Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.
Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.
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SQSTM1/p62的上调有助于镍诱导的人支气管上皮细胞的恶性转化
DOI：
10.1080/15548627.2016.1196313
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发表时间：
2016-10-02
期刊：
影响因子：
13.3
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Huang H;Zhu J;Li Y;Zhang L;Gu J;Xie Q;Jin H;Che X;Li J;Huang C;Chen LC;Lyu J;Gao J;Huang C
慢性肺部炎症被认为与镍暴露引起的肺癌的发展有关。因此，确定导致镍诱导的持续炎症微环境导致人支气管上皮细胞转化的分子机制具有重要意义。在目前的研究中，我们确定SQSTM 1/p62作为一种新的镍上调的蛋白质，这是重要的镍诱导的炎症TNF的表达，随后导致人支气管上皮细胞的转化。我们发现，镍暴露诱导SQSTM 1蛋白在人肺上皮细胞在体外和小鼠肺组织在体内上调。在人肺鳞状细胞癌中也观察到SQSTM 1上调。进一步的研究表明，敲低SQSTM 1表达显着抑制转化的人肺上皮细胞在慢性镍暴露，而异位表达SQSTM 1促进这种转化。机制研究表明，镍上调SQSTM 1是上调SQSTM 1 mRNA转录和促进SQSTM 1蛋白降解的折衷结果。我们证明，镍引发的SQSTM 1蛋白降解介导的宏自噬/自噬通过MTOR-ULK 1-BECN 1轴，而RELA是重要的SQSTM 1转录上调镍暴露后。此外，SQSTM 1上调表现出其通过对镍诱导的炎症性TNF mRNA稳定性施加动力来促进镍诱导的细胞转化。因此，MTOR-ULK 1-BECN 1自噬级联反应对镍诱导的TNF表达和细胞转化起抑制作用。总的来说，我们的研究结果表明，一种新的SQSTM 1调控网络，促进镍诱导的致瘤作用在人支气管上皮细胞，这是负控制的自噬级联镍暴露后。
ABSTRACT Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.
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DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
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发表时间：
1999-11-15
期刊：
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