亞砷酸鹽暴露膀胱上皮細(xì)胞中HER2活化因子的研究

2018年8月，中國醫(yī)科大學(xué)公共衛(wèi)生學(xué)院職業(yè)與環(huán)境衛(wèi)生系(Department of Occupational and Environmental Health, School of Public Health, China Medical University,Shenyang 110122, Liaoning, China) Shuhua Xi老師研究團隊在《TOXICOLOGICAL SCIENCES》上發(fā)表論文：

“HER2 Activation Factors in Arsenite-Exposed Bladder Epithelial Cells”

“亞砷酸鹽暴露膀胱上皮細(xì)胞中HER2活化因子的研究”

Abstract：

Chronic exposure to arsenic in drinking water is associated with an increased risk of bladder cancer in arseniasis-endemic areas throughout the world. Human epidermal growth factor receptor 2 (HER2) was recently reported to be involved in the development of bladder cancer. However, until this point, little is known about HER2 activation and its mechanism in arsenite-exposed urothelial cells. The aim of this study was to identify factors associated with HER2 activation in an arsenite-exposed human bladder epithelial cell line. Results of this study demonstrated that levels of phosphorylated HER2 increased significantly in cells treated with arsenite. Additionally, the protein levels of epidermal growth factor (EGF), transforming growth factor α (TGFα), soluble ectodomain fragment of E-cadherin (sE-cad), and neuregulin 1 (NRG1) were also increased significantly in these cells. Meanwhile, the protein levels of heat shock protein 90 (HSP90) and plasma membrane calcium ATPases 2 (PMCA2) increased, while those of Interleukin-6 (IL-6) and N-myc downstream regulated gene 1 (NDRG1) decreased significantly. Pretreatment of arsenite-exposed cells with exogenous EGF, TGFα, NRG1, and HSP90 could promote, whereas exogenous IL-6 and NDRG1 could suppress, the phosphorylation of HER2. Furthermore, reduction of EGF, TGFα, NRG1, PMCA2, or HSP90 via its neutralizing antibody, siRNA, or inhibitor suppressed, whereas knockdown of E-cadherin promoted, the phosphorylation of HER2. In conclusion, our results suggested that HER2 might be activated through promoting the dimerization of HER2 with other members of HER family, maintaining the stability of phosphorylated HER2, and attenuating the suppression of HER2 activation in arsenite-exposed cells.

摘要：

在世界各地砷中毒流行地區(qū)，長期接觸飲用水中的砷與膀胱癌風(fēng)險增加有關(guān)。人表皮生長因子受體2 (HER2)最近被報道參與膀胱癌的發(fā)展。然而，在此之前，對暴露于亞砷酸鹽的尿路上皮細(xì)胞中HER2的激活及其機制知之甚少。本研究的目的是確定與亞砷酸鹽暴露的人膀胱上皮細(xì)胞系中HER2激活相關(guān)的因素。本研究結(jié)果表明，在亞砷酸鹽處理的細(xì)胞中，磷酸化的HER2水平顯著增加。此外，表皮生長因子(EGF)、轉(zhuǎn)化生長因子α (TGFα)、E-cadherin可溶性外結(jié)構(gòu)域片段(sE-cad)和神經(jīng)調(diào)節(jié)蛋白1 (NRG1)的蛋白水平也顯著升高。同時，熱休克蛋白90 (HSP90)和質(zhì)膜鈣atp酶2 (PMCA2)蛋白水平升高，白介素6 (IL-6)和N-myc下游調(diào)控基因1 (NDRG1)蛋白水平顯著降低。外源性EGF、TGFα、NRG1和HSP90預(yù)處理亞砷酸鹽暴露細(xì)胞可促進HER2的磷酸化，而外源性IL-6和NDRG1可抑制HER2的磷酸化。此外，EGF、TGFα、NRG1、PMCA2或HSP90通過其中和抗體、siRNA或抑制劑的減少可抑制，而E-cadherin的下調(diào)可促進HER2的磷酸化。綜上所述，科研人員的研究結(jié)果表明，在亞砷酸鹽暴露的細(xì)胞中，HER2可能通過促進HER2與HER家族其他成員的二聚化，維持磷酸化HER2的穩(wěn)定性以及減弱HER2活化的抑制而被激活。

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