WNT signaling and distant metastasis in colon cancer through transcriptional activity of nuclear β-Catenin depend on active PI3K signaling.
WNT signaling and distant metastasis in colon cancer through transcriptional activity of nuclear β-Catenin depend on active PI3K signaling.
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DOI：
10.18632/oncotarget.1626
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发表时间：
2014-05-30
期刊：
影响因子：
--
通讯作者：
Jung A
中科院分区：
文献类型：
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作者：
Ormanns S;Neumann J;Horst D;Kirchner T;Jung A
我们确定了活性PI 3 K信号传导与β-连环蛋白的核积累是否是完全激活经典WNT信号传导所必需的，并检查了两种信号传导途径与结肠癌进展的相关性。使用报告基因测定，我们检查了在有或没有β-连环蛋白核积聚的情况下PI 3 K抑制后β-连环蛋白介导的转录的激活。异位诱导以及组成性激活的WNT信号传导严格需要PI 3 K活性，而PI 3 K抑制对β-连环蛋白亚细胞定位没有影响，但损害β-连环蛋白与WNT靶基因启动子的结合并降低WNT靶基因表达。核β-连环蛋白的转录活性依赖于活性PI 3 K信号传导，因为在PI 3 K抑制后，β-连环蛋白的核积累不能诱导WNT报告基因转录。β-连环蛋白的PI 3 K依赖性转录反式激活依赖于AKT靶位点丝氨酸552处磷酸化以外的事件，因为S552 D-磷酸模拟β-连环蛋白突变体在抑制PI 3 K时不能恢复WNT信号传导。为了研究PI 3 K途径活化（活化PIK 3CA突变或PTEN表达的丧失）和核β-连环蛋白表达的预后价值，在55对匹配的具有或不具有远处转移的原发性右侧结肠癌病例中测定两个变量。PIK 3CA基因的激活突变或PTEN表达的缺失与远处转移无关，而核β-连环蛋白的高表达结合PI 3 K通路的激活鉴定了发生远处转移的病例。PI 3 K途径的激活与细胞核β-连环蛋白表达无关。我们的结论是，核β-连环蛋白的转录活性依赖于PI 3 K活性。然而，PI 3 K本身并不影响β-连环蛋白的亚细胞定位。这两种因子协同作用以实现完整的WNT信号传导活性，并与结肠癌的远处转移相关。因此，高核β-连环蛋白表达和同时PI 3 K通路活化的检测鉴定了具有远处转移高风险的结肠癌患者。
We determined whether active PI3K signaling together with nuclear accumulation of β-Catenin is necessary to fully activate canonical WNT signaling and examined the association of both signaling pathways with colon cancer progression. Using reporter gene assays we examined the activation of β-Catenin mediated transcription upon PI3K inhibition with or without β-Catenin nuclear accumulation. Ectopically induced as well as constitutively active WNT signaling strictly required PI3K activity whereas PI3K inhibition had no effect on β-Catenin subcellular localization but impaired β-Catenin binding to WNT target gene promoters and decreased WNT target gene expression. Transcriptional activity of nuclear β-Catenin depended on active PI3K signaling as nuclear accumulation of β-Catenin failed to induce WNT reporter gene transcription upon PI3K inhibition. PI3K dependend transcriptional transactivation of β-Catenin relies on events beyond phosphorylation at the AKT target site serine 552, as S552D-phosphomimetic β-Catenin mutants were unable to restore WNT signaling when inhibiting PI3K. To study the prognostic value of PI3K pathway activation (activating PIK3CA mutations or loss of PTEN expression) and nuclear β-Catenin expression, both variables were determined in 55 matched pairs of primary right sided colon cancer cases with or without distant metastasis. Activating mutations in the PIK3CA gene or loss of PTEN expression did not correlate with distant metastasis while high nuclear β-Catenin expression combined with activation of the PI3K pathway identified cases in which distant metastasis had occurred. Activation of the PI3K pathway was not associated with nuclear β-Catenin expression. We conclude that the transcriptional activity of nuclear β-Catenin depends on PI3K activity. However, PI3K on its own does not affect β-Catenin subcellular localization. Both factors synergize for full WNT signaling activity and are associated with distant metastasis in colon cancer. Thus, the detection of high nuclear β-Catenin expression and simultaneous PI3K pathway activation identifies colon cancer patients with a high risk for distant metastasis.