Targeting YBX1: A novel therapeutic strategy for gastric cancer through regulation of cellular senescence and mTOR signaling

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-08-14 DOI:10.1016/j.tice.2025.103089

Wenze Zhang , Yanjuan Jia , Anqi Wang , Rui Guo , Zhuomin Fu , Wanxia Wang

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引用次数: 0

Abstract

Gastric cancer (GC) continues to pose a significant challenge for treatment due to its heterogeneity and the limitations of current strategies. There is an urgent need to find new molecular targets and strategies that can overcome therapy limitations and enhance outcomes. The modern “one-two punch" therapy involves inducing senescence and using a second drug to target senescent cancer cells, potentially offering an effective treatment. However, it remains an emerging research area for GC. In this study, we aimed to investigate the role of YBX1, a multifunctional RNA- and DNA-binding protein, in GC progression and its therapeutic potential in senescence-based strategies. We found that YBX1, which is elevated in gastric cancer cells and correlated with poor prognosis in gastric cancer patients, acts as a central hub linking the mTOR, ROS, and DDR pathways. YBX1 mRNA and protein levels were significantly higher in GC tissues than in adjacent normal tissues (P < 0.001), and high expression was associated with reduced overall survival (P < 0.05). Importantly, YBX1 promotes the proliferation of GC cells (P < 0.01) and inhibits senescence by regulating the mTOR signaling pathway. Targeting YBX1 could offer a “one-two punch” therapeutic approach for GC, since inhibiting mTOR induces senolytic effects on senescent cancer cells. Furthermore, YBX1 knockdown increases ROS levels (P < 0.0001) and disrupts DNA damage repair, enhancing its potential as a therapeutic target. In vivo xenograft studies confirmed that YBX1 inhibition reduces tumor growth and downregulates Ki67, pmTOR, and p4EBP1 expression (P < 0.001), while upregulating cellular senescence markers (P < 0.01), supporting its critical role in GC progression. Thus, this study underscores YBX1 as a pivotal regulator of GC cell proliferation, senescence, and survival, offering a promising avenue for targeted therapies. By leveraging YBX1 inhibition, this work lays a foundation for developing precision medicine approaches in GC treatment.

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靶向YBX1：通过调控细胞衰老和mTOR信号传导治疗胃癌的新策略

胃癌（GC）由于其异质性和当前策略的局限性，继续对治疗构成重大挑战。迫切需要找到新的分子靶点和策略，以克服治疗局限性并提高疗效。现代的“组合拳”疗法包括诱导衰老和使用第二种药物靶向衰老的癌细胞，可能提供有效的治疗。然而，它仍然是GC的一个新兴研究领域。在这项研究中，我们旨在研究YBX1（一种多功能RNA和dna结合蛋白）在GC进展中的作用及其在基于衰老的策略中的治疗潜力。我们发现YBX1在胃癌细胞中升高，与胃癌患者预后不良相关，是连接mTOR、ROS和DDR通路的中心枢纽。胃癌组织中YBX1 mRNA和蛋白水平显著高于邻近正常组织（P < 0.001），高表达与总生存率降低相关（P < 0.05）。重要的是，YBX1通过调节mTOR信号通路促进GC细胞增殖（P < 0.01），抑制衰老。靶向YBX1可以提供一种“组合拳”治疗胃癌的方法，因为抑制mTOR可诱导衰老癌细胞的衰老作用。此外，YBX1敲低会增加ROS水平（P < 0.0001），破坏DNA损伤修复，增强其作为治疗靶点的潜力。体内异种移植研究证实，YBX1抑制可抑制肿瘤生长，下调Ki67、pmTOR和p4EBP1的表达（P < 0.001），同时上调细胞衰老标志物（P < 0.01），支持其在胃癌进展中的关键作用。因此，本研究强调YBX1是胃癌细胞增殖、衰老和存活的关键调节因子，为靶向治疗提供了一条有希望的途径。通过利用YBX1的抑制作用，本工作为开发GC治疗的精准医学方法奠定了基础。

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

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.