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.
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.