TIPE3 promotes non-small cell lung cancer progression via the protein kinase B/extracellular signal-regulated kinase 1/2-glycogen synthase kinase 3β-β-catenin/Snail axis.
TIPE3 promotes non-small cell lung cancer progression via the protein kinase B/extracellular signal-regulated kinase 1/2-glycogen synthase kinase 3β-β-catenin/Snail axis.
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TIPE3 通过蛋白激酶 B/细胞外信号调节激酶 1/2-糖原合酶激酶 3β-β-连环蛋白/Snail 轴促进非小细胞肺癌进展
DOI：
10.21037/tlcr-21-147
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发表时间：
2021-03
影响因子：
4
通讯作者：
Xu C
中科院分区：
文献类型：
--
作者：
Li Q;Yu D;Yu Z;Gao Q;Chen R;Zhou L;Wang R;Li Y;Qian Y;Zhao J;Rosell R;Tao M;Xie Y;Xu C
肿瘤坏死因子-α诱导的蛋白8样3（TNFAIP 8L 3，也称为TIPE 3）已被证明激活PI 3 K-AKT和MEK-ERK通路。然而，TIPE 3在肺癌进展中的作用在很大程度上是未知的。采用免疫组化和Western blotting方法分析TIPE 3在肺癌临床组织和细胞中的表达。分别通过转移TIPE 3编码序列和shRNA建立TIPE 3过表达和敲低NSCLC细胞系。进行体外功能测定以评估TIPE 3对NSCLC细胞增殖和转移的影响。使用肿瘤异种移植小鼠模型来检查TIPE 3在NSCLC细胞体内生长中的作用。采用Western blotting、免疫荧光和免疫组织化学方法检测TIPE 3与AKT/ERK 1/2-GSK 3 β-β-catenin/Snail通路相关分子的相关性。采用PI 3 K、MEK或GSK 3 β激酶和蛋白酶体抑制试验以及β-Trcp和STUB 1 siRNA试验来确定AKT/ERK 1/2-GSK 3 β信号传导和泛素-蛋白酶体途径对TIPE 3对β-catenin、Snail 1和Slug表达的调节作用的贡献。我们证明TIPE 3在肺癌组织和细胞中升高。TIPE 3的表达水平与肺癌患者的恶性临床病理特征如肿瘤大小、病理分期、淋巴结转移呈正相关。TIPE 3的敲低抑制NSCLC细胞的增殖和生长以及它们的迁移和侵袭能力，而TIPE 3的过表达促进这些生物学过程。机制数据显示，TIPE 3促进AKT和ERK 1/2信号传导，失活GSK 3 β活性，并增强β-catenin、Snail 1和Slug在NSCLC细胞中的表达和转录活性。激酶或蛋白酶体抑制和β-Trcp或STUB 1敲低测定进一步揭示TIPE 3以泛素-蛋白酶体依赖性方式通过AKT/ERK 1/2-GSK 3 β途径上调β-连环蛋白、Snail 1和Slug。更重要的是，临床数据表明TIPE 3的表达水平与肺癌中AKT/ERK 1/2-GSK 3 β-β-catenin/Snail通路的激活呈正相关。我们的研究结果表明，TIPE 3的上调通过AKT/ERK 1/2-GSK 3 β轴激活β-catenin、Snail 1和Slug转录信号而显著促进人类NSCLC的进展。因此，TIPE 3可能代表NSCLC的潜在治疗靶点。
Tumor necrosis factor-α-induced protein 8-like 3 (TNFAIP8L3, also called TIPE3) has been shown to activate PI3K-AKT and MEK-ERK pathways. However, the roles of TIPE3 in progression of lung cancer are largely unknown. Immunohistochemistry and western blotting were carried out to analyze the expression of TIPE3 in lung cancer clinical tissues and cells. TIPE3-overexpressing and knock-down NSCLC cell lines were established by transfer of TIPE3 coding sequence and shRNA, respectively. In vitro functional assays were performed to assess the effects of TIPE3 on proliferation and metastasis of NSCLC cells. Tumor xenograft mouse model was used to examine the roles of TIPE3 in growth of NSCLC cells in vivo. Western blotting, immunofluorescence, and immunohistochemistry were conducted to evaluate the association of TIPE3 and molecules related to AKT/ERK1/2-GSK3β-β-catenin/Snail pathway. PI3K, MEK, or GSK3β kinase and proteasome inhibition assays as well as β-Trcp and STUB1 siRNA assays were employed to determine the contribution of AKT/ERK1/2-GSK3β signaling and ubiquitin-proteasome pathway to the regulatory effects of TIPE3 on expression of β-catenin, Snail1, and Slug. We demonstrated that TIPE3 was elevated in lung cancer tissues and cells. The expression level of TIPE3 was positively correlated with malignant clinicopathological characteristics of lung cancer patients, such as tumor size, pathologic stage, and lymph node metastasis. Knockdown of TIPE3 suppressed the proliferation and growth of NSCLC cells as well as their migration and invasion ability, whereas TIPE3 overexpression facilitated these biological processes. Mechanistic data showed that TIPE3 promoted AKT and ERK1/2 signaling, inactivated GSK3β activity, and enhanced the expression and transcriptional activity of β-catenin, Snail1, and Slug in NSCLC cells. Kinase or proteasome inhibition and β-Trcp or STUB1 knockdown assays further revealed that TIPE3 upregulated β-catenin, Snail1, and Slug via the AKT/ERK1/2-GSK3β pathway, in an ubiquitin-proteasome-dependent manner. More importantly, clinical data demonstrated that the expression level of TIPE3 was positively associated with the activation of AKT/ERK1/2-GSK3β-β-catenin/Snail pathway in lung cancer. Our findings indicate that upregulation of TIPE3 promotes the progression of human NSCLC considerably by activating β-catenin, Snail1, and Slug transcriptional signaling via the AKT/ERK1/2-GSK3β axis. Therefore, TIPE3 may represent a potential therapeutic target for NSCLC.