Altered long non-coding RNAs expression in normal and diseased primary human airway epithelial cells exposed to diesel exhaust particles

Exposure to diesel exhaust particles (DEP) has been linked to a variety of adverse health effects, including increased morbidity and mortality from cardiovascular diseases, chronic obstructive pulmonary disease (COPD), metabolic syndrome, and lung cancer. The epigenetic changes caused by air pollution have been associated with increased health risks. However, the exact molecular mechanisms underlying the lncRNA-mediated pathogenesis induced by DEP exposure have not been revealed. Through RNA-sequencing and integrative analysis of both mRNA and lncRNA profiles, this study investigated the role of lncRNAs in altered gene expression in healthy and diseased human primary epithelial cells (NHBE and DHBE-COPD) exposed to DEP at a dose of 30 μg/cm². We identified 503 and 563 differentially expressed (DE) mRNAs and a total of 10 and 14 DE lncRNAs in NHBE and DHBE-COPD cells exposed to DEP, respectively. In both NHBE and DHBE-COPD cells, enriched cancer-related pathways were identified at mRNA level, and 3 common lncRNAs <i>OLMALINC, AC069234.2,</i> and <i>LINC00665</i> were found to be associated with cancer initiation and progression. In addition, we identified two <i>cis</i>-acting (<i>TMEM51-AS1</i> and <i>TTN-AS1</i>) and several <i>trans</i>-acting lncRNAs (e.g. <i>LINC01278, SNHG29, AC006064.4, TMEM51-AS1</i>) only differentially expressed in COPD cells, which could potentially play a role in carcinogenesis and determine their susceptibility to DEP exposure. Overall, our work highlights the potential importance of lncRNAs in regulating DEP-induced gene expression changes associated with carcinogenesis, and individuals suffering from COPD are likely to be more vulnerable to these environmental triggers.

柴油机尾气颗粒（diesel exhaust particles, DEP）暴露与多种不良健康效应相关，包括心血管疾病、慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）、代谢综合征及肺癌的发病率与死亡率升高。空气污染引发的表观遗传改变与健康风险升高相关。然而，DEP暴露诱导的长链非编码RNA（long non-coding RNA, lncRNA）介导的发病机制的确切分子机制尚未阐明。本研究通过RNA测序（RNA-sequencing）及信使RNA（messenger RNA, mRNA）与lncRNA表达谱的整合分析，探究了在暴露于30 μg/cm²浓度DEP的健康及患病人类原代上皮细胞（NHBE与DHBE-COPD）中，lncRNA在基因表达改变中的作用。本研究分别在DEP暴露的NHBE与DHBE-COPD细胞中，鉴定出503个和563个差异表达（differentially expressed, DE）mRNA，以及共计10个和14个差异表达lncRNA。在NHBE与DHBE-COPD细胞中，均在mRNA层面鉴定出富集的癌症相关通路；同时发现3种共有的lncRNA：OLMALINC、AC069234.2及LINC00665，均与癌症的发生与进展相关。此外，本研究鉴定出仅在COPD细胞中差异表达的2种顺式作用（cis-acting）lncRNA：TMEM51-AS1与TTN-AS1，以及若干反式作用（trans-acting）lncRNA（如LINC01278、SNHG29、AC006064.4及TMEM51-AS1），这些lncRNA可能在癌变过程中发挥作用，并影响细胞对DEP暴露的易感性。综上，本研究揭示了lncRNA在调控DEP诱导的、与癌变相关的基因表达改变中的潜在重要性，且罹患COPD的个体对这类环境诱因的易感性可能更高。