Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, USA.
Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, USA.
Toxicol Appl Pharmacol. 2019 Jul 1;374:65-76. doi: 10.1016/j.taap.2019.04.023. Epub 2019 Apr 29.
Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2'-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.
尼古丁是香烟烟雾的成分之一，越来越多的证据表明烟草烟雾对肾脏具有毒性和致癌性。尼古丁本身对肾脏的致癌性及其潜在的分子机制尚不清楚。因此，本研究旨在确定慢性尼古丁暴露对人肾上皮细胞（HK-2 细胞）的致癌作用。还评估了尼古丁暴露对细胞重编程、氧化还原状态和生长信号通路基因表达的影响，以了解潜在的分子机制。结果表明，慢性尼古丁暴露可诱导 HK-2 细胞生长和肿瘤转化。在暴露于尼古丁的细胞中观察到细胞内活性氧（ROS）水平升高、获得干细胞样球体形成和上皮-间充质转化（EMT）变化。用抗氧化剂 N-乙酰半胱氨酸（NAC）处理可使 HK-2 细胞中的 EMT 和干细胞特性消失，表明尼古丁诱导的 ROS 在这些形态变化中起作用。结果还表明，ROS 通过调节 AKT 通路在癌变早期控制干细胞特性。此外，暴露于尼古丁的细胞中表观遗传调节基因的表达发生改变，而 NAC 可逆转这些变化。表观遗传治疗药物 5-氮杂-2'-脱氧胞苷和 Trichostatin A 也可使干细胞特性消失。这表明，尼古丁诱导的氧化应激引起的表观遗传改变导致了肿瘤转化过程中的干细胞特性。据我们所知，这是第一项表明 ROS 介导的表观遗传修饰作为尼古丁在人肾上皮细胞中致癌性的潜在机制的报告。本研究进一步表明，表观遗传治疗药物具有作为尼古丁诱导的肾癌药理学干预的潜力。
