Yu Wenwen, Shi Yubo, Bao Xiaoqiong, Chen Xiangxiang, Ni Yangyang, Wang Jincong, Ye Hua
Department of Respiratory and Critical Care Medicine of Affiliated Yueqing Hospital, Wenzhou Medical University, Yueqing 325600, China.
Korean J Physiol Pharmacol. 2025 May 1;29(3):337-347. doi: 10.4196/kjpp.24.275. Epub 2025 Mar 7.
Lung adenocarcinoma (LUAD) is a global malignancy with significant chemoresistance impacting patient prognosis. The pro-tumorigenic role of hyaluronan- mediated motility receptor (HMMR) in LUAD is recognized. This study was designed to investigate the underlying mechanisms by which HMMR affects chemoresistance in LUAD. Bioinformatics presented the expression patterns of HMMR in LUAD patients and the association between HMMR levels and patient survival, followed by qRT-PCR to verify HMMR expression in LUAD tissues and cells. Further, bioinformatics was leveraged to identify the signaling pathways enriched by HMMR and its relevance to glycolytic genes, we also analyzed changes in the glycolytic activity of LUAD cells by manipulating HMMR expression. Stemness was evaluated through cell aggregation assays and Western blot, and drug responsiveness was gauged using CCK-8 assays, alongside flow cytometry for apoptosis analysis. HMMR was highly expressed in LUAD tissues and cells, and this overexpression correlated with poorer prognoses in patients. GSEA showed that HMMR was notably enriched in the glycolysis and gluconeogenesis pathways, correlating positively with the expression of key glycolytic genes. Cellular experiments confirmed that HMMR knockdown notably suppressed aerobic glycolysis in LUAD cells. Moreover, overexpression of HMMR could further enhance the stemness and cisplatin resistance of LUAD cells by stimulating glycolysis. In brief, this study has validated that high levels of HMMR in LUAD are predictive of poor patient prognosis, and that overexpression of HMMR can catalyze aerobic glycolysis, thus promoting stemness and chemoresistance in LUAD cells. Thus, HMMR could be a target for improving chemosensitivity in LUAD.
肺腺癌（LUAD）是一种全球性恶性肿瘤，具有显著的化疗耐药性，影响患者预后。透明质酸介导的运动受体（HMMR）在LUAD中的促肿瘤作用已得到认可。本研究旨在探讨HMMR影响LUAD化疗耐药性的潜在机制。生物信息学展示了LUAD患者中HMMR的表达模式以及HMMR水平与患者生存之间的关联，随后通过qRT-PCR验证LUAD组织和细胞中HMMR的表达。此外，利用生物信息学来识别由HMMR富集的信号通路及其与糖酵解基因的相关性，我们还通过操纵HMMR表达分析了LUAD细胞糖酵解活性的变化。通过细胞聚集试验和蛋白质免疫印迹评估干性，并使用CCK-8试验测定药物反应性，同时通过流式细胞术进行凋亡分析。HMMR在LUAD组织和细胞中高表达，这种过表达与患者较差的预后相关。基因集富集分析（GSEA）表明，HMMR在糖酵解和糖异生途径中显著富集，与关键糖酵解基因的表达呈正相关。细胞实验证实，敲低HMMR可显著抑制LUAD细胞的有氧糖酵解。此外，HMMR的过表达可通过刺激糖酵解进一步增强LUAD细胞的干性和顺铂耐药性。简而言之，本研究证实LUAD中高水平的HMMR预示着患者预后不良，并且HMMR的过表达可催化有氧糖酵解，从而促进LUAD细胞的干性和化疗耐药性。因此，HMMR可能是提高LUAD化疗敏感性的一个靶点。
