Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC.
Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC.
复制标题
蛋白 4.1N 在 NSCLC 中充当潜在的肿瘤抑制因子，将 PP1 与 JNK-c-Jun 通路调节联系起来。
DOI：
10.18632/oncotarget.6312
复制
发表时间：
2016-01-05
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Wang Z;Ma B;Li H;Xiao X;Zhou W;Liu F;Zhang B;Zhu M;Yang Q;Zeng Y;Sun Y;Sun S;Wang Y;Zhang Y;Weng H;Chen L;Ye M;An X;Liu J
蛋白4.1N是蛋白4.1家族的一员，在实体瘤中被认为是一种潜在的肿瘤抑制因子。本研究旨在探讨4.1N在非小细胞肺癌（NSCLC）中的作用及其机制。我们证实4.1N的表达水平与NSCLC细胞系的转移特性和临床NSCLC组织的组织学分级呈负相关。特异性敲除4.1N促进体外肿瘤细胞增殖、迁移和粘附，以及小鼠异种移植模型中的肿瘤生长和转移。此外，我们还发现PP1是一个新的与4.1N相互作用的分子，并且4.1N的FERM结构域介导了PP1与4.1N的相互作用。此外，4.1N的异位表达可通过增强PP1活性及PP1与p-JNK的相互作用阻断JNK-c-Jun信号通路。相应地，JNK-c-Jun通路的潜在下游转移靶点（ezrin和MMP 9）和细胞周期靶点（p53、p21和p19）的表达也受到4.1N的调节。我们的数据表明，下调4.1N表达是NSCLC发展的关键步骤，通过PP1抑制JNK-c-Jun信号传导是4.1N的关键抗肿瘤机制之一。
Protein 4.1N is a member of protein 4.1 family and has been recognized as a potential tumor suppressor in solid tumors. Here, we aimed to investigate the role and mechanisms of 4.1N in non-small cell lung cancer (NSCLC). We confirmed that the expression level of 4.1N was inversely correlated with the metastatic properties of NSCLC cell lines and histological grade of clinical NSCLC tissues. Specific knockdown of 4.1N promoted tumor cell proliferation, migration and adhesion in vitro, and tumor growth and metastasis in mouse xenograft models. Furthermore, we identified PP1 as a novel 4.1N-interacting molecule, and the FERM domain of 4.1N mediated the interaction between 4.1N and PP1. Further, ectopic expression of 4.1N could inactivate JNK-c-Jun signaling pathway through enhancing PP1 activity and interaction between PP1 and p-JNK. Correspondingly, expression of potential downstream metastasis targets (ezrin and MMP9) and cell cycle targets (p53, p21 and p19) of JNK-c-Jun pathway were also regulated by 4.1N. Our data suggest that down-regulation of 4.1N expression is a critical step for NSCLC development and that repression of JNK-c-Jun signaling through PP1 is one of the key anti-tumor mechanisms of 4.1N.