Adenovirus-mediated TIPE2 overexpression inhibits gastric cancer metastasis via reversal of epithelial-mesenchymal transition
Adenovirus-mediated TIPE2 overexpression inhibits gastric cancer metastasis via reversal of epithelial-mesenchymal transition
复制标题
腺病毒介导的TIPE2过表达通过逆转上皮间质转化抑制胃癌转移
DOI：
10.1038/cgt.2017.3
复制
发表时间：
2017-04-01
影响因子：
6.4
通讯作者：
Xie, Y.
中科院分区：
文献类型：
--
作者：
Yin, H.;Huang, X.;Xie, Y.
肿瘤坏死因子-α诱导蛋白8样蛋白2(TNFAIP8L2，又称TIPE2)参与了免疫负性调节和肿瘤的发生。我们先前发现TIPE2在人胃癌中缺失，而TIPE2的修复通过诱导细胞凋亡、蛋白激酶B(PKB/AKT)和细胞外信号调节的激酶-1/2(ERK1/2)信号转导通路的损伤来抑制胃癌的生长。然而，它与胃癌上皮-间充质转化(EMT)的相关性在很大程度上是难以捉摸的。在本报告中，我们开展了腺病毒介导的人TIPE2基因转移(AdVTIPE2)在AGS和HGC-27人胃癌细胞中的功能获得研究。通过创伤愈合实验和Transwell侵袭实验分别检测AdVTIPE2对AGS和HGC-27肿瘤细胞体外迁移和侵袭的影响。我们还观察了AdVTIPE2对AGS和HGC-27肿瘤细胞体内肺转移的影响。BALB/c裸鼠皮下注射。在BALB/c裸鼠模型中，AdVTIPE2能显著抑制AGS和HGC-27肿瘤细胞的迁移、侵袭和转移能力。在机制上，AdVTIPE2明显上调AGS和HGC-27肿瘤细胞的E-钙粘素上皮标志物，下调N-钙粘附素和Vimentin间充质标志物、Snail1、Snail2/slug和ZEB1 EMT诱导转录因子(EMT-Tf)，以及含有29个基序(TRIM29)和磷酸酶再生肝3(PRL-3)的胃癌特异性转移标志物。重要的是，糖原合成酶-3β(GSK-3β)抑制剂和26S蛋白酶体抑制剂MG132的检测表明，TIPE_2可能通过抑制AKT信号通路而下调Snail1和Snail2/slug，这可能是通过抑制AKT信号而实现的。我们的研究首次证明TIPE2可能通过逆转EMT而抑制胃癌细胞的迁移、侵袭和转移，提示TIPE2可能成为治疗人胃癌EMT和转移的新靶点。
Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2; also termed TIPE2) has been shown to be involved in both the immune-negative modulation and cancer. We previously found that TIPE2 is lost in human gastric cancer, and TIPE2 restoration suppresses gastric cancer growth by induction of apoptosis and impairment of protein kinase B (PKB/AKT) and extracellular signal-regulated kinase-1/2 (ERK1/2) signaling. However, its correlation with epithelial-mesenchymal transition (EMT) in gastric cancer is largely elusive. In the present report, we carried out a gain-of-function study in AGS and HGC-27 human gastric cancer cells by adenovirus-mediated human TIPE2 gene transfer (AdVTIPE2). We then examined the effects of AdVTIPE2 on in vitro migration and invasion of AGS and HGC-27 tumor cells by wound-healing assay and Transwell invasion assay, respectively. We also investigated the effects of AdVTIPE2 on in vivo lung metastasis of AGS and HGC-27 tumor cells by intravenous (i.v.) injection in athymic BALB/c nude mice. We demonstrated that AdVTIPE2 remarkably suppressed the migratory, invasive and metastatic potential of AGS and HGC-27 tumor cells in vitro and in vivo in BALB/c nude mouse model. Mechanistically, AdVTIPE2 obviously upregulated E-cadherin epithelial marker in AGS and HGC-27 tumor cells, whereas it downregulated N-cadherin and Vimentin mesenchymal markers, Snail1, Snail2/Slug and Zeb1 EMT-inducing transcription factors (EMT-TFs), and tripartite motif-containing 29 (TRIM29) and phosphatase regenerating liver 3 (PRL-3) gastric cancer-specific metastasis markers. Importantly, glycogen synthase kinase-3 beta (GSK-3 beta) inhibitor VIII and 26S proteasome inhibitor MG132 assays revealed that TIPE2 downregulated Snail1 and Snail2/Slug in a GSK-3 beta- and proteasome-dependent manner possibly by impairing AKT signaling. Our data provided the first evidence that TIPE2 inhibits gastric cancer cell migration, invasion and metastasis very probably via reversal of EMT, revealing that TIPE2 may be a novel therapeutic target for human gastric cancer EMT and metastasis.