Growth-arrest-specific 7C protein inhibits tumor metastasis via the N-WASP/FAK/F-actin and hnRNP U/β-TrCP/β-catenin pathways in lung cancer.
Growth-arrest-specific 7C protein inhibits tumor metastasis via the N-WASP/FAK/F-actin and hnRNP U/β-TrCP/β-catenin pathways in lung cancer.
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DOI：
10.18632/oncotarget.6229
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发表时间：
2015-12-29
期刊：
影响因子：
--
通讯作者：
Wang YC
中科院分区：
文献类型：
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作者：
Tseng RC;Chang JW;Mao JS;Tsai CD;Wu PC;Lin CJ;Lu YL;Liao SY;Cheng HC;Hsu HS;Wang YC
生长停滞特异性蛋白7（GAS 7）属于一组与肌动蛋白细胞骨架协调的衔接蛋白。在人GAS 7同种型中，只有GAS 7 C具有Src同源3结构域。我们在这里报告，GAS 7 C作为一个迁移抑制剂，可以作为肺癌的预后生物标志物。GAS 7 C过表达减少肺癌迁移，而GAS 7 C敲低增强癌细胞迁移。重要的是，异位过表达的GAS 7 C与N-WASP紧密结合，从而使纤连蛋白/整联蛋白/FAK途径失活，这反过来导致F-肌动蛋白动力学的抑制。此外，GAS 7 C的过表达螯合hnRNP U，从而通过β-TrCP泛素降解途径降低β-连环蛋白的水平。使用肺癌异种移植物也证实了GAS 7 C过表达的抗转移作用。我们的临床资料显示，23.6%（25/106）的肺癌患者表现出GAS 7 C mRNA的低表达，这与较差的总生存率相关。此外，在60.0%的转移性肺癌患者中检测到低GAS 7 C mRNA表达，表明低GAS 7 C表达与癌症进展之间存在关联。mRNA表达与启动子甲基化呈负相关，提示GAS 7 C基因低表达可能与启动子甲基化有关。我们的研究结果提供了新的证据表明，低GAS 7 C与预后不良，促进肺癌转移。低GAS 7 C通过促进N-WASP/FAK/F-actin细胞骨架动力学增加癌细胞运动性。它还通过hnRNP U/β-TrCP复合物的形成增强β-连环蛋白的稳定性。因此，GAS 7 C在肺癌中起转移抑制剂的作用。
Growth-arrest-specific 7 (GAS7) belongs to a group of adaptor proteins that coordinate the actin cytoskeleton. Among human GAS7 isoforms, only GAS7C possesses a Src homology 3 domain. We report here that GAS7C acts as a migration suppressor and can serve as a prognostic biomarker in lung cancer. GAS7C overexpression reduces lung cancer migration, whereas GAS7C knockdown enhances cancer cell migration. Importantly, ectopically overexpressed GAS7C binds tightly with N-WASP thus inactivates the fibronectin/integrin/FAK pathway, which in turn leads to the suppression of F-actin dynamics. In addition, overexpression of GAS7C sequesters hnRNP U and thus decreases the level of β-catenin protein via the β-TrCP ubiquitin-degradation pathway. The anti-metastatic effect of GAS7C overexpression was also confirmed using lung cancer xenografts. Our clinical data indicated that 23.6% (25/106) of lung cancer patients showed low expression of GAS7C mRNA which correlated with a poorer overall survival. In addition, low GAS7C mRNA expression was detected in 60.0% of metastatic lung cancer patients, indicating an association between low GAS7C expression and cancer progression. A significant inverse correlation between mRNA expression and promoter hypermethylation was also found, which suggests that the low level of GAS7C expression was partly due to promoter hypermethylation. Our results provide novel evidence that low GAS7C correlates with poor prognosis and promotes metastasis in lung cancer. Low GAS7C increases cancer cell motility by promoting N-WASP/FAK/F-actin cytoskeleton dynamics. It also enhances β-catenin stability via hnRNP U/β-TrCP complex formation. Therefore, GAS7C acts as a metastasis suppressor in lung cancer.