Targeting HNRNPA2B1 to Overcome Chemotherapy Resistance in Gastric Cancer Stem Cells: Mechanisms and Therapeutic Potential.

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biological Chemistry Pub Date : 2025-01-25 DOI:10.1016/j.jbc.2025.108234

Miao Yu, Bingyuan Fei, Songtao Chu

{"title":"Targeting HNRNPA2B1 to Overcome Chemotherapy Resistance in Gastric Cancer Stem Cells: Mechanisms and Therapeutic Potential.","authors":"Miao Yu, Bingyuan Fei, Songtao Chu","doi":"10.1016/j.jbc.2025.108234","DOIUrl":null,"url":null,"abstract":"<p><p>Gastric cancer (GC) remains a significant global health challenge, particularly due to the resistance of gastric cancer stem cells (GCSCs) to chemotherapy. This study investigates the role of heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), a member of the heterogeneous nuclear ribonucleoproteins (hnRNPs), in modulating mitochondrial metabolic reprogramming and contributing to chemoresistance in GCSCs. Through extensive analysis of tumor cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets, HNRNPA2B1 was identified as a key regulator in GCSCs, correlating with poor prognosis and enhanced resistance to chemoresistance. CRISPR-Cas9 mediated knockout of HNRNPA2B1 in GCSCs led to a significant decrease in mitochondrial function, reduced migration, invasion, and sphere formation abilities, and markedly increased apoptosis. These changes were accompanied by a shift in metabolic activity, evidenced by decreased oxygen consumption and increased extracellular acidification. Our results highlight HNRNPA2B1 as a pivotal factor in sustaining the malignant phenotype of GCSCs and present it as a potential therapeutic target to improve chemotherapy efficacy in GC.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108234"},"PeriodicalIF":4.0000,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biological Chemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jbc.2025.108234","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Gastric cancer (GC) remains a significant global health challenge, particularly due to the resistance of gastric cancer stem cells (GCSCs) to chemotherapy. This study investigates the role of heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), a member of the heterogeneous nuclear ribonucleoproteins (hnRNPs), in modulating mitochondrial metabolic reprogramming and contributing to chemoresistance in GCSCs. Through extensive analysis of tumor cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets, HNRNPA2B1 was identified as a key regulator in GCSCs, correlating with poor prognosis and enhanced resistance to chemoresistance. CRISPR-Cas9 mediated knockout of HNRNPA2B1 in GCSCs led to a significant decrease in mitochondrial function, reduced migration, invasion, and sphere formation abilities, and markedly increased apoptosis. These changes were accompanied by a shift in metabolic activity, evidenced by decreased oxygen consumption and increased extracellular acidification. Our results highlight HNRNPA2B1 as a pivotal factor in sustaining the malignant phenotype of GCSCs and present it as a potential therapeutic target to improve chemotherapy efficacy in GC.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

胃癌（GC）仍然是全球健康面临的重大挑战，特别是由于胃癌干细胞（GCSC）对化疗的耐药性。本研究探讨了异质核核糖核蛋白（hnRNPs）中的异质核核糖核蛋白A2/B1（HNRNPA2B1）在调节线粒体代谢重编程和导致胃癌干细胞化疗耐药性中的作用。通过对肿瘤癌症基因组图谱（TCGA）和基因表达总集（GEO）数据集的广泛分析，HNRNPA2B1被确定为GCSCs中的一个关键调控因子，与预后不良和化疗耐药性增强相关。在 CRISPR-Cas9 介导下敲除 GCSCs 中的 HNRNPA2B1 会导致线粒体功能显著下降，迁移、侵袭和球形成能力降低，凋亡明显增加。这些变化伴随着代谢活动的改变，表现为耗氧量减少和细胞外酸化增加。我们的研究结果突显了 HNRNPA2B1 是维持 GCSCs 恶性表型的关键因素，并将其作为改善 GC 化疗疗效的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

自引率

4.20%

发文量

1233

期刊介绍： The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.