Table_1_Multiomics Landscape Uncovers the Molecular Mechanism of the Malignant Evolution of Lung Adenocarcinoma Cells to Chronic Low Dose Cadmium Exposure.xls

Cadmium (Cd) from cigarette smoke and polluted air can lead to lung adenocarcinoma after long-term inhalation. However, most studies are based on short-term exposure to this toxic metal at high concentrations. Here, we investigate the effects of long-term exposure of A549 cells (lung adenocarcinoma) to cadmium at low concentrations using morphological and multiomics analyses. First, we treated A549 cells continuously with CdCl2 at 1μM for 8 months and found that CdCl2 promoted cellular migration and invasion. After that, we applied transmission electron and fluorescence microscopies and did not observe significant morphological changes in Golgi apparatus, endoplasmic reticulum, lysosomes, or mitochondria on Cd treated cells; microfilaments, in contrast, accumulated in lamellipodium and adhesion plaques, which suggested that Cd enhanced cellular activity. Second, by using whole-exome sequencing (WES) we detected 4222 unique SNPs in Cd-treated cells, which included 382 unique non-synonymous mutation sites. The corresponding mutated genes, after GO and KEGG enrichments, were involved mainly in cell adhesion, movement, and metabolic pathways. Third, by RNA-seq analysis, we showed that 1250 genes (784 up and 466 down), 1623 mRNAs (1023 up and 591 down), and 679 lncRNAs (375 up and 304 down) were expressed differently. Furthermore, GO enrichment of these RNA-seq results suggested that most differentially expressed genes were related to cell adhesion and organization of the extracellular matrix in biological process terms; KEGG enrichment revealed that the differentially expressed genes took part in 26 pathways, among which the metabolic pathway was the most significant. These findings could be important for unveiling mechanisms of Cd-related cancers and for developing cancer therapies in the future.

镉（Cd）自香烟烟雾及污染空气中吸入后，长期累积可诱发肺腺癌。然而，多数研究基于对这种有毒金属的高浓度短期暴露。本研究中，我们采用形态学和多组学分析方法，探究了A549细胞（肺腺癌）长期接触低浓度镉的影响。首先，我们对A549细胞持续以1μM的CdCl2处理8个月，发现CdCl2促进了细胞的迁移和侵袭。随后，通过透射电子显微镜和荧光显微镜观察，我们并未在镉处理细胞中观察到高尔基体、内质网、溶酶体或线粒体的显著形态学变化；相反，微丝在层状伪足和粘附斑中积累，这表明镉增强了细胞活性。其次，利用全外显子测序（WES），我们在镉处理细胞中检测到4222个独特的单核苷酸多态性（SNPs），其中包含382个独特的非同义突变位点。经过GO和KEGG富集后，相应的突变基因主要参与细胞粘附、运动和代谢途径。第三，通过RNA测序分析，我们观察到1250个基因（其中784个上调，466个下调）、1623个mRNA（其中1023个上调，591个下调）和679个长非编码RNA（其中375个上调，304个下调）的表达发生改变。此外，这些RNA测序结果的GO富集分析表明，大多数差异表达基因与细胞粘附和细胞外基质的组织在生物过程中有关；KEGG富集分析揭示了差异表达基因参与了26条途径，其中代谢途径最为显著。这些发现对于揭示镉相关癌症的发病机制，以及未来开发癌症治疗策略具有重要意义。