title: VEGF promotes gastric cancer development by upregulating CRMP4.
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.
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Sile
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Ertao
authors.initials: E
authors.lastname: Zhai
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Chuangqi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Shirong
authors.initials: S
authors.lastname: Cai
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C102926:DPYSL3 protein, human; D009124:Muscle Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: ERK/AKT pathway; angiogenesis; gastric cancer; immunohistochemistry