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 (p< 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 (p< 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.
肺鳞状细胞癌是肺癌的第二大主要病因。尽管其特征表现为高DNA突变负荷和基因组复杂性，但DNA修复在肺鳞癌发生发展中的作用尚不明确。本研究旨在深入探讨DNA修复蛋白着色性干皮病C组蛋白在肺鳞癌发生中的作用。通过局部暴露于N-亚硝基-三氯乙基脲，对XPC基因敲除型、杂合型及野生型小鼠进行干预，并在8至24周不同时间点采用盲法评估肺部组织学特征及癌前病变进展。结果显示，与野生型NTCU处理组相比，XPC敲除组高级别不典型增生及肺鳞癌发生率显著升高（56%对比34%），且肺鳞癌平均累及范围更广（p<0.05）。N-乙酰半胱氨酸预处理虽能减轻支气管肺泡炎症，但未能阻止肺鳞癌发生。通过Ki67阳性细胞百分比检测发现，NTCU处理组、高级别不典型增生及肺鳞癌组织中细胞增殖显著增强，且在XPC缺陷状态下更为明显（方差分析p<0.01）。值得注意的是，与野生型小鼠相比，XPC敲除小鼠的癌前不典型增生发生更早，且更快进展至更高组织学分级。综上所述，本研究证实XPC在鳞状上皮不典型增生向肺鳞癌进展过程中具有保护作用。目前肺鳞癌早期发展的动物模型较为有限，该模型或可为研究肺鳞癌发生发展机制提供重要平台。
肿瘤(癌症)患者之家