Zhang Wenze, Jia Yanjuan, Wang Anqi, Guo Rui, Fu Zhuomin, Wang Wanxia
The First College of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China.
NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China.
Tissue Cell. 2025 Dec;97:103089. doi: 10.1016/j.tice.2025.103089. Epub 2025 Aug 14.
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.
由于胃癌（GC）的异质性和当前治疗策略的局限性，其治疗仍然面临重大挑战。迫切需要找到能够克服治疗局限性并改善治疗效果的新分子靶点和策略。现代的“双拳出击”疗法包括诱导衰老并使用第二种药物靶向衰老癌细胞，这可能提供一种有效的治疗方法。然而，对于胃癌来说，这仍是一个新兴的研究领域。在本研究中，我们旨在探究多功能RNA和DNA结合蛋白YBX1在胃癌进展中的作用及其在基于衰老的治疗策略中的治疗潜力。我们发现，YBX1在胃癌细胞中表达升高，且与胃癌患者的不良预后相关，它是连接mTOR、ROS和DDR通路的核心枢纽。YBX1的mRNA和蛋白水平在GC组织中显著高于相邻正常组织（P < 0.001），高表达与总生存期缩短相关（P < 0.05）。重要的是，YBX1促进GC细胞增殖（P < 0.01）并通过调节mTOR信号通路抑制衰老。靶向YBX1可为胃癌提供“双拳出击”的治疗方法，因为抑制mTOR可对衰老癌细胞产生促衰老溶解作用。此外，敲低YBX1可增加ROS水平（P < 0.0001）并破坏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，抑制YBX1可减少肿瘤生长并下调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前景的途径。通过利用对YBX1的抑制作用，这项工作为开发胃癌治疗的精准医学方法奠定了基础。
