Amphiregulin reflects brain metastasis progression and leads to PD-L1 expression in non-small cell lung cancer cells

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-09-20 DOI:10.1016/j.biopha.2025.118600

Dimitri Leite Ferreira , Tiphaine Biojout , Céline Bazille , Maelle Guyot , Lucie Malandain , Laureline Charrier , Jérôme Toutain , Elodie Peres , Samuel Valable , Jeannick Madelaine , Jérôme Levallet , Guénaëlle Levallet , Emmanuel Bergot

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引用次数: 0

Abstract

Background

The Hippo kinase Nuclear Dbf2-related kinase 2 (NDR2) promotes brain metastasis (BM) in non-small cell lung cancer (NSCLC) by the disrupting Yes-associated protein 1 (YAP-1), suggesting a role in circulating tumor cells and/or brain colonization. The underlying mechanism remains to be clarified.

Methods

Human bronchial epithelial tumor cells (A549, H1975, H2030 and the brain-tropic H2030-BrM3 line) with or without NDR2 depletion (via siRNA or shRNA), were exposed to shear stress (up to 40 dyn/cm² for 3 h) using an Ibidi® pump system, in the presence or absence of exogenous Amphiregulin (AREG), and subsequently reseeded or not. Viability, apoptosis, proliferation, and YAP-1-dependent gene expression were analyzed. H2030-BrM3 cells (shControl or shNDR2) were injected intracardially into nude athymic mice (n = 10/group) to evaluate plasma AREG levels correlation with BM. AREG expression was assessed in human NSCLC tumor samples from primary and/or brain metastatic sites.

Results

NSCLC cells tolerated shear stress and showed reduced apoptosis after reseeding when expressing NDR2. Shear stress induced a dedifferentiation (via Sox2/9 variation) and increased AREG expression in most NSCLC cell lines. AREG enhanced NSCLC cells survival and proliferation under shear stress. In mice, plasma AREG levels correlated with BM volume. In human NSCLC samples, AREG-positive tumors displayed elevated Programmed Death-Ligand 1 (PD-L1), suggesting immune escape. Exogenous AREG treatment in H2030-BrM3 cells induced PD-L1 expression in vitro.

Conclusion

AREG supports tumor adaptation to mechanical stress and may drive immune tolerance via PD-L1. Its correlation with BM burden highlights its potential as a biomarker and therapeutic target in NSCLC.

查看原文本刊更多论文

双调节蛋白反映非小细胞肺癌细胞脑转移的进展并导致PD-L1的表达

Hippo激酶核dbf2相关激酶2 （NDR2）通过破坏ye相关蛋白1 （YAP-1）促进非小细胞肺癌（NSCLC）的脑转移（BM），提示在循环肿瘤细胞和/或脑定殖中起作用。其潜在机制仍有待澄清。方法将NDR2（通过siRNA或shRNA）缺失或不缺失的人支气管上皮肿瘤细胞（A549, H1975， H2030和脑致敏H2030- brm3系）在Ibidi®泵系统中暴露于剪切应力（高达40 dyn/cm²，持续3 h）下，存在或不存在外源性双调节蛋白（AREG），随后重新接种或不重新接种。分析细胞活力、细胞凋亡、细胞增殖和yap -1依赖性基因表达。将H2030-BrM3细胞（shControl或shNDR2）心内注射至裸胸腺小鼠（n = 10/组），评价血浆AREG水平与BM的相关性。在原发和/或脑转移部位的人类非小细胞肺癌肿瘤样本中评估AREG表达。结果表达NDR2的snsclc细胞可耐受剪切胁迫，并可减少再播种后的凋亡。在大多数NSCLC细胞系中，剪切应力诱导去分化（通过Sox2/9变异）并增加AREG表达。AREG增强剪切应激下NSCLC细胞的存活和增殖。在小鼠中，血浆AREG水平与脑脊膜体积相关。在人类非小细胞肺癌样本中，areg阳性肿瘤显示程序性死亡配体1 （PD-L1）升高，提示免疫逃逸。外源性AREG处理H2030-BrM3细胞诱导PD-L1体外表达。结论areg支持肿瘤对机械应力的适应，并可能通过PD-L1驱动免疫耐受。其与脑转移负荷的相关性突出了其作为非小细胞肺癌生物标志物和治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.