Weeden Clare E, Chen Yunshun, Ma Stephen B, Hu Yifang, Ramm Georg, Sutherland Kate D, Smyth Gordon K, Asselin-Labat Marie-Liesse
ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
PLoS Biol. 2017 Jan 26;15(1):e2000731. doi: 10.1371/journal.pbio.2000731. eCollection 2017 Jan.
Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolated from heavy smokers proliferate extensively, whereas their alveolar progenitor cell counterparts have limited colony-forming capacity. We demonstrate that this difference arises in part because of the ability of BSCs to repair their DNA more efficiently than alveolar cells following ionizing radiation or chemical-induced DNA damage. Analysis of mice harbouring a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA damage repair by nonhomologous end joining (NHEJ), indicated that BSCs preferentially repair their DNA by this error-prone process. Interestingly, polyploidy, a phenomenon associated with genetically unstable cells, was only observed in the human BSC subset. Expression signature analysis indicated that BSCs are the likely cells of origin of human SqCC and that high levels of NHEJ genes in SqCC are correlated with increasing genomic instability. Hence, our results favour a model in which heavy smoking promotes proliferation of BSCs, and their predilection for error-prone NHEJ could lead to the high mutagenic burden that culminates in SqCC. Targeting DNA repair processes may therefore have a role in the prevention and therapy of SqCC.
肺鳞状细胞癌（SqCC）是肺癌的第二大常见亚型，与吸烟密切相关且表现出基因组不稳定性。导致SqCC形成的细胞起源和分子过程在很大程度上尚未得到探索。在此，我们表明，从重吸烟者中分离出的人类基底干细胞（BSC）大量增殖，而其肺泡祖细胞的集落形成能力有限。我们证明，这种差异部分源于BSC在电离辐射或化学诱导的DNA损伤后比肺泡细胞更有效地修复其DNA的能力。对DNA依赖性蛋白激酶催化亚基（DNA-PKcs）发生突变的小鼠进行分析，DNA-PKcs是通过非同源末端连接（NHEJ）进行DNA损伤修复的关键酶，结果表明BSC优先通过这种易出错的过程修复其DNA。有趣的是，多倍体，一种与基因不稳定细胞相关的现象，仅在人类BSC亚群中观察到。表达特征分析表明，BSC可能是人类SqCC的起源细胞，并且SqCC中高水平的NHEJ基因与基因组不稳定性增加相关。因此，我们的结果支持一种模型，即大量吸烟促进BSC的增殖，并且它们对易出错的NHEJ的偏好可能导致最终形成SqCC的高诱变负担。因此，靶向DNA修复过程可能在SqCC的预防和治疗中发挥作用。
