Inhibition of gastric cancer invasion and metastasis by PLA2G2A, a novel beta-catenin/TCF target gene.
Elevated expression of the PLA2G2A phospholipase in gastric cancer (GC) is associated with improved patient survival. To elucidate function and regulation of PLA2G2A in GC, we analyzed a panel of GC cell lines. PLA2G2A was specifically expressed in lines with constitutive Wnt activity, implicating beta-catenin-dependent Wnt signaling as a major upstream regulator of PLA2G2A expression. The invasive ability of PLA2G2A-expressing AGS cells was enhanced by PLA2G2A silencing, whereas cellular migration in non-PLA2G2A-expressing N87 cells was inhibited by enforced PLA2G2A expression, indicating that PLA2G2A is both necessary and sufficient to function as an inhibitor of GC invasion in vitro. We provide evidence that antiinvasive effect of PLA2G2A occurs, at least in part, through its ability to inhibit the S100A4 metastasis mediator gene. Consistent with its invasion inhibitor role, PLA2G2A expression was elevated in primary gastric, colon, and prostrate early-stage tumors, but was decreased in metastatic and late-stage tumors. There was a strong association between PLA2G2A promoter methylation status and PLA2G2A expression, suggesting that the loss of PLA2G2A expression in late-stage cancers may be due to epigenetic silencing. Supporting this, among the non-PLA2G2A-expressing lines, pharmacologic inhibition of epigenetic silencing reactivated PLA2G2A in Wnt-active lines, but in non-Wnt-active lines, a combination of Wnt hyperactivation and inhibition of epigenetic silencing were both required for PLA2G2A reactivation. Our results highlight the complexity of PLA2G2A regulation and provide functional evidence for PLA2G2A as an important regulator of invasion and metastasis in GC.
Cellular and Molecular Research, National Cancer Center, Genome Institute of Singapore, Singapore, Singapore.
Kumaresan
K
Ganesan
Tatiana
T
Ivanova
Yonghui
Y
Wu
Vikneswari
V
Rajasegaran
Jeanie
J
Wu
Ming Hui
MH
Lee
Kun
K
Yu
Sun Young
SY
Rha
Hyun Cheol
HC
Chung
Bauke
B
Ylstra
Gerrit
G
Meijer
Kon Oi
KO
Lian
Heike
H
Grabsch
Patrick
P
Tan
D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D054501:Group II Phospholipases A2 / Q000235:genetics*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D051820:TCF Transcription Factors / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics*
D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human