CD51 promotes gastric cancer stemness via blocking Numb-mediated Notch1 degradation

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-06-22 DOI:10.1016/j.canlet.2025.217886

Juzheng Peng , Yuehan Yin , Xuan Liu , Cuncan Deng , Peizhu Wang , Xiaojie Hu , Jiefu Chen , Sicheng Peng , Kuan Li , Li Zhong , Zhijun Zhou , Yulong He , Jiancheng Wang

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引用次数: 0

Abstract

Gastric cancer (GC) remains a lethal malignancy with poor prognosis largely due to cancer stem cell (CSC)-driven metastasis, recurrence, and chemoresistance. This study identifies CD51 (integrin αv) as a pivotal regulator of GC stemness and malignant progression. Bioinformatics analysis of TCGA data revealed significant CD51 upregulation in GC tissues, correlating with advanced tumor stage and poor survival. Functional assays demonstrated that CD51 enhances CSC properties, including tumorsphere formation, migration, invasion, and oxaliplatin resistance. Mechanistically, CD51 interacts with Numb, a negative regulator of Notch signaling, to divert Notch1 receptor trafficking from lysosomal degradation to plasma membrane recycling, thereby amplifying Notch pathway activation. Single-cell RNA sequencing and clinical validations confirmed CD51's superior correlation with stemness scores compared to canonical CSC markers. Pharmacological inhibition of CD51 using cilengitide suppressed CSC phenotypes in vitro and inhibited tumor growth in patient-derived organoids and xenograft models. These findings establish CD51 as a novel CSC biomarker and therapeutic target, offering a strategy to disrupt Notch-dependent stemness and chemoresistance in GC.

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CD51通过阻断麻木介导的Notch1降解促进胃癌干性。

胃癌（GC）仍然是一种预后不良的致死性恶性肿瘤，主要是由于癌症干细胞（CSC）驱动的转移、复发和化疗耐药。本研究发现CD51（整合素αv）是胃癌干细胞和恶性进展的关键调节因子。TCGA数据的生物信息学分析显示，CD51在胃癌组织中显著上调，与肿瘤分期晚期和生存率低相关。功能分析表明，CD51增强了CSC的特性，包括肿瘤球形成、迁移、侵袭和奥沙利铂耐药性。从机制上讲，CD51与Notch信号的负调节因子Numb相互作用，将Notch1受体转运从溶酶体降解转移到质膜再循环，从而放大Notch通路的激活。单细胞RNA测序和临床验证证实，与标准CSC标记物相比，CD51与干细胞评分的相关性更强。西伦吉肽对CD51的药理抑制在体外抑制CSC表型，并抑制患者来源的类器官和异种移植模型中的肿瘤生长。这些发现确立了CD51作为一种新的CSC生物标志物和治疗靶点，提供了一种破坏GC中notch依赖性干性和化疗耐药的策略。

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

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.