Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers.
OBJECTIVE
To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor 1 (FGFR1) and ephrin ligands.


METHODS
Eleven gastric carcinoma cell lines, 24 paired surgical fresh specimens of gastric adenocarcinoma and adjacent nontumor tissue, 74 conventional formalin-fixed, paraffin-embedded tumor specimens, and 55 specimens spotted on tissue microarray (TMA) were analyzed. Reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assays were performed.


RESULTS
Overexpression of EphA4 mRNA expression was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Overexpression of EphA4, analyzed by immunohistochemistry, was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression, at the protein level, was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth.


CONCLUSIONS
Our results suggest that overexpression of EphA4 plays a role in gastric cancer.
First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8543, Japan.
Mariko
M
Oki
Hiroyuki
H
Yamamoto
Hiroaki
H
Taniguchi
Yasushi
Y
Adachi
Kohzoh
K
Imai
Yasuhisa
Y
Shinomura
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D036342:Ephrins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D015854:Up-Regulation
D036342:Ephrins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C496348:FGFR1 protein, human; D036122:Receptor, EphA4; D051496:Receptor, Fibroblast Growth Factor, Type 1