YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/β-catenin axis

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Gene Medicine Pub Date : 2024-04-27 DOI:10.1002/jgm.3689

Xiaodong Shi, Zhiliang Hu, Shilei Bai, Chen Zong, Hui Xue, Yao Li, Fengwei Li, Liangrui Chen, Jianbing Xuan, Yong Xia, Lixin Wei, Feng Shen, Kui Wang

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Abstract

Background

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear.

Methods

Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/β-catenin pathways.

Results

YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/β-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/β-catenin axis.

Conclusions

YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/β-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

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YBX1通过AKT/β-catenin轴促进肝内胆管癌的干性和顺铂不敏感性

背景肝内胆管癌（ICC）是一种侵袭性极强的恶性肿瘤，其特点是预后不良，并与肿瘤干性密切相关。然而，调控 ICC 干性的关键分子仍然难以捉摸。虽然Y-盒结合蛋白1（YBX1）通过增强干性和化疗耐药性对多种癌症的预后产生负面影响，但它对ICC的干性和顺铂敏感性的影响仍不清楚。方法分析了三个大样本和单细胞RNA-seq数据集，以研究YBX1在ICC中的表达及其与干性的关系。临床样本和集落/球形成试验验证了YBX1在干性和顺铂敏感性中的作用。AZD5363和KYA1979K探讨了YBX1与磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（PKB/AKT）和WNT/β-catenin通路的相互作用。结果 YBX1在ICC中明显上调，与较差的总生存率和较短的术后复发时间相关，在化疗无反应的ICC组织中YBX1含量较高。YBX1高表达组的干性评分明显升高，与YBX1上调相关的基因富集在多个干性相关通路中。此外，YBX1的表达与多个干性相关基因（SOX9、OCT4、CD133、CD44和EPCAM）显著相关。此外，YBX1的过表达能显著增强ICC细胞的集落和球形形成能力，加速体内肿瘤生长，并降低其对顺铂的敏感性。相反，下调YBX1则会产生相反的效果。转录组分析强调了 YBX1 与 PI3K/AKT 和 WNT/β-catenin 通路之间的联系。此外，AZD5363和KYA1979K被用于阐明YBX1通过调节AKT/β-catenin轴促进ICC干性。结论 YBX1在ICC中上调，并通过AKT/β-catenin轴促进干性和顺铂不敏感性。我们的研究描述了一种改善 ICC 预后的新型潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.