SYNJ2BP promotes the degradation of PTEN through the lysosome-pathway and enhances breast tumor metastasis via PI3K/AKT/SNAI1 signaling
SYNJ2BP promotes the degradation of PTEN through the lysosome-pathway and enhances breast tumor metastasis via PI3K/AKT/SNAI1 signaling
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SYNJ2BP 通过溶酶体途径促进 PTEN 降解，并通过 PI3K/AKT/SNAI1 信号增强乳腺肿瘤转移
DOI：
10.18632/oncotarget.21058
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发表时间：
2017-10-27
期刊：
影响因子：
--
通讯作者：
Chen, Huan
中科院分区：
文献类型：
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作者：
Wang, Miao;Wu, Huijian;Chen, Huan
SYNJ2BP在乳腺癌转移中发挥重要作用。然而，与 SYNJ2BP 在转移中的功能相关的分子机制仍不清楚。在本研究中，我们研究了SYNJ2BP在肿瘤转移中的作用并建立了相关的潜在机制。 SYNJ2BP 的过度表达促进细胞迁移和侵袭。相反，沉默 SYNJ2BP 会抑制细胞迁移和侵袭。 SYNJ2BP 增加了 AKT 和 GSK3β 的磷酸化水平（可被 PI3K 抑制剂 LY294002 和 GSK3β 抑制剂 LiCl 抑制），并调节 SNAI1 在细胞核中的积累以及 SNAI1 靶基因 E-cadherin（EMT 标记）的表达。已知PTEN的稳定性受泛素化调节。然而，在这项研究中，我们还证明SYNJ2BP通过溶酶体途径介导PTEN蛋白的降解，并通过促进PTEN与自噬溶酶体的共定位以及LC3-II和p62的表达来诱导PI3K/AKT信号的激活。体内研究发现，SYNJ2BP的过表达显着增加了BALB/c小鼠中4T1细胞的转移。此外，SYNJ2BP 在乳腺癌中高表达（p = 0.0031），但在正常乳腺组织中不表达，而对 SNAI1 阳性人类乳腺癌组织样本的分析显示，SYNJ2BP 的表达与 p-AKT 的表达之间存在显着相关性（p < 0.005）。总的来说，我们的数据确定了一种肿瘤诱导剂SYNJ2BP，它可以通过溶酶体介导的PTEN降解激活PI3K/AKT/GSK3β/SNAI1信号通路，并在乳腺癌进展过程中促进EMT和肿瘤转移。
SYNJ2BP plays an important role in breast cancer metastasis. However, the molecular mechanism associated with the function of SYNJ2BP in metastasis remains unclear. In this study, we investigated the role of SYNJ2BP in tumor metastasis and established the associated underlying mechanism. Over-expression of SYNJ2BP promoted both cell migration and invasion. In contrast, silencing SYNJ2BP caused the suppression of cell migration and invasion. SYNJ2BP increased the levels of phosphorylation for AKT and GSK3β, which could be inhibited by the PI3K inhibitor, LY294002, and the GSK3β inhibitor, LiCl, and regulated the accumulation of SNAI1 in the nucleus and the expression of the SNAI1 target gene, E-cadherin (EMT marker). It is known that the stability of PTEN is regulated by ubiquitination. However, in this study, we additionally demonstrated that SYNJ2BP mediated the degradation of PTEN protein by the lysosome-pathway and induced the activation of PI3K/AKT signaling by promoting the co-localization of PTEN with autophagy-lysosomes and the expression of LC3-II and p62. In vivo study, the overexpression of SYNJ2BP significantly increased the metastasis of 4T1 cells in BALB/c mice. In addition, SYNJ2BP was highly expressed in breast carcinoma (p = 0.0031), but not in normal breast tissue, while analysis of tissue samples taken from SNAI1-positive human breast cancers showed a significant correlation between the expression of SYNJ2BP and that of p-AKT (p < 0.005). Collectively, our data identified a tumor inducer, SYNJ2BP, which could activate the PI3K/AKT/GSK3β/SNAI1 signaling pathway through the lysosome-mediated degradation of PTEN, and promote both EMT and tumor metastasis during the progression of breast cancer.