Src promotes EGF-induced epithelial-to-mesenchymal transition and migration in gastric cancer cells by upregulating ZEB1 and ZEB2 through AKT.

Epithelial-to-mesenchymal transition (EMT) plays important roles in the migration, invasion, and metastasis of cancer cells. However, the role of Src in epidermal growth factor (EGF)-induced EMT and migration in gastric cancer cells remains to be clarified. In the current study, the effect of Src on EGF-stimulated EMT and migration was explored in gastric cancer cells. EGF induced EMT in gastric cancer cells and increased their migratory ability, which was accompanied by the phosphorylation of Src. PP2, the Src inhibitor, markedly suppressed EGF-mediated EMT and migration in gastric cancer cells. Additionally, EGF-stimulated upregulation of zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger E-box binding homeobox 2 (ZEB2) was significantly repressed by PP2. Further analysis showed that EGF-stimulated phosphorylation of protein kinase B (AKT) was almost completely abolished by PP2, whereas that of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3) was only mildly suppressed. Moreover, LY294002, the AKT inhibitor, significantly inhibited EGF-induced upregulation of ZEB1 and ZEB2 as well as EMT and migration stimulated by EGF in gastric cancer cells. However, neither ERK inhibitor nor STAT3 inhibitor repressed EGF-induced EMT-related changes. Taken together, these results suggest that Src promotes EGF-stimulated EMT and migration by upregulation of ZEB1 and ZEB2 through AKT signaling pathway in gastric cancer cells.

Zhao L ，Li X ，Song N ，Li A ，Hou K ，Qu X ，Che X ，Liu Y ... -  《-》

Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells.

Li H ，Xu L ，Li C ，Zhao L ，Ma Y ，Zheng H ，Li Z ，Zhang Y ，Wang R ，Liu Y ，Qu X ... -  《Molecular Cancer》

Neogenin-1 Promotes Cell Proliferation, Motility, and Adhesion by Up-Regulation of Zinc Finger E-Box Binding Homeobox 1 Via Activating the Rac1/PI3K/AKT Pathway in Gastric Cancer Cells.

Neogenin-1 (Neo1) has been reported to be involved in diverse physiology and pathology functions, including cell proliferation, differentiation and migration. The present study aimed to explore the functional role of neogenin-1 (Neo1) in gastric cancer (GC), together with underlying mechanisms. Neo1 expression was analyzed by qRT-PCR and Western blot analysis in both human GC cell lines and normal gastric epithelial cell line. Neo1 was respectively overexpressed or silenced by transfection with pcDNA3.1 or siRNA, and then the cells were incubated with or without different concentrations of cisplatin, transforming growth factor (TGF)-β1, and/or inhibitors of Rac-1 and PI3K. Thereafter, cell viability, invasion, and adhesion were measured by CCK-8, wound healing and adhesion assays, respectively. The expression levels of key factors involved in epithelial mesenchymal transition (EMT) and the PI3K/AKT pathway were analyzed by Western blot analysis. The results showed that the Neo1 level was significantly increased in GC cell lines, with the highest level in SGC-7901 cells. Overexpression of Neo1 significantly reduced the GC cell sensitivity to cisplatin and increased the cell viability, motility and adhesion ability, and while silencing of Neo1 showed contrary results. Moreover, overexpression of Neo1 dramatically downregulated the E-Cadherin level and upregulated the levels of N-Cadherin and Vimentin. In addition, the data revealed that Neo1 positively regulated the expression of Zinc finger E-box-binding homeobox 1 (ZEB1) by activating the Rac1/PI3K/AKT pathway. Neo1 could promote cell proliferation, motility, and adhesion by up-regulation of ZEB1 via activating the Rac1/PI3K/AKT pathway in GC cells.

Qu H ，Sun H ，Wang X 《-》

Long non-coding RNA ZEB2-AS1 promotes the proliferation, metastasis and epithelial mesenchymal transition in triple-negative breast cancer by epigenetically activating ZEB2.

The triple-negative breast cancer is the most malignant type of breast cancer. Its pathogenesis and prognosis remain poor despite the significant advances in breast cancer diagnosis and therapy. Meanwhile, long noncoding RNAs (LncRNAs) play a pivotal role in the progression of malignant tumors. In this study, we found that LncRNA-ZEB2-AS1 was dramatically up-regulated in our breast cancer specimens and cells (MDA231), especially in metastatic tumor specimens and highly invasive cells, and high lncRNA-ZEB2-AS1 expression is associated with clinicopathologic features and short survival of breast cancer patients. LncRNA-ZEB2-AS1 promotes the proliferation and metastasis of MDA231 cells in SCID mice. Thus, it is regarded as an oncogene in triple-negative breast cancer. It is mainly endo-nuclear and situated near ZEB2, positively regulating ZEB2 expression and activating the epithelial mesenchymal transition via the PI3K/Akt/GSK3β/Zeb2 signaling pathway. Meanwhile, EGF-induced F-actin polymerization in MDA231 cells can be suppressed by reducing lncRNA-ZEB2-AS1 expression. The migration and invasion of triple-negative breast cancer can be altered through cytoskeleton rearrangement. In summary, we demonstrated that lncRNA-ZEB2-AS1 is an important factor affecting the development of triple-negative breast cancer and thus a potential oncogene target.

Zhang G ，Li H ，Sun R ，Li P ，Yang Z ，Liu Y ，Wang Z ，Yang Y ，Yin C ... -  《-》

MiR-338-3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1/Met/Akt signaling.

Huang N ，Wu Z ，Lin L ，Zhou M ，Wang L ，Ma H ，Xia J ，Bin J ，Liao Y ，Liao W ... -  《Oncotarget》