Proteome derangement in malignant epithelial cells and its stroma following exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Proteome derangement in malignant epithelial cells and its stroma following exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
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暴露于4-（甲基硝基氨基氨基）后，恶性上皮细胞及其基质中的蛋白质组破坏 - 1-（3-吡啶基）-1-丁酮。
DOI：
10.1007/s00204-022-03426-8
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发表时间：
2023-03
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
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作者：
发现恶性肺上皮细胞蛋白质组和/或肿瘤微环境的新变化对于诊断、预后和/或治疗开发至关重要。采用时间依赖性4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮(NNK)诱导的小鼠肺肿瘤模型来筛选肺肿瘤的蛋白质组。然后建立 NNK 转化的人肺上皮 BEAS-2B 细胞来评估上皮细胞特异性蛋白质的变化。在 NNK 治疗的小鼠中观察到肿瘤负荷呈持续时间依赖性增加，在 NNK 暴露后第 8、12、16 和 20 周分别为 2/12 (17%)、8/12 (67%)、9/12 (75%) 和 10/10 (100%)。通过二维差异凝胶电泳检测并通过质谱鉴定总共 25 个差异表达蛋白（≤两倍变化），主要是结构蛋白、信号蛋白和代谢蛋白。钙调节蛋白、埃兹蛋白、组胺释放因子 (HRF) 和无机焦磷酸酶 1 (PPA1) 出现变化，并通过免疫印迹进一步证实。此外，免疫组织化学 (IHC) 分析表明肿瘤组织上皮细胞中 E-钙粘蛋白表达上调，波形蛋白表达降低。 NNK 转化的 BEAS-2B 细胞中肿瘤表型的获得通过增强的伤口闭合和增加的贴壁独立集落形成来证明。在转化的BEAS-2B细胞中，E-钙粘蛋白、埃兹蛋白和PPA1（但不包括钙调蛋白和HRF）的蛋白表达上调，正如在肿瘤组织中观察到的那样。使用小鼠肺肿瘤组织的IHC染色进一步揭示HRF的上调不是肺上皮细胞特异性的。总而言之，NNK 暴露后的肿瘤发生可能是由肺上皮细胞中的蛋白质失调以及肿瘤微环境中存在的其他细胞类型产生的蛋白质组紊乱引发的。
Discovering novel changes in the proteome of malignant lung epithelial cells and/or the tumor-microenvironment is paramount for diagnostic, prognostic, and/or therapy development. A time-dependent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung tumor model was used to screen the proteome of lung tumors. NNK-transformed human lung epithelial BEAS-2B cells were then established to evaluate the epithelial cell-specific protein changes. A duration-dependent increase of tumor burden was observed in NNK-treated mice, 2/12 (17%), 8/12 (67%), 9/12 (75%), and 10/10 (100%) at weeks 8, 12, 16, and 20 after the NNK exposure, respectively. A total of 25 differentially expressed proteins (≤ twofold change), predominantly structural, signaling, and metabolic proteins, were detected by two-dimensional difference gel electrophoresis and identified by mass spectrometry. Calregulin, ezrin, histamine releasing factor (HRF), and inorganic pyrophosphatase 1 (PPA1) exhibited changes and were further confirmed via immunoblotting. In addition, immunohistochemistry (IHC) analysis indicated upregulated E-cadherin and decreased vimentin expression in epithelial cells of tumor tissues. Acquisition of a neoplastic phenotype in NNK-transformed BEAS-2B cells was demonstrated by enhanced wound closure and increased anchorage independent colony formation. In transformed BEAS-2B cells, protein expression of E-cadherin, ezrin, and PPA1 (but not calregulin and HRF) was upregulated, as was observed in tumor tissues IHC staining using mouse lung tumor tissues further revealed that HRF upregulation was not lung epithelial cell specific. Altogether, tumorigenesis after NNK exposure may be initiated by protein dysregulation in lung epithelial cells together with proteome derangement derived from other cell types existing in the tumor-microenvironment.
DOI：
10.3390/ijerph120100064
发表时间：
2014-12-23
影响因子：
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作者：
Cheng G;Li J;Zheng M;Zhao Y;Zhou J;Li W
通讯作者：
Li W