Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin-vascular endothelial growth factor pathway.
Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin-vascular endothelial growth factor pathway.
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DOI：
10.1016/j.taap.2013.04.018
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发表时间：
2013-08-15
影响因子：
3.8
通讯作者：
Yang, Chengfeng
中科院分区：
文献类型：
--
作者：
Wang, Zhishan;Humphries, Brock;Xiao, Hua;Jiang, Yiguo;Yang, Chengfeng
关键词：
砷暴露是一个主要的健康问题，会增加癌症风险，但砷致癌的机制尚未阐明。我们和其他人最近报道砷引起的细胞恶性转化伴随着上皮间质转化（EMT）。然而，EMT 在砷致癌过程中的作用尚不清楚。尽管先前的研究表明内皮细胞短期暴露于砷会刺激血管生成，但长期暴露于砷而发生恶性转化的细胞是否具有促血管生成作用仍有待确定。本研究的目的是探讨砷转化的人支气管上皮细胞进行 EMT 对血管生成的影响及其潜在机制。结果发现，来自砷转化细胞的条件培养基强烈刺激人脐静脉内皮细胞（HUVEC）的管形成。此外，在接种砷转化细胞后，在小鼠异种移植肿瘤组织中检测到血管生成增强。机制研究表明，砷转化细胞中的β-连环蛋白被激活，上调其靶基因表达，包括刺激血管生成的血管内皮生长因子（VEGF）。在砷转化细胞中稳定表达 microRNA-200b 可逆转 EMT，抑制 β-catenin 激活，降低 VEGF 表达并减少 HUVEC 的管形成。 siRNA 敲低 β-连环蛋白可降低 VEGF 表达。将 VEGF 中和抗体添加到来自砷转化细胞的条件培养基中会损害 HUVEC 的管形成。逆转录酶-PCR 分析表明，砷转化细胞中经典 Wnt 配体的 mRNA 水平没有增加。这些发现表明砷转化细胞中的 EMT 通过激活 β-catenin-VEGF 途径促进血管生成。
Arsenic exposure represents a major health concern increasing cancer risks, yet the mechanism of arsenic carcinogenesis has not been elucidated. We and others recently reported that cell malignant transformation by arsenic is accompanied by epithelial to mesenchymal transition (EMT). However, the role of EMT in arsenic carcinogenesis is not well understood. Although previous studies showed that short term exposure of endothelial cells to arsenic stimulated angiogenesis, it remains to be determined whether cells that were malignantly transformed by long term arsenic exposure have a pro-angiogenic effect. The objective of this study was to investigate the effect of arsenic-transformed human bronchial epithelial cells that underwent EMT on angiogenesis and the underlying mechanism. It was found that the conditioned medium from arsenic-transformed cells strongly stimulated tube formation by human umbilical vein endothelial cells (HUVECs). Moreover, enhanced angiogenesis was detected in mouse xenograft tumor tissues resulting from inoculation of arsenic-transformed cells. Mechanistic studies revealed that β-catenin was activated in arsenic-transformed cells up-regulating its target gene expression including angiogenic-stimulating vascular endothelial growth factor (VEGF). Stably expressing microRNA-200b in arsenic-transformed cells that reversed EMT inhibited β-catenin activation, decreased VEGF expression and reduced tube formation by HUVECs. SiRNA knockdown β-catenin decreased VEGF expression. Adding a VEGF neutralizing antibody into the conditioned medium from arsenic-transformed cells impaired tube formation by HUVECs. Reverse transcriptase-PCR analysis revealed that the mRNA levels of canonical Wnt ligands were not increased in arsenic-transformed cells. These findings suggest that EMT in arsenic-transformed cells promotes angiogenesis through activating β-catenin-VEGF pathway.
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