LAMB3通过EGFR-MAPK-PKM级联促进喉癌糖酵解重编程和进展

文献信息

中文摘要

喉癌（LC）仍然是一种预后不良的难治性恶性肿瘤，需要确定新的治疗靶点。本研究探讨细胞外基质蛋白层粘连蛋白亚基β-3（LAMB3）在LC进展中的功能作用及其潜在机制。对多个GEO数据集的生物信息学分析表明，LAMB3在LC组织中显著过表达，且LAMB3高表达与患者总生存期缩短相关。使用两种不同的LC细胞系进行的功能验证显示，敲低LAMB3在体外有效抑制细胞增殖、迁移、克隆形成能力和糖酵解代谢，并在异种移植模型中抑制肿瘤生长。在机制上，我们发现LAMB3激活EGFR-MAPK信号轴，增加EGFR和ERK的磷酸化，导致关键糖酵解酶PKM的转录上调，从而增强糖酵解通量，表现为葡萄糖摄取和乳酸产生增加。关键的是，LAMB3的致癌效应完全依赖于该轴；PKM的基因沉默以及EGFR或MAPK的药理学抑制均可在体外和体内消除LAMB3驱动的糖酵解重编程和促肿瘤表型。我们的研究结果确立LAMB3作为一种新的预后生物标志物，并揭示LAMB3-EGFR-MAPK-PKM信号轴作为喉癌干预的有前景的治疗靶点。

英文摘要

Laryngeal carcinoma (LC) remains a challenging malignancy with poor prognosis, necessitating the identification of novel therapeutic targets. This study investigates the functional role and underlying mechanism of the extracellular matrix protein Laminin Subunit Beta-3 (LAMB3) in LC progression. Bioinformatics analysis of multiple GEO datasets demonstrated that LAMB3 is significantly overexpressed in LC tissues and that high LAMB3 expression correlates with reduced overall survival in patients. Functional validation using two distinct LC cell lines revealed that knockdown of LAMB3 potently suppresses cellular proliferation, migration, clonogenic capacity, and glycolytic metabolism in vitro, and inhibits tumor growth in xenograft models. Mechanistically, we identified that LAMB3 activates the EGFR-MAPK signaling axis, increasing the phosphorylation of EGFR and ERK, leading to transcriptional upregulation of the key glycolytic enzyme PKM, resulting in enhanced glycolytic flux, as evidenced by increased glucose uptake and lactate production. Critically, the oncogenic effects of LAMB3 are entirely dependent on this axis; both genetic silencing of PKM and pharmacological inhibition of the EGFR or MAPK abrogate LAMB3-driven glycolytic reprogramming and tumor-promoting phenotypes in vitro and in vivo. Our findings establish LAMB3 as a novel prognostic biomarker and reveal the LAMB3-EGFR-MAPK-PKM signaling axis as a promising therapeutic target for intervention in laryngeal carcinoma.