N6-甲基腺苷阅读器 hnRNPA2B1 能识别并稳定 NEAT1,从而赋予胃癌化疗抗性。

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2024-03-21 DOI:10.1002/cac2.12534
Jiayao Wang, Jiehao Zhang, Hao Liu, Lingnan Meng, Xianchun Gao, Yihan Zhao, Chen Wang, Xiaoliang Gao, Ahui Fan, Tianyu Cao, Daiming Fan, Xiaodi Zhao, Yuanyuan Lu
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引用次数: 0

摘要

背景:化疗耐药性是胃癌(GC)治疗失败的主要原因:耐药性是胃癌(GC)治疗失败的主要原因。异构核糖核蛋白 A2B1(hnRNPA2B1)是一种 N6-甲基腺苷(m6A)结合蛋白,与多种癌症有关。然而,m6A修饰和hnRNPA2B1是否在GC化疗耐药性中发挥作用,目前尚不清楚。本研究旨在探讨 hnRNPA2B1 在 GC 化疗耐药性中的作用及其下游机制:方法:通过定量 PCR(qPCR)、Western 印迹、免疫荧光和免疫组化染色等方法分析和验证了 hnRNPA2B1 在公开数据集中的表达情况。在体外和体内研究了 hnRNPA2B1 在 GC 化疗耐药性中的生物学功能。通过RNA测序、甲基化RNA免疫沉淀、RNA免疫沉淀和RNA稳定性检测来评估hnRNPA2B1与结合RNA之间的关联。通过生物信息分析、qPCR、Western 印迹、免疫荧光和球形成实验评估了 hnRNPA2B1 在维持 GC 干性中的作用。通过RNAscope和多重免疫组化分析了辅助化疗患者GC标本中hnRNPA2B1和下游调控因子的表达模式:结果:hnRNPA2B1在GC细胞和组织中的表达升高,尤其是在耐多药(MDR)GC细胞系中。hnRNPA2B1的表达与GC患者的不良预后有关,尤其是接受5-氟尿嘧啶治疗的患者。沉默hnRNPA2B1能在体外和体内抑制细胞增殖并诱导细胞凋亡,从而有效地使GC细胞对化疗敏感。在机制上,hnRNPA2B1与长非编码RNA NEAT1相互作用,并以m6A依赖性的方式稳定NEAT1。此外,hnRNPA2B1和NEAT1通过Wnt/β-catenin信号通路共同增强了GC细胞的干性。在接受化疗的GC患者的临床标本中,非应答者与应答者相比,hnRNPA2B1、NEAT1、CD133和CD44的表达水平明显升高:我们的研究结果表明,hnRNPA2B1与lncRNA NEAT1相互作用并使其稳定,从而通过Wnt/β-catenin通路维持干性特性,并加剧GC的化疗耐药性。
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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N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer

Background

Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance.

Methods

The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry.

Results

Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders.

Conclusion

Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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