Abstract
This study aimed to investigate the precise role of CRMP4 in gastric tumor growth and patient survival. The mRNA and protein expression levels of CRMP4, VEGF and VEGFR2 were validated by qRT-PCR and immunohistochemistry. We investigated the effects on tumor growth of overexpression and knockdown of CRMP4 both in vitro and in vivo by constructing stable gastric cell lines using lentiviral-mediated transduction and shRNA interference-mediated knockdown of CRMP4 expression. We further validated the role of the ERK/AKT signaling pathways in VEGF and CRMP4 expression using ERK and PI3K inhibitors. Increased expression of VEGF and CRMP4 were observed in gastric cancer tissues compared with tumor-adjacent tissue. We found that higher CRPM4 expression was associated with lymph node metastasis, TNM stage, tumor differentiation and poorer prognosis in gastric cancer patients. In HGC27 and SGC7901 gastric cancer cells, VEGF upregulated CRMP4 in time and dose-dependent manners. Overexpression of CRMP4 increased cell proliferation, migration and invasion, whereas knockdown of CRMP4 expression had opposite effects. VEGF activated CRMP4 expression in gastric cancer cells, and this effect was significantly inhibited by MAPK and PI3K inhibitors (PD98059 and LY294002). In mice, CRMP4 overexpression also resulted in increased tumor growth. These results suggest that increased CRMP4 expression mediated by the activation of VEGF signaling facilitates gastric tumor growth and metastasis, which may have clinical implications associated with a reduced survival rate in gastric cancer patients.
Highlights
Gastric cancer is the third most common malignant disease and the leading cause of high morbidity and mortality in cancer patients worldwide [1, 2]
These results suggest that increased CRMP4 expression mediated by the activation of vascular endothelial growth factor (VEGF) signaling facilitates gastric tumor growth and metastasis, which may have clinical implications associated with a reduced survival rate in gastric cancer patients
VEGF and CRMP4 proteins and mRNA expression levels are elevated in gastric cancer tissues
Summary
Gastric cancer is the third most common malignant disease and the leading cause of high morbidity and mortality in cancer patients worldwide [1, 2]. A recent report investigating the incidence of cancer and associated mortality in China showed that gastric cancer ranked second among all malignancies, with nearly 1 million cases and cancer-related deaths [3]. VEGFR2 expression is typically limited to vessel endothelial cells, and is widely considered as the main receptor driving angiogenesis [10]. VEGF and VEGF receptors, VEGF receptor 2 (VEGFR2/Flk-1), are considered to constitute the key signaling system regulating endothelial cell proliferation and migration [10, 11]. Clinical trials have shown that administration of anti-VEGF antibody combined with chemotherapy significantly prolonged the survival of colorectal cancer patients [12] and progression-free survival in gastric cancer patients [13]
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