Sears Catherine R, Zhou Huaxin, Hulsey Emily, Aidoo Bea A, Sandusky George E, Al Nasrallah Nawar
Pulmonary and Critical Care Section, Department of Medicine, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA.
Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cancers (Basel). 2024 Apr 13;16(8):1495. doi: 10.3390/cancers16081495.
Lung squamous cell carcinoma (LUSC) is the second leading cause of lung cancer. Although characterized by high DNA mutational burdens and genomic complexity, the role of DNA repair in LUSC development is poorly understood. We sought to better understand the role of the DNA repair protein Xeroderma Pigmentosum Group C (XPC) in LUSC development. XPC knock-out (KO), heterozygous, and wild-type (WT) mice were exposed topically to N-nitroso-tris-chloroethylurea (NTCU), and lungs were evaluated for histology and pre-malignant progression in a blinded fashion at various time-points from 8-24 weeks. High-grade dysplasia and LUSC were increased in XPC KO compared with XPC WT NTCU mice (56% vs. 34%), associated with a higher mean LUSC lung involvement ( < 0.05). N-acetylcysteine pre-treatment decreased bronchoalveolar inflammation but did not prevent LUSC development. Proliferation, measured as %Ki67+ cells, increased with NTCU treatment, in high-grade dysplasia and LUSC, and in XPC deficiency ( < 0.01, ANOVA). Finally, pre-LUSC dysplasia developed earlier and progressed to higher histologic classification sooner in XPC KO compared with WT mice. Overall, this supports the protective role of XPC in squamous dysplasia progression to LUSC. Mouse models of early LUSC development are limited; this may provide a valuable model to study mechanisms of LUSC development and progression.
肺鳞状细胞癌（LUSC）是肺癌的第二大主要病因。尽管其具有高DNA突变负荷和基因组复杂性的特征，但DNA修复在LUSC发生发展中的作用仍知之甚少。我们试图更好地了解DNA修复蛋白色素性干皮病C组（XPC）在LUSC发生发展中的作用。将XPC基因敲除（KO）、杂合子和野生型（WT）小鼠局部暴露于N-亚硝基三氯乙基脲（NTCU），并在8至24周的不同时间点以盲法评估肺部的组织学和癌前病变进展情况。与XPC野生型NTCU小鼠相比，XPC基因敲除小鼠的高级别发育异常和LUSC增加（56%对34%），且LUSC累及肺的平均范围更大（P<0.05）。N-乙酰半胱氨酸预处理可减轻支气管肺泡炎症，但不能预防LUSC的发生。以Ki67+细胞百分比衡量的增殖在NTCU处理、高级别发育异常和LUSC以及XPC缺陷时均增加（P<0.01，方差分析）。最后，与野生型小鼠相比，XPC基因敲除小鼠的LUSC前发育异常更早出现，且更快进展为更高的组织学分级。总体而言，这支持了XPC在鳞状发育异常进展为LUSC过程中的保护作用。早期LUSC发生发展的小鼠模型有限；这可能为研究LUSC发生发展机制提供一个有价值的模型。
