Inhibition of gastric cancer invasion and metastasis by PLA2G2A, a novel β-catenin/TCF target gene
Inhibition of gastric cancer invasion and metastasis by PLA2G2A, a novel β-catenin/TCF target gene
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DOI：
10.1158/0008-5472.can-07-6517
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Ganesan, Kumaresan;Ivanova, Tatiana;Tan, Patrick
PLA 2G 2A磷脂酶在胃癌（GC）中的表达升高与患者生存期改善相关。为了阐明PLA 2G 2A在GC中的功能和调节，我们分析了一组GC细胞系。PLA 2G 2A在具有组成性Wnt活性的品系中特异性表达，暗示β-连环蛋白依赖性Wnt信号传导是PLA 2G 2A表达的主要上游调节因子。表达PLA 2G 2A的AGS细胞的侵袭能力通过PLA 2G 2A沉默而增强，而在不表达PLA 2G 2A的N87细胞中的细胞迁移通过强制PLA 2G 2A表达而被抑制，这表明PLA 2G 2A在体外作为GC侵袭的抑制剂起作用是必要的且足够的。我们提供的证据表明PLA 2G 2A的抗侵袭作用至少部分是通过其抑制S100 A4转移介导基因的能力而发生的。与其侵袭抑制剂作用一致，PLA 2G 2A表达在原发性胃、结肠和前列腺早期肿瘤中升高，但在转移性和晚期肿瘤中降低。PLA 2G 2A启动子甲基化状态与PLA 2G 2A表达之间存在强相关性，表明晚期癌症中PLA 2G 2A表达的丧失可能是由于表观遗传沉默。支持这一点的是，在非PLA 2G 2A表达系中，表观遗传沉默的药理学抑制在Wnt活性系中重新激活了PLA 2G 2A，但在非Wnt活性系中，PLA 2G 2A重新激活需要Wnt超活化和表观遗传沉默抑制的组合。我们的研究结果突出了MAMA调节的复杂性，并为PLA 2G 2A作为胃癌侵袭和转移的重要调节因子提供了功能证据。
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 MAMA regulation and provide functional evidence for PLA2G2A as an important regulator of invasion and metastasis in GC.