Loss of the 14-3-3σ is essential for LASP1-mediated colorectal cancer progression via activating PI3K/AKT signaling pathway.
Loss of the 14-3-3σ is essential for LASP1-mediated colorectal cancer progression via activating PI3K/AKT signaling pathway.
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14-3-3sigma 的缺失对于 LASP1 通过激活 PI3K/AKT 信号通路介导的结直肠癌进展至关重要。
DOI：
10.1038/srep25631
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发表时间：
2016-05-09
影响因子：
4.6
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Shao Z;Cai Y;Xu L;Yao X;Shi J;Zhang F;Luo Y;Zheng K;Liu J;Deng F;Li R;Zhang L;Wang H;Li M;Ding Y;Zhao L
LIM和SH3蛋白1 （LASP1）可促进结直肠癌（CRC）的进展和转移，但阐明其分子机制的直接证据尚不清楚。在此，我们的蛋白质组学数据显示LASP1与14-3-3σ相互作用并降低14-3-3σ在CRC中的表达。lasp1介导的结直肠癌细胞侵袭性需要缺失14-3-3σ。体外功能增益和功能损失实验表明，14-3-3σ抑制CRC细胞的细胞迁移能力，降低AKT的磷酸化水平。我们进一步观察到AKT与14-3-3σ在结直肠癌细胞中的共定位。PI3K抑制剂LY294002可显著抑制AKT磷酸化，从而抑制14-3-3σ siRNA介导的侵袭性表型。临床上，14-3-3σ在结直肠癌组织中经常下调。14-3-3σ的下调与结直肠癌患者的肿瘤进展和不良预后有关。多因素分析证实14-3-3σ低表达是结直肠癌的独立预后因素。低14-3-3σ和高LASP1表达的组合对结直肠癌患者的总生存率有不利的影响。我们的研究为进一步研究LASP1-14-3-3σ轴作为晚期结直肠癌新型抗癌治疗靶点铺平了道路。
LIM and SH3 protein 1 (LASP1) can promote colorectal cancer (CRC) progression and metastasis, but the direct evidence that elucidates the molecular mechanism remains unclear. Here, our proteomic data showed that LASP1 interacted with 14-3-3σ and decreased the expression of 14-3-3σ in CRC. Deletion of 14-3-3σ was required for LASP1-mediated CRC cell aggressiveness. In vitro gain- and loss-of-function assays showed that 14-3-3σ suppressed the ability of cell migration and decreased the phosphorylation of AKT in CRC cells. We further observed clearly co-localization between AKT and 14-3-3σ in CRC cells. Treatment of PI3K inhibitor LY294002 markedly prevented phosphorylation of AKT and subsequently counteract aggressive phenotype mediated by siRNA of 14-3-3σ. Clinically, 14-3-3σ is frequently down-regulated in CRC tissues. Down-regulation of 14-3-3σ is associated with tumor progression and poor prognosis of patients with CRC. Multivariate analysis confirmed low expression of 14-3-3σ as an independent prognostic factor for CRC. A combination of low 14-3-3σ and high LASP1 expression shows a worse trend with overall survival of CRC patients. Our research paves the path to future investigation of the LASP1-14-3-3σ axis as a target for novel anticancer therapies of advanced CRC.