Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, Research Center on Health and Environment (RENSMA), Huelva-21007, Spain.
Pneumology Area of Juan Ramón Jiménez Hospital, Huelva, Spain.
Metallomics. 2018 Oct 17;10(10):1444-1451. doi: 10.1039/c8mt00139a. Epub 2018 Aug 31.
Lung cancer (LC) is one of the most common causes of cancer-related deaths in the world and it is well known that trace elements play important roles in the carcinogenic process activating and inhibiting enzymatic reactions and metalloproteins, in which they usually participate as cofactors. A cross-sectional study was conducted on 48 lung cancer patients and 39 controls (56 men and 31 women), aged 44-76 years between March 2011 and June 2012. Eleven elements have been included in the study: V, Cr, Mn, Fe, Co, Cu, Zn, Se, Mo, Cd, and Pb, some of them considered toxic (V, Cd, Cr and Pb), while others are essential (Co, Mo, Se, Fe and Zn), and they have been analyzed by ICP-QQQ-MS in serum, urine and for the first time in bronchoalveolar lavage fluid (BALF). In order to understand the involvement of metals in this process, an analytical metallomic approach based on non-denaturing precipitation of proteins (NDPP) has been optimized for the fractionation of high molecular mass (HMM) and low molecular mass (LMM) metal species, in order to distinguish between metal species that affect the biological activity and toxicological potential of the elements. In this work, the NDPP followed by the analysis of metals by ICP-QQQ-MS has been applied for the first time to serum, urine and BALF samples from lung cancer patients and controls in order to get metal-size molecule profiles (MSMP), which can be used as metal-based biomarkers of altered metabolic processes such as oxidative stress and homeostasis. In this sense, we have demonstrated that several metals are good biomarkers when they are related to labile complexes, complexed with low molecular mass ligands, or in the form of metalloproteins (i.e. V and Cr in HMM and Cu in LMM), which has been described for the first time. On the other hand, metal dyshomeostasis biomarkers are proposed using metal ratios and correlations. Finally, the ratios between elements were shown to be important biomarkers for lung cancer in serum (V/Mn, V/Pb, V/Zn, Cr/Pb), urine (Cr/Cd, Mn/Cd, V/Cd, Co/Cd, Cd/Pb) and BALF (V/Cu), which reflects the dyshomeostasis of metals in lung cancer. In this sense, several metals are correlated to others suggesting also the existence of an interconnected homeostasis in lung cancer.
肺癌（LC）是世界上癌症相关死亡的最常见原因之一，众所周知，微量元素在致癌过程中发挥着重要作用，它们可以激活和抑制酶反应和金属蛋白酶，通常作为辅助因子参与其中。2011 年 3 月至 2012 年 6 月期间，对 48 名肺癌患者和 39 名对照者（56 名男性和 31 名女性）进行了一项横断面研究。研究中纳入了 11 种元素：V、Cr、Mn、Fe、Co、Cu、Zn、Se、Mo、Cd 和 Pb，其中一些被认为是有毒的（V、Cd、Cr 和 Pb），而另一些则是必需的（Co、Mo、Se、Fe 和 Zn），并通过电感耦合等离子体质谱-QQQ-MS 对其在血清、尿液中的含量进行了分析，这是首次对支气管肺泡灌洗液（BALF）中的这些元素进行了分析。为了了解金属在这一过程中的作用，本研究基于非变性沉淀蛋白（NDPP）建立了一种分析金属组学方法，对高分子量（HMM）和低分子量（LMM）金属物种进行了分离，以便区分影响元素生物活性和毒理学潜力的金属物种。在这项工作中，首次将 NDPP 与电感耦合等离子体质谱-QQQ-MS 分析相结合，应用于肺癌患者和对照者的血清、尿液和 BALF 样本中，以获得金属大小分子图谱（MSMP），可作为反映氧化应激和内稳态等代谢过程改变的金属基生物标志物。从这个意义上说，我们已经证明，当某些金属与不稳定的配合物、与低分子量配体结合的配合物或金属蛋白酶的形式（即 HMM 中的 V 和 Cr 以及 LMM 中的 Cu）相关时，它们是很好的生物标志物，这是首次描述。另一方面，金属失调生物标志物是通过金属比值和相关性来提出的。最后，结果表明，血清（V/Mn、V/Pb、V/Zn、Cr/Pb）、尿液（Cr/Cd、Mn/Cd、V/Cd、Co/Cd、Cd/Pb）和 BALF（V/Cu）中元素比值对于肺癌是重要的生物标志物，这反映了肺癌中金属的失调。从这个意义上说，有几个金属与其他金属相关，这也表明肺癌中存在相互关联的内稳态。
