POLE Deficiency Exacerbates Diesel Engine Exhaust-Induced Genomic Instability and Malignant Transformation of Bronchial Epithelial Cells.

IF 14.1 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Pimei Zhang, Zhaoxu Wu, Qiang Ju, Nuo Xu, Xian Chen, Hongguang Chen, Shuaishuai Yang, Jing Ji, Yanjie Zhao
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引用次数: 0

Abstract

Diesel engine exhaust (DEE) is classified as a Group I carcinogen, yet direct experimental evidence that DEE induce carcinogenesis is lacking. Here, it is innovatively discovered that 120 µg mL-1 DEE exposure for 20 weeks, original bronchial epithelial cells exhibit abnormal morphology, form colonies in soft agar, and readily develop the lumps under the subcutaneous tissue of immunodeficient mice, which are pathologically confirmed as lung squamous cell carcinoma. Whole genome sequencing and RNA sequencing identify DEE-induced mutational signatures (DBS3, ID1/ID2), associated with polymerase epsilon (POLE) exonuclease domain mutations and mismatch repair (MMR) deficiency. Besides, 52 exonic mutations, 734 copy number variations (CNVs), and 2519 differentially expressed genes (DEGs) are discovered which are enriched in the suppressed DNA damage repair pathways and the activated lung cancer related signaling pathways including JAK-STAT, PI3K-Akt, MAPK in the DEE-induced malignant transformed cells. Further assays confirm DEE-induced malignant transformed cells harbor both POLE and MMR defects, leading to high mutation burden and genomic instability. Additionally, POLE deficiency exacerbates DEE-induced DNA damage and genomic instability, promoting the cell malignant transformation. This study highlights the importance of gene-environment interaction in carcinogenesis and emphasizes the critical role of POLE deficiency in DEE-induced malignant transformation of lung cells.

极缺乏加剧了柴油机排气诱导的基因组不稳定性和支气管上皮细胞的恶性转化。
柴油机废气(DEE)被列为一类致癌物,但缺乏DEE致癌的直接实验证据。本研究创新性地发现,120µg mL-1 DEE暴露20周后,原有支气管上皮细胞形态异常,在软琼脂中形成菌落,并极易在免疫缺陷小鼠皮下组织下形成肿块,病理证实为肺鳞状细胞癌。全基因组测序和RNA测序鉴定了dee诱导的突变特征(DBS3, ID1/ID2),与聚合酶epsilon (POLE)外切酶结构域突变和错配修复(MMR)缺陷相关。此外,在dee诱导的恶性转化细胞中,发现52个外显子突变、734个拷贝数变异(copy number variations, cnv)和2519个差异表达基因(differentialexpressed genes, deg)富集于被抑制的DNA损伤修复通路和激活的肺癌相关信号通路,包括JAK-STAT、PI3K-Akt、MAPK。进一步的分析证实,dee诱导的恶性转化细胞同时具有POLE和MMR缺陷,导致高突变负担和基因组不稳定性。此外,POLE缺乏加剧了dee诱导的DNA损伤和基因组不稳定,促进细胞恶性转化。本研究强调了基因-环境相互作用在癌变中的重要性,并强调了极点缺乏在dee诱导的肺细胞恶性转化中的关键作用。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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