underlying E-cadherin downregulation in lung adenocarcinoma tissues. Gene knockdown was performed using viral shRNA. Immunoblotting, immunofluorescence, immunoprecipitation, and xenograft models in vivo were integratively applied to explore RNF43-induced EMT in lung adenocarcinoma cell lines. Results Protein antibody microarray analysis and E3 ligase profiling revealed that the RING finger protein 43 (RNF43) was linked to E-cadherin downregulation within the context of c-Src activation in lung adenocarcinoma tissues. In addition, the c-Src-Caspase-8 interaction markedly increased c-Src activity. Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation, thus allowing the nuclear translocation of β-catenin and upregulation of Vimentin and RNF43 expression in lung adenocarcinoma cells. Decreased E-cadherin expression and increased Vimentin expression induced the EMT phenotype and promoted tumor metastasis. The Frizzled 8 (Frz8)-RNF43-induced ubiquitination of phosphorylated E-cadherin was blocked by a monoclonal antibody against the cysteine-rich domain (CRD) of Frz8 but not by antibodies against the protease domain (PA) of RNF43. Conclusions Our data suggest that RNF43 participates in the regulation of EMT in the metastasis of lung adenocarcinoma through the ubiquitination and degradation of phosphorylated E-cadherin by activated c-Src. Electronic supplementary material The online version of this article (10.1186/s12885-019-5880-1) contains supplementary material, which is available to authorized users.

Sphingosine kinase1 (SphK1) is an oncogenic enzyme that regulates tumor cell apoptosis, proliferation and survival. SphK1 has been reported to promote the development of non-small cell lung cancer (NScLc), although the underlying mechanism remains to be determined. The aim of the present study was to examine the expression and function of SphK1 in NScLc and to explore the underlying molecular mechanism. The results of the present study demonstrated that SphK1 expression was upregulated in NScLc tissues and cell lines. Overexpression of SphK1 increased the proliferation and migration of NScLc cells. Additionally, overexpression of SphK1 induced expression of antiapoptotic and migration-associated genes, such as Bcl-2, matrix metallopeptidase 2 and cyclin d1. Of note, signal transducer and activator of transcription 3 (STAT3) was also activated in the SphK1-overexpressing cells. By treatment with a STAT3 inhibitor, it was demonstrated that the SphK1-induced changes in expression of target genes, as well as the increase in proliferation and migration of NScLc cells were mediated by STAT3. In conclusion, the effects of SphK1 overexpression on the development of NScLc were demonstrated to be mediated by the activation of STAT3. These results suggested that inhibition of the SphK1-STAT3 axis may be a potential strategy for the treatment of NScLc.

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DEAD (Asp-Glu-Ala-Asp) box protein 5 (DDX5), a prototypical member of the DEAD/H-box protein family, has been involved in several human malignancies. However, the expression and biological role of DDX5 in esophageal cancer (EC) remain largely unknown. In this study, we examined the role of DDX5 in regulating EC cell proliferation and tumorigenesis and explored its possible molecular mechanism. We found that DDX5 was overexpressed in human EC cell lines. In addition, knockdown of DDX5 significantly inhibited the proliferation of EC cells in vitro and the growth of EC xenografts in vivo. Knockdown of DDX5 also suppressed the migration/invasion and epithelial-to-mesenchymal transition (EMT) phenotype in EC cells. Furthermore, we observed that knockdown of DDX5 inhibited the expression of β-catenin, c-Myc, and cyclin D1 in EC cells. In conclusion, our findings provide the first evidence that siRNA-DDX5 inhibited the proliferation and invasion of EC cells through suppressing the Wnt/β-catenin signaling pathway. Therefore, DDX5 may be a novel potential therapeutic target for the prevention and treatment of EC.