Ponchel Théophile, Loeffler Emma, Ancel Julien, Brisebarre Audrey, Lalun Nathalie, Dalstein Véronique, Durlach Anne, Deslée Gaëtan, Dedieu Stéphane, Polette Myriam, Nawrocki-Raby Béatrice
Université de Reims Champagne-Ardenne, INSERM, P3Cell, UMR-S 1250, Reims, France.
Université de Reims Champagne-Ardenne, INSERM, P3Cell, UMR-S 1250, Reims, France; CHU de Reims, Hôpital Maison Blanche, Service de Pneumologie, Reims, France.
Eur J Cell Biol. 2025 Mar;104(1):151475. doi: 10.1016/j.ejcb.2024.151475. Epub 2024 Dec 26.
The tumor suppressor fragile histidine triad (FHIT) is frequently lost in non-small cell lung cancer (NSCLC). We previously showed that a down-regulation of FHIT causes an up-regulation of the activity of HER2 associated to an epithelial-mesenchymal transition (EMT) and that lung tumor cells harboring a FHIT/pHER2 phenotype are sensitive to anti-HER2 drugs. Here, we sought to decipher the FHIT-regulated HER2 signaling pathway in NSCLC. Transcriptomic analysis of tumor cells isolated from NSCLC revealed the endocytic receptor low density lipoprotein receptor-related protein 1 (LRP1), a central regulator of membrane trafficking and cell signaling, as a potential player of this signaling. In a cohort of 80 NSCLC assessed by immunohistochemistry, we found a significant association between a low FHIT expression and a high pHER2 and LRP1 expression by tumor cells. Experiments of FHIT silencing showed that FHIT regulated LRP1 expression both at the mRNA and protein levels in lung cell lines. Analyzing the relationship between LRP1 and HER2, we observed that an anti-HER2 targeted therapy reversed LRP1 overexpression induced by FHIT silencing whereas LRP1 silencing did not affect HER2 activity. Studying the functional role of LRP1, we showed that cell proliferation and invasion induced by FHIT silencing were LRP1-dependent. In addition, we found that the induction of vimentin upon FHIT inactivation was counteracted by LRP1 silencing. These results suggest that LRP1 acts downstream of HER2 to induce EMT and tumor progression following FHIT loss. Dual targeting of HER2 and LRP1 might represent a therapeutic strategy to more efficiently inhibit HER2 signaling in FHIT-negative NSCLC.
肿瘤抑制因子脆性组氨酸三联体（FHIT）在非小细胞肺癌（NSCLC）中经常缺失。我们之前表明，FHIT的下调会导致与上皮-间质转化（EMT）相关的HER2活性上调，并且具有FHIT/pHER2表型的肺肿瘤细胞对抗HER2药物敏感。在此，我们试图破解NSCLC中FHIT调控的HER2信号通路。对从NSCLC分离出的肿瘤细胞进行转录组分析，发现内吞受体低密度脂蛋白受体相关蛋白1（LRP1）作为膜转运和细胞信号的中心调节因子，是该信号通路的潜在参与者。在通过免疫组织化学评估的80例NSCLC队列中，我们发现肿瘤细胞中FHIT低表达与pHER2和LRP1高表达之间存在显著关联。FHIT沉默实验表明，FHIT在肺细胞系的mRNA和蛋白质水平上均调控LRP1表达。分析LRP1与HER2之间的关系，我们观察到抗HER2靶向治疗可逆转FHIT沉默诱导的LRP1过表达，而LRP1沉默并不影响HER2活性。研究LRP1的功能作用，我们表明FHIT沉默诱导的细胞增殖和侵袭是LRP1依赖性的。此外，我们发现FHIT失活后波形蛋白的诱导可被LRP1沉默抵消。这些结果表明，LRP1在FHIT缺失后在HER2下游发挥作用，诱导EMT和肿瘤进展。双重靶向HER2和LRP1可能代表一种在FHIT阴性NSCLC中更有效抑制HER2信号的治疗策略。
