SWI/SNF Complex Gene Mutations Promote the Liver Metastasis of Non-small Cell Lung Cancer Cells in NSI Mice

• Published in: Zhongguo fei ai za zhi 2023-10, Vol.26 (10), p.753-764
• Main Authors: GAO, Lingling, XIE, Zhi, LIN, Shouheng, LV, Zhiyi, ZHOU, Wenbin, CHEN, Ji, ZHU, Linlin, ZHANG, Li, ZENG, Penghui, HUANG, Xiaodan, YAN, Wenqing, CHEN, Yu, LU, Danxia, ZHANG, Shuilian, GUO, Weibang, LI, Peng, ZHANG, Xuchao
• Format: Article
• Language: Chinese
• Subjects: Apolipoproteins; Cell cycle; Dehydrogenases; Enzymes; Gene expression; Immunohistochemistry; Liver; Lung cancer; lung neoplasms; Medical prognosis; Metastasis; Mutation; neoplasm metastasis; Protein expression; Proteins; swi/snf complex
• ISSN: 1009-3419; 1999-6187
• DOI: 10.3779/j.issn.1009-3419.2023.102.35

背景与目的 SWI/SNF复合体（switch/sucrose nonfermentable chromatin-remodeling complex, SWI/SNF）是一种重要的染色质重塑复合物，其亚基变异在多种肿瘤中存在，并与多种肿瘤细胞生物学特征相关。但其基因突变是否参与非小细胞肺癌（non-small cell lung cancer, NSCLC）肝转移过程尚不清楚。本研究拟探究SWI/SNF复合体基因突变对NSCLC肝转移的影响及潜在机制。方法 我们使用全外显子组测序（whole-exome sequencing, WES）分析了NSCLC细胞H1299、H23和H460中SWI/SNF复合体基因突变。通过CRISPR/Cas9（clustered regularly interspaced short palindromic repeats）技术构建了ARID1A基因稳定敲除的H1299细胞株，建立了小鼠模型模拟NSCLC肝转移，观察不同基因突变对肝转移的影响。利用RNA-Seq和蛋白印迹分析差异基因的表达，并通过免疫组化技术（immunohistochemistry, IHC）检测了SWI/SNF复合体调控的靶分子在小鼠肝转移灶中的表达。结果 WES分析确定了SWI/SNF复合体基因的突变情况。动物实验结果显示SWI/SNF复合体基因突变与免疫缺陷小鼠较高的肝转移率相关。转录组测序和蛋白印迹分析显示SWI/SNF复合体基因突变细胞中ALDH1A1和APOBEC3B表达上调，尤其是ARID1A蛋白缺失的H460和H1299 sgARID1A中ALDH1A1表达水平显著上升。IHC染色亦显示H460和H1299 sgARID1A细胞肝转移灶中ALDH1A1高表达。结论 本研究强调了SWI/SNF复合体基因ARID1A和SMARCA4等突变在促进肺癌细胞肝转移中的关键作用。这些基因突变可能通过促进ALDH1A1与APOBEC3B高表达进而发挥肝特异性转移的作用，为深入探究肺癌肝转移分子机制提供了新线索。Background and objective The switch/sucrose nonfermentable chromatin-remodeling (SWI/SNF) complex is a pivotal chromatin remodeling complex, and the gen