WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways
WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways
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WSTF通过PI3K/Akt和IL-6/STAT3信号通路诱导EMT促进肺癌细胞增殖和侵袭
DOI：
10.1016/j.cellsig.2016.07.008
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发表时间：
2016-11-01
影响因子：
4.8
通讯作者：
Zhang, Tao
中科院分区：
文献类型：
--
作者：
Meng, Jin;Zhang, Xu-Tao;Zhang, Tao
威廉姆斯综合征转录因子(WSTF)由BAZ1B基因编码，首次被鉴定为威廉姆斯综合征患者的半合子缺失基因。据报道，WSTF蛋白参与转录、复制、染色质重塑和DNA损伤反应，也是一种酪氨酸蛋白激酶。然而，WSTF在癌症中的作用尚不清楚。在这里，我们发现WSTF过表达促进肺癌A549和H1299细胞的增殖、克隆形成、迁移和侵袭。在小鼠异种移植模型中，WSTF的过表达也促进了肿瘤的生长和肺癌细胞的侵袭能力。基因芯片和随后的qRT-PCR验证表明，WSTF的过表达显著上调了EMT(上皮向间充质转化)标志物纤维连接蛋白(FN1)和EMT诱导基因Fos和CEACAM6的表达。WSTF过表达后，E-钙粘蛋白表达下调、N-钙粘蛋白和FN1表达上调等EMT标志物的变化在mRNA和蛋白水平得到进一步证实，表现为典型的EMT形态改变。此外，WSTF还激活了PI3K/Akt和IL-6/STAT3致癌信号通路。PI3K抑制剂ZSTK474或STAT3抑制剂氯硝柳胺通过抑制细胞增殖、迁移和侵袭而逆转WSTF过表达的作用，并降低p-Akt、p-STAT3和IL-6水平。ZSTK474和氯硝柳胺还逆转了WSTF过表达的A549细胞的EMT标志物和EMT诱导蛋白，包括Snail、Slug、Twist和CEACAM6。综上所述，这些结果表明WSTF可能通过激活PI3K/Akt和IL-6/STAT3通路促进EMT，从而在肺癌中作为癌蛋白而促进肿瘤的侵袭。(C)2016 Elsevier Inc.保留所有权利。
Williams syndrome transcription factor (WSTF), which is encoded by the BAZ1B gene, was first identified as a hemizygously deleted gene in patients with Williams syndrome. WSTF protein has been reported to be involved in transcription, replication, chromatin remodeling and DNA damage response, and also functions as a tyrosine protein kinase. However, the function of WSTF in cancer is not known. Here, we show that WSTF overexpression promotes proliferation, colony formation, migration and invasion of lung cancer A549 and H1299 cells. WSTF overexpression also promotes tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. cDNA microarray and subsequent qRT-PCR validation revealed that WSTF overexpression significantly upregulated the expression of EMT (epithelial to mesenchymal transition) marker fibronectin (FN1) and EMT-inducing genes Fos and CEACAM6. The changes of EMT markers including downregulated E-cadherin and upregulated N-cadherin and FN1 were further confirmed at both mRNA and protein levels upon WSTF overexpression, with typical morphological changes of EMT. Furthermore, WSTF activates both PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways. Treatment with PI3K inhibitor ZSTK474 or STAT3 inhibitor niclosamide reversed the effects of WSTF overexpression by inhibiting cell proliferation, migration and invasion, with decreased level of p-Akt, p-STAT3 and IL-6. ZSTK474 and niclosamide also reversed EMT markers and EMT-inducing proteins including Snail, Slug, Twist and CEACAM6 in WSTF-overexpressing A549 cells. Taken together, these results demonstrate that WSTF may act as an oncoprotein in lung cancer to accelerate tumor aggressiveness by promoting EMT via activation of PI3K/Akt and IL-6/STAT3 pathways. (C) 2016 Elsevier Inc. All rights reserved.