Aeroallergen Der p 2 promotes motility of human non-small cell lung cancer cells via toll-like receptor-mediated up-regulation of urokinase-type plasminogen activator and integrin/focal adhesion kinase signaling.
Aeroallergen Der p 2 promotes motility of human non-small cell lung cancer cells via toll-like receptor-mediated up-regulation of urokinase-type plasminogen activator and integrin/focal adhesion kinase signaling.
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DOI：
10.18632/oncotarget.14514
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Kao SH
中科院分区：
文献类型：
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作者：
Lin CH;Lin HH;Kuo CY;Kao SH
屋尘螨 (HDM) 过敏原是导致呼吸道过敏和气道重塑的主要原因之一。在此，我们假设主要的 HDM 过敏原 Der p 2 可以增加非小细胞肺癌 (NSCLC) 细胞的细胞运动性和侵袭性。我们的结果表明，低剂量（1 和 3 μg/mL）重组 Der p 2 蛋白（DP2）增强了人 NSCLC 细胞 A549、H1299 和 CL1-5 的迁移和侵袭性，但对它们的生长没有显着改变。进一步的研究表明，在暴露于 DP2 的 A549 细胞中，整合素 αV 水平增加，其下游信号包括粘着斑激酶 (FAK) 和桩蛋白被激活。同时，DP2 还激活 FAK 相关信号传导效应器，例如 Src、磷脂酰肌醇 3 激酶 (PI3K)、AKT、p38 丝裂原激活蛋白激酶 (P38)、细胞外信号调节激酶 1/2 (ERK1/2) 和 c-Jun N 末端激酶 (JNK)。我们的研究结果还表明，DP2 增加了尿激酶型纤溶酶原激活激酶 (uPA) 和 uPA 受体 (uPAR) 的表达水平，随后增强了 uPAR 与整合素 αV 的结合。此外，还证明了 Toll 样受体 2/4 (TLR2/4) 触发的 ERK1/2 激活参与了 uPA 和 uPAR 表达的增加。总的来说，这些发现表明 DP2 可以增强 NSCLC 细胞的细胞运动性和侵袭性，这归因于 TLR2/4-ERK1/2 激活、uPA 和 uPAR 表达增加、uPAR 与整合素 αV 的结合增强以及随后的 FAK 信号级联反应。因此，我们认为DP2可能通过促进癌细胞的转移能力而加剧NSCLC。
House dust mite (HDM) allergens are one of the major causes leading to respiratory hypersensitiveness and airway remodeling. Here we hypothesized that a major HDM allergen Der p 2 could increase cell motility and invasiveness of non-small cell lung cancer (NSCLC) cells. Our results showed that low dose (1 and 3 μg/mL) recombinant Der p 2 protein (DP2) enhanced the migration and invasiveness of human NSCLC cell A549, H1299 and CL1-5, but nonsignificantly altered their growth. Further investigation revealed that integrin αV level was increased and its downstream signaling including focal adhesion kinase (FAK) and paxillin were activated in A549 cells exposed to DP2. In parallel, DP2 also activated the FAK-associated signaling effectors such as Src, phosphatidyl inositol 3-kinase (PI3K), AKT, p38 mitogen-activated protein kinase (P38), extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Our findings also revealed that DP2 increased expression level of urokinase type plasminogen-activated kinase (uPA) and uPA receptor (uPAR), and subsequently enhanced the binding of uPAR to integrin αV. Moreover, the involvement of toll-like receptor 2/4 (TLR2/4)-triggered ERK1/2 activation in the increased expression of uPA and uPAR was also demonstrated. Collectively, these findings indicate that DP2 can enhance cell motility and invasiveness of NSCLC cells, attributing to TLR2/4-ERK1/2 activation, increased uPA and uPAR expression, enhanced binding of uPAR to integrin αV, and the consequent FAK signaling cascades. Thus, we suggest that DP2 may exacerbate NSCLC via promoting metastatic ability of carcinoma cell.