Akt activation is responsible for enhanced migratory and invasive behavior of arsenic-transformed human bronchial epithelial cells.
Akt activation is responsible for enhanced migratory and invasive behavior of arsenic-transformed human bronchial epithelial cells.
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AKT激活负责增强砷转化的人支气管上皮细胞的迁移和侵入性行为。
DOI：
10.1289/ehp.1104061
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发表时间：
2012-01
影响因子：
10.4
通讯作者：
Yang C
中科院分区：
文献类型：
--
作者：
Wang Z;Yang J;Fisher T;Xiao H;Jiang Y;Yang C
背景：砷是最常见的环境污染物之一。长期砷暴露可导致人支气管上皮细胞（HBEC）恶性转化和肺癌。但砷致肺癌的机制尚不清楚，砷转化细胞（As-转化细胞）的迁移和侵袭特性也鲜有研究。目的：探讨转化HBEC的迁移和侵袭行为及其机制。方法：将p53基因敲低的HBEC暴露于2.5 μM亚砷酸钠中16周，获得p53 lowHBEC。通过transwell迁移和伤口愈合试验评估细胞迁移。使用Matrigel包被的transwell小室评价细胞侵袭。基因过表达，小干扰RNA（siRNA）敲低，和药理学抑制剂被用来确定负责增强细胞迁移和侵袭的潜在机制。结果：Transwell迁移和侵袭试验显示As转化的p53 lowHBEC具有高度迁移性和侵袭性。Akt（也称为蛋白激酶B）和细胞外信号调节蛋白激酶1/2（Erk 1/2）在AS转化的p53 lowHBEC中被强烈激活。在转化的p53 lowHBECs中稳定表达microRNA 200 b可消除Akt和Erk 1/2的激活，并完全抑制细胞的迁移和侵袭。药理学失活Akt而非Erk 1/2显著降低细胞迁移和侵袭。Akt的抑制降低了上皮-间充质转化诱导转录因子锌指E盒结合同源盒因子1（ZEB 1）和ZEB 2的表达。ZEB 1和ZEB 2的siRNA敲低损害了转化的p53 lowHBEC的迁移和侵袭。结论：Akt激活通过促进ZEB 1和ZEB 2的表达，在使转化的HBEC迁移和侵袭中起关键作用。
Background: Arsenic is one of the most common environmental contaminants. Long-term exposure to arsenic causes human bronchial epithelial cell (HBEC) malignant transformation and lung cancer. However, the mechanism of arsenic lung carcinogenesis is not clear, and the migratory and invasive properties of arsenic-transformed cells (As-transformed cells) have rarely been studied. Objectives: This study was designed to investigate the migratory and invasive behavior of As-transformed HBECs and the underlying mechanism. Methods: As-transformed p53lowHBECs were generated by exposing p53-knockdown HBECs to sodium arsenite (2.5 μM) for 16 weeks. Cell migration was assessed by transwell migration and wound-healing assay. Cell invasion was evaluated using Matrigel-coated transwell chambers. Gene overexpression, small interfering RNA (siRNA) knockdowns, and pharmacological inhibitors were used to determine the potential mechanism responsible for enhanced cell migration and invasion. Results: Transwell migration and invasion assays revealed that As-transformed p53lowHBECs were highly migratory and invasive. Akt (also known as protein kinase B) and extracellular signal–regulated protein kinase 1/2 (Erk1/2) were strongly activated in As-transformed p53lowHBECs. Stable expression of microRNA 200b in As-transformed p53lowHBECs abolished Akt and Erk1/2 activation and completely suppressed cell migration and invasion. Pharmacological inactivation of Akt but not Erk1/2 significantly decreased cell migration and invasion. Inhibition of Akt reduced the expression of epithelial-to-mesenchymal transition–inducing transcription factors zinc-finger E-box–binding homeobox factor 1 (ZEB1) and ZEB2. siRNA knockdown of ZEB1 and ZEB2 impaired As-transformed p53lowHBEC migration and invasion. Conclusions: Akt activation plays a critical role in enabling As-transformed HBEC migration and invasion by promoting ZEB1 and ZEB2 expression.
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影响因子：
5.6
作者：
Li, Guanwu;Lee, Lai-Sheung;Chiu, Jen-Fu
通讯作者：
Chiu, Jen-Fu
影响因子：
4.8
作者：
Simeonova, PP;Wang, SY;Luster, MI
通讯作者：
Luster, MI
影响因子：
10.4
作者：
Ouyang W;Luo W;Zhang D;Jian J;Ma Q;Li J;Shi X;Chen J;Gao J;Huang C
通讯作者：
Huang C
影响因子：
3.8
作者：
Lencinas, Alejandro;Broka, Derrick M.;Runyan, Raymond B.
通讯作者：
Runyan, Raymond B.
DOI：
10.1083/jcb.200601018
发表时间：
2006-03-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee JM;Dedhar S;Kalluri R;Thompson EW
通讯作者：
Thompson EW