Transglutaminase-2 induces N-cadherin expression in TGF-β1-induced epithelial mesenchymal transition via c-Jun-N-terminal kinase activation by protein phosphatase 2A down-regulation
Transglutaminase-2 induces N-cadherin expression in TGF-β1-induced epithelial mesenchymal transition via c-Jun-N-terminal kinase activation by protein phosphatase 2A down-regulation
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DOI：
10.1016/j.ejca.2012.11.036
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发表时间：
2013-05-01
影响因子：
8.4
通讯作者：
Lee, Chang Hoon
中科院分区：
文献类型：
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作者：
Park, Mi Kyung;You, Hye Jin;Lee, Chang Hoon
上皮-间质转化（EMT）是肿瘤细胞启动转移的关键事件，导致E-钙粘蛋白向N-钙粘蛋白的转换。在A549肺癌细胞或其他肺癌细胞中，在TGF-β 1诱导的EMT中，转氨酶-2（Tgase-2）表达增加。Tgase-2在TGF-β 1诱导的EMT中的作用和潜在机制尚不清楚。通过化学抑制剂、基因沉默和过表达等方法研究了TGF-β 1对A549细胞EMT的影响，发现胱胺和TGF-β 1基因沉默均能抑制TGF-β 1诱导的EMT。Tgase-2或c-Jun-N-末端激酶（JNK）抑制剂SP 600125的抑制显著降低和Tgase-2的过度表达增加了N-钙粘蛋白的表达。使用Tgase-2过表达的A549细胞（A549 TG 2）和Tgase-2沉默的A549细胞（A549 shTG 2）检查Tgase-2和JNK在TGF-β 1诱导的A549细胞EMT中的关系。JNK活化在A549 TG 2细胞中显著增加，而在A549 shTG 2细胞中显著降低。相反，PP 2A在A549 TG 2和A549细胞中表达降低，而在A549 shTG 2细胞中表达增加。通过将A549 WT和A549 shTG 2细胞注射到SCID小鼠中，在体内肺癌原位模型中也证实了Tgase-2参与N-钙粘蛋白表达。与注射A549 shTG 2细胞组相比，注射表达TGase-2的A549 WT细胞组小鼠肺癌组织中N-cadherin的表达和JNK的活化增加，而PP 2A的表达降低。这些结果表明，Tgase-2通过PP 2A下调JNK激活来诱导TGF-β 1诱导的EMT中N-cadherin的表达，Tgase-2/PP 2A/JNK可能是影响A549肺癌细胞EMT中N-cadherin转换的新轴。(C)2012爱思唯尔有限公司保留所有权利。
Epithelial-mesenchymal-transition (EMT) is a key event for tumour cells to initiate metastasis leading to switching of E-cadherin to N-cadherin. Transglutaminase-2 (Tgase-2) expression is increased in TGF-beta 1-induced EMT in A549 lung cancer cells or other lung cancer cells. The role and underlying mechanism of Tgase-2 in N-cadherin switching of TGF-beta 1-induced EMT are not known. The involvement and mechanisms of Tgase-2 were investigated in A549 cells using chemical inhibitors, gene silencing and over-expression.TGF-beta 1-induced EMT was suppressed by cystamine or gene silencing of Tgase-2. Suppression of Tgase-2 or the c-Jun-N-terminal kinase (JNK) inhibitor, SP600125, significantly reduced and over-expression of Tgase-2 increased the expression of N-cadherin. The relationship between Tgase-2 and JNK in the TGF-beta 1-induced EMT of A549 cells was examined using Tgase-2 over-expressed A549 cells (A549TG2) and Tgase-2 silenced A549 cells (A549shTG2). JNK activation was significantly increased in A549TG2 cells and decreased in A549shTG2 cells. In contrast, PP2A expression was decreased in A549TG2 and A549 cells and increased in A549shTG2 cells. The involvement of Tgase-2 in N-cadherin expression was also confirmed in an in vivo lung cancer orthotopic model by injection of A549WT and A549shTG2 cells into SCID mice. Tgase-2 expressing A549WT cells-injected mice group showed increased expressions of N-cadherin and JNK activation, but decreased expression of PP2A in lung cancer tissue comparing with the A549shTG2 cells-injected group. These results suggested that Tgase-2 induces N-cadherin expression of TGF-beta 1-induced EMT via JNK activation by PP2A down-regulation, and Tgase-2/PP2A/JNK might be a novel axis that affects N-cadherin switching in the EMT of A549 lung cancer cells. (C) 2012 Elsevier Ltd. All rights reserved.