Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Abstract

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 B-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.

HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

“…However, there was no significant difference in the mobility of AGS cells stably transfected with HSulf-1 and control cells. In accordance with these observations, we found that mRNA levels of metastasis-related genes, such as DKK1, MMP-2, S100A4, and S100P, (22,(28)(29)(30) were downregulated in HSulf-1 transfected MKN28 cells, but that there were no noticeable change in the expression of these genes in AGS cells (Fig. 2d).…”

“…(17) Dysregulation of the Wnt signaling pathway has been implicated in gastric carcinogenesis and metastasis. (22,23,(31)(32)(33) Therefore, in the present study, we first assessed the expression profile of Wnt pathway genes in AGS and MKN28 cells. As shown in Figure 3(a), the expression of several Wnt ligands was elevated in both cell lines (i.e.…”

“…(21) Accumulating evidence indicates a close correlation between the Wnt signaling pathway and the initiation and progression of gastric cancer. (22,23) We have recently demonstrated downregulation of HSulf-1 in human gastric cancer. (24) To further evaluate the role of HSulf-1 in the tumorigenesis and metastasis of gastric cancer, in the present study we restored HSulf-1 expression in gastric cancer cell lines that lack endogenous HSulf-1 expression and investigated its effects on the growth rate and invasiveness of the cells in vitro and in vivo.…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Cby was first identified as an interactor with b-catenin in humans, which suggested it could be a tumor suppressor gene [204] . Silencing of PLA2G2A (phospholipase A2) enhances the invasive ability of gastric cancer cells [205] . Surprisingly, PLA2G2A, which is an independent predictor of favorable outcome for patients with gastric cancer [206,207] , is also a direct Wnt target gene and it has been found upregulated in early stages of gastric cancer.…”

“…Surprisingly, PLA2G2A, which is an independent predictor of favorable outcome for patients with gastric cancer [206,207] , is also a direct Wnt target gene and it has been found upregulated in early stages of gastric cancer. Ganesan et al [205] have proposed that in late-stage tumors, Wnt signaling is still active driving expression of protooncogenes; however, PLA2G2A expression is decreased possibly by epigenetic inactivation and/or genomic deletions, resulting tumors with a highly aggressive clinical phenotype. Moreover, the overexpression of the Wnt signalling regulator sFRP1 has been correlated with activation of TGFb signalling pathway, thereby it may induce cell proliferation, EMT and invasion [130] .…”