近日，卫生毒理学研究团队在表观遗传学在PM2.5致肺毒性中的机制研究领域取得新进展。相关研究成果以“MicroRNA-760 resists ambient PM2.5-induced apoptosis in human bronchial epithelial cells through elevating heme-oxygenase 1 expression”为题，在线发表在期刊Environmental Pollution (IF=6.7). (DOI: https://doi.org/10.1016/j.envpol.2021.117213) 上。
细颗粒物PM2.5是肺癌发病的明确环境因素，PM2.5应答通路相关基因的表达失调是肺癌发生的关键事件，然而其失调机制尚未阐明。HMOX1作为细胞内重要的抗氧化酶，在细胞中发挥着重要作用。有研究表明，PM2.5诱导的ROS可能作为信号分子激活抗氧化酶HMOX1的表达，但是具体的机制仍需阐明。MicroRNAs (miRNAs)是调控基因表达的重要表观遗传因子。miRNA的经典调控机制认为miRNA可结合靶基因的3’ UTR区，通过降解mRNA或抑制翻译进程下调靶基因表达。也有部分报道miRNA以非经典调控机制行使功能。
在本研究中的结果显示，hsa-miR-760是作为PM2.5暴露的应答miRNA。更重要的是，我们揭示了一种新的miRNA调控机制，即hsa-miR-760通过靶向HMOX1的编码区而上调HMOX1的mRNA和蛋白表达。我们还确定YBX1是参与hsa-miR-760和HMOX1相互作用的关键蛋白。此外，我们观察到外源性hsa-miR-760转染能有效提高HMOX1的表达，从而降低ROS水平，降低 PM2.5暴露诱导的细胞凋亡。这部分研究结果为阐明miRNA的新的调控功能提供了线索和机制，揭示了环境PM2.5 暴露下HMOX1的新的调控机制，拓宽了miRNA在PM2.5 中的机制研究。于典科教授为本文的通讯作者，博士研究生许琳为本文的第一作者。上述研究得到了国家自然科学基金项目（91743113, 91943301, 81973075）的支持。
Recently, the research team of toxicology of our school has made great progress in the field of the epigenetic mechanisms underlying PM2.5-induced lung damage. The related research results were published in the journal Environmental Pollution (IF=6.7). (DOI: https://doi.org/10.1016/j.envpol.2021.117213) under the title of " MicroRNA-760 resists ambient PM2.5-induced apoptosis in human bronchial epithelial cells through elevating heme-oxygenase 1 expression ".
Long-term exposure to airborne PM2.5 is a definite risk factor for lung cancer. The expression changes for genes, which are involved in toxicity pathways of carcinogenesis, are considered as the key events of lung carcinogenesis by PM2.5 exposure. However, the mechanism underlying these gene expression changes remains to be further elucidated. Heme-oxygenase 1 (HMOX1) has been considered as one of the major molecular antioxidant defenses to mediate cytoprotective effects. Several lines of evidence have indicated that PM2.5-induced oxidative stress might function as a signaling molecule to activate HMOX1 expression. However, the detailed mechanism remains unrevealed. MicroRNAs (miRNAs) are a class of small non-coding RNAs with multiple functions in diverse biological and pathological processes. MiRNAs typically suppress gene expression at post-transcriptional levels, but increasing evidences showed that specific miRNAs might increase the target gene expression.
In this study, we explored the hypothesis that PM2.5 might modulate specific miRNA expression, which contributes to HMOX1 upregulation to resist PM2.5-induced lung injury. We observed a significant up-regulation of hsa-miR-760 in the lung cells upon PM2.5 exposure, and manifested that hsa-miR-760 might upregulate HMOX1 expression by binding to the coding region, i. e., an unconventional miRNA function. Further, we discovered that hsa-miR-760 up-regulates HMOX1 by elevating the mRNA stability in a YBX1-dependent manner. We also found that upregulation of hsa-miR-760 has an anti-apoptosis effect in lung cells exposed to PM2.5. Our results revealed a novel “non-conventional” miRNA function in toxicology research, which offered new clues to elucidate the diverse function of miRNAs in carcinogenesis.
Prof. Dianke Yu were corresponding author of the study. Students Lin Xu, was the first authors. The above research was supported by National Natural Science Foundation of China (Grant No. 91743113, 91943301, and 81973075).