Chronic Oxidative Stress Leads to Malignant Transformation Along With Acquisition of Stem Cell Characteristics, and Epithelial to Mesenchymal Transition in Human Renal Epithelial Cells
Chronic Oxidative Stress Leads to Malignant Transformation Along With Acquisition of Stem Cell Characteristics, and Epithelial to Mesenchymal Transition in Human Renal Epithelial Cells
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DOI：
10.1002/jcp.24922
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发表时间：
2015-08-01
影响因子：
5.6
通讯作者：
Singh, Kamaleshwar P.
中科院分区：
文献类型：
--
作者：
Mahalingaiah, Prathap Kumar S.;Ponnusamy, Logeswari;Singh, Kamaleshwar P.
细胞大分子氧化损伤被认为是多种肾癌病因共有的共同途径。慢性氧化应激是否足以诱导人肾细胞恶性转化尚不清楚。因此，本研究的目的是评估h2o2诱导的慢性氧化应激对HK-2正常肾上皮细胞生长和恶性转化的影响。本研究表明，慢性氧化应激可促进正常肾上皮细胞在非细胞毒剂量下的生长和肿瘤转化，并增加对细胞毒水平的适应。基因表达变化、细胞周期分析、锚定独立生长试验和裸鼠体内致瘤性证实了这一点。在慢性氧化应激的细胞中，干细胞标记基因的上调揭示了干细胞的特征，而间充质标记基因的上调也表明了EMT的形态学变化。抗氧化剂NAC不能逆转慢性氧化应激诱导的生长，这表明这些细胞的生物功能紊乱是永久性的。氧化应激诱导的生长的部分逆转，以及分别通过沉默Oct 4和Snail1来适应，表明这些变化是由干细胞和EMT特征的获得介导的。总之，这项研究首次表明，长期暴露于氧化应激水平升高足以通过获得干细胞特性诱导肾上皮细胞恶性转化。此外，EMT在增加肾细胞对氧化应激的适应性反应中起重要作用。j .细胞。中国生物医学工程学报，23(3):1616 - 1622,2015。(c) 2014 Wiley期刊公司
Oxidative injury to cellular macromolecules has been suggested as a common pathway shared by multiple etiological factors for kidney cancer. Whether the chronic oxidative stress alone is sufficient to induce malignant transformation in human kidney cells is not clear. Therefore, the objective of this study was to evaluate the effect of H2O2-induced chronic oxidative stress on growth, and malignant transformation of HK-2 normal kidney epithelial cells. This study revealed that chronic oxidative stress causes increased growth and neoplastic transformation in normal kidney epithelial cells at non-cytotoxic dose and increased adaptation to cytotoxic level. This was confirmed by gene expression changes, cell cycle analysis, anchorage independent growth assay and in vivo tumorigenicity in nude mice. Stem cells characteristics as revealed by up-regulation of stem cell marker genes, and morphological changes indicative of EMT with up regulation of mesenchymal markers were also observed in cells exposed to chronic oxidative stress. Antioxidant NAC did not reverse the chronic oxidative stress-induced growth, and adaptation suggesting that perturbed biological function in these cells are permanent. Partial reversal of oxidative stress-induced growth, and adaptation by silencing of Oct 4 and Snail1, respectively, suggest that these changes are mediated by acquisition of stem cell and EMT characteristics. In summary, this study for the first time suggests that chronic exposure to elevated levels of oxidative stress is sufficient to induce malignant transformation in kidney epithelial cells through acquisition of stem cell characteristics. Additionally, the EMT plays an important role in increased adaptive response of renal cells to oxidative stress. J. Cell. Physiol. 230: 1916-1928, 2015. (c) 2014 Wiley Periodicals, Inc.