PO.ET06.04 · 实验与分子治疗

整合素α5的原位与功能分析揭示其在非小细胞肺癌肿瘤进展中的作用

In situ and functional analysis of Integrin-alpha 5 reveals its role in tumor progression in non-small cell lung cancer

编号 2984 展板 6 时间 4/20 02:00–05:00 区域 Section 13 主讲 Mirei Ka, BS;MS

分会场 Molecular Targets 1

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作者与单位 Authors & Affiliations

Mirei Ka¹, Takahiro Ando², Munetoshi Hinata³, Kousuke Watanabe⁴, Akiko Kunita⁴, Masanori Kawakami², Masaaki Sato⁵, Hiroyuki Okada⁶, Hironori Hojo⁷, Tetsuo Ushiku³, Cecilia C. Krona⁸, Patrick Micke⁸, Katsutoshi Oda¹, Hidenori Kage²

¹Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan,²Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan,³Department of Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan,⁴Next-Generation Precision Medicine Development Laboratory, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan,⁵Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan,⁶Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan,⁷Bioinformatics Research Unit, Graduate School of Dentistry, The University of Osaka, Suita City, Japan,⁸Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden

摘要 Abstract

中文摘要

[背景] 整合素是介导细胞与相邻细胞及细胞外基质黏附的跨膜受体，从而调控基本的细胞过程。整合素表达异常已被证明与多种癌症类型的肿瘤进展和转移相关，主要通过其与肿瘤微环境组分的相互作用。整合素α5（ITGA5）通常与常见共享的β1亚基形成异二聚体，并作为纤连蛋白和纤维蛋白原的受体发挥功能。本研究旨在探究ITGA5在非小细胞肺癌（NSCLC）中的临床和生物学意义。 [方法] 生存分析基于东京大学医院NSCLC患者队列（n = 100）和癌症基因组图谱（TCGA；n = 986）的RNA-seq数据集。蛋白表达通过免疫组织化学（IHC）在来自东京大学医院（n = 20）和乌普萨拉大学医院（瑞典；n = 312，其中还包含大量突变数据）的NSCLC患者诊断组织样本中进行分析。ITGA5的生物学相关性在使用Calu-1细胞的异种移植模型中通过ITGA5抑制剂（GLPG0187）进行实验评估，并通过bulk RNA-seq分析检测来自同一细胞系的ITGA5敲低效应。 [结果] RNA和蛋白水平的生存分析一致表明，高ITGA5表达在多个队列中与更短的生存期相关（TCGA RNA：p=0.011；东京大学医院RNA：p=0.025；东京大学医院蛋白：p=0.038；乌普萨拉大学医院蛋白：p=0.013）。值得注意的是，蛋白IHC分析表明ITGA5在肿瘤细胞中的影响大于在基质细胞中的影响。与对照相比，抑制ITGA5可在体内抑制肿瘤生长。Bulk RNA-seq数据显示，ITGA5敲低改变了参与整合素介导信号传导的基因表达。FERMT2、SEMA7A和CCN1/CCN2等基因在敲低后表达降低，这与它们在整合素激活、ECM重塑和促侵袭信号传导中的作用一致。此外，该分析显示与炎症和肿瘤免疫（如CSF3、CXCL8、IL6ST）、EMT（如TGFBR1、CDH2、PXN）和mTOR信号传导（如PIK3R2、STAT3、HRAS）相关的通路发生下调。 [结论] 我们的研究在临床背景下对ITGA5在RNA和蛋白水平的表达进行了全面分析。结果表明ITGA5在促进肺癌肿瘤进展和不良预后中发挥关键作用，为进一步研究ITGA5作为具有生物标志物和治疗潜力的靶点提供了依据，以用于ITGA5表达升高的NSCLC患者。

查看英文原文 English abstract

[Background] Integrins are transmembrane receptors that mediate cell adhesion to adjacent cells and the extracellular matrix, thereby regulating fundamental cellular processes. Abnormal integrin expression has been linked to tumor progression and metastasis across multiple cancer types, primarily through their interactions with components of the tumor microenvironment. Integrin alpha-5 (ITGA5) typically forms a heterodimer with the commonly shared beta-1 subunit and functions as a receptor for fibronectin and fibrinogen. This study aimed to investigate the clinical and biological significance of ITGA5 in non-small cell lung cancer (NSCLC). [Methods] Survival analysis was based on RNA-seq data sets from NSCLC patient cohorts of the University of Tokyo Hospital (n = 100) and The Cancer Genome Atlas (TCGA; n = 986). Protein expression was analyzed by immunohistochemistry (IHC) in diagnostic tissue samples from NSCLC patients from The University of Tokyo Hospital (n = 20) and from the Uppsala University Hospital (Sweden; n = 312), which also included extensive mutation data. The biological relevance of ITGA5 was experimentally evaluated in a xenograft model with Calu-1 cells using an ITGA5 inhibitor (GLPG0187), and the effect of ITGA5 knockdown derived from the same cell line was analyzed by bulk RNA-seq analysis. [Results] Both RNA and protein-level survival analyses consistently revealed that high ITGA5 expression was associated with shorter survival across multiple cohorts (TCGA RNA: p=0.011; University of Tokyo Hospital RNA: p=0.025; University of Tokyo Hospital protein: p=0.038; Uppsala University Hospital protein: p=0.013). Notably, protein IHC analysis indicated a greater impact of ITGA5 in tumors than in stromal cells. ITGA5 inhibition suppressed tumor growth in vivo compared to controls. Bulk-RNA seq data showed that ITGA5 knockdown altered the expression of genes involved in integrin-mediated signaling. Genes such as FERMT2, SEMA7A, and CCN1/CCN2 showed decreased expression following knockdown, consistent with their roles in integrin activation, ECM remodeling, and pro-invasive signaling. In addition, this analysis showed downregulation of pathways related to inflammation and tumor immunity (e.g., CSF3, CXCL8, IL6ST), EMT (e.g., TGFBR1, CDH2, PXN), and mTOR signaling (e.g., PIK3R2, STAT3, HRAS). [Conclusion] Our study provides a comprehensive analysis of ITGA5 expression on RNA and protein levels in the clinical context. The results indicate an essential role of ITGA5 in promoting tumor progression and poor prognosis in lung cancer, providing the rationale for further studying ITGA5 as a target with biomarker and therapeutic potential for NSCLC patients with elevated ITGA5 expression.

利益披露 Disclosure

M. Ka, None.. T. Ando, None.. M. Hinata, None. K. Watanabe, Konica Minolta ). A. Kunita, None.. M. Kawakami, None.. M. Sato, None.. H. Okada, None.. H. Hojo, None.. T. Ushiku, None.. C. C. Krona, None.. P. Micke, None. K. Oda, Konica Minolta ). H. Kage, Konica Minolta ).

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