Epidermal Growth Factor-Like Domain-Containing Protein 7 (EGFL7) Enhances EGF Receptor−AKT Signaling, Epithelial−Mesenchymal Transition, and Metastasis of Gastric Cancer Cells

Abstract

Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial–mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR−AKT−Snail signaling pathway. Disruption of EGFL7−EGFR−AKT−Snail signaling may a promising therapeutic strategy for gastric cancer.

Expression of epidermal growth factor-like domain 7 may be a predictive marker of the effect of neoadjuvant chemotherapy for locally advanced uterine cervical cancer

“…As high EGFL7 expression is associated with acquired chemoresistance, tumor cells that exhibit lower EGFL7 expression may have a greater sensitivity to NAC treatment. In addition, a correlation between EGFL7 and Snail expression levels was observed These results were concordant with a previous study that reported that EGFL7 is able to positively regulate EMT by EGFR-mediated AKT phosphorylation through the activation of Snail expression (27). The results of the current study support the hypotheses that the overexpression of EGFL7 may have a role in the development of tumor chemoresistance through EMT, and increasing resistance to cell apoptosis by activating Snail expression; therefore, EGFL7 may be an effective prognostic factor regarding the efficacy of NAC treatment for locally advanced uterine cervical cancer.…”

“…The first hypothesis was that high expression levels of EGFL7 may have a role in the development of chemoresistance due to decreased drug delivery caused by reduced vascular integrity in tumors tissues. The second hypothesis was that the promotion of EMT by EGFL7 may induce the development of tumor cell resistance to chemotherapy; EMT is regulated by EGFR-mediated AKT phosphorylation induced by EGFL7, which then activates Snail and the subsequent suppression of E-cadherin transcription (27). Numerous studies have previously reported that EMT may have a function in acquired chemoresistance (28)(29)(30)(31)(32).…”

“…Certain studies have reported that high expression levels of EGFL7 are associated with lymph node metastasis, poor prognosis and advanced disease stage in numerous types of human cancer, including colon cancer, pancreatic cancer, epithelial ovarian cancer and laryngeal squamous cell cancer (23)(24)(25)(26). Luo et al (27) reported that the expression of EGFL7 in gastric cancer cells promotes the epithelial-to-mesenchymal transition (EMT) and tumor metastasis by epidermal growth factor receptor (EGFR)-mediated protein kinase B (AKT) phosphorylation, which subsequently activates Snail and suppresses the transcription of E-cadherin. Numerous studies have demonstrated that increased EMT may lead to chemoresistance in bladder, lung, breast and ovarian cancers (28)(29)(30)(31)(32).…”

Suppression of the Epidermal Growth Factor-like Domain 7 and Inhibition of Migration and Epithelial-Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

“…Several studies have shown that EGF promotes cancer cell migration with activation of EMT (Luo et al, 2014). And EGFL7 contains two EGF-like domains in its protein organization.…”

“…In recent years, the targeting of EMTrelated pathways in human tumor cell lines and murine models revealed the crucial importance of EMT in the aggressiveness and invasion of pancreatic cancer (Kurahara et al, 2012). Luo et al reported that EGFL7 promotes tumor invasion by activating EMT through an EGFR-AKT-Snail signaling pathway in gastric cancer (Luo et al, 2014). Thus, we assumed that EGFL7 may also promote cancer invasion by inducing EMT in pancreatic cancer.…”