Parker Rebecca E, McSwain Leon, Zhou Wei, Marcus Adam I, Fu Haian, Ramalingam Suresh S, Zhang Shirley, Gilbert-Ross Melissa
Cancer Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA, USA.
Department Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
J Cancer Res Clin Oncol. 2025 Jul 26;151(7):223. doi: 10.1007/s00432-025-06269-9.
This study characterizes the functional effects and clinical characteristics of high mRNA and high PER1 protein expression in treatment resistant lung adenocarcinoma.
HBEC3-KT cells were modified by CRISPR knockout and A549 cells by LKB1 addback using stable transfection. RNA sequencing and western blot were used to profile gene and protein expression. Pooled siRNA knockdown of PER1 was used to assess impacts on cell proliferation and 3D invasion. Human lung adenocarcinoma data were analyzed using cBioPortal.
mRNA and protein are upregulated in -mutant lung adenocarcinoma tumors and -knockout human bronchial epithelial cells (HBEC3-KT). Addback of wildtype LKB1 in A549 lung cancer cells is sufficient to decrease PER1 protein levels. Knockdown of PER1 decreased cell growth, proliferation, and 3D invasion in LKB1-deficient cell models. High expression in lung cancer patients correlates with LKB1 mutation status, decreased expression of the gene that encodes PD-L1, and altered hypoxia and immune and stromal ESTIMATE scores.
PER1 has oncogenic activity in LKB1-mutant lung cancer cells and high expression in lung adenocarcinoma patients may represent an independent biomarker of resistance to immunotherapy.
The online version contains supplementary material available at 10.1007/s00432-025-06269-9.
本研究旨在表征治疗抵抗性肺腺癌中高mRNA和高PER1蛋白表达的功能效应及临床特征。
使用稳定转染通过CRISPR基因敲除对HBEC3-KT细胞进行改造，通过LKB1回补对A549细胞进行改造。采用RNA测序和蛋白质印迹分析基因和蛋白质表达。使用PER1的混合小干扰RNA敲低来评估对细胞增殖和三维侵袭的影响。利用cBioPortal分析人肺腺癌数据。
在LKB1突变型肺腺癌肿瘤和LKB1敲除的人支气管上皮细胞（HBEC3-KT）中，mRNA和蛋白质表达上调。在A549肺癌细胞中回补野生型LKB1足以降低PER1蛋白水平。在LKB1缺陷细胞模型中，敲低PER1可降低细胞生长、增殖和三维侵袭能力。肺癌患者中高PER1表达与LKB1突变状态、编码PD-L1的基因表达降低以及缺氧、免疫和基质ESTIMATE评分改变相关。
PER1在LKB1突变型肺癌细胞中具有致癌活性，肺腺癌患者中的高PER1表达可能代表免疫治疗耐药的独立生物标志物。
网络版包含可在10.1007/s00432-025-06269-9获取的补充材料。
