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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

32卷

期数:

2026年03期

页码:

228-235

栏目:

肿瘤疾病专题

出版日期:

2026-05-20

文章信息/Info

Title:

Multi-omics data screening identifies IGFBP7 as a critical gene in ESCC

文章编号:

1006-8147（2026）03-0228-08

作者:

李心悦; 孟歆怿; 赵倩

天津医科大学基础医学院医学细胞生物学系，天津300070

Author(s):

LI Xinyue; MENG Xinyi; ZHAO Qian

Department of Medical Cell Biology， School of Basic Medicine， Tianjin Medical University， Tianjin 300070， China

关键词:

食管鳞状细胞癌; 枢纽基因; 生物信息学; DNA甲基化; 预后标志物

Keywords:

esophageal squamous cell carcinoma;  Hub genes;  bioinformatics;  DNA methylation;  prognostic biomarker

分类号:

R735.1

DOI:

10.20135/j.issn.1006-8147.2026.03.0228

文献标志码:

A

摘要:

目的：通过整合多组学数据系统识别食管鳞状细胞癌（ESCC）中受表观遗传与转录调控协同作用的关键基因，并选取代表性基因胰岛素样生长因子结合蛋白7（IGFBP7）进行实验验证。方法：基于GEO（GeneExpressionOmnibus）数据库获取ESCC的转录组（GSE149609）、甲基化（GSE157807）和染色质可及性（GSE167488）数据，识别肿瘤与正常组织间的差异基因、差异甲基化区域和差异开放区域。通过多组学交集筛选关键候选基因，并利用TCGA（TheCancerGenomeAtlas）数据库中ESCC队列进行生存和诊断验证。针对关键基因IGFBP7，构建IGFBP7敲低的KYSE-30细胞模型作为sh-IGFBP7组，转染空载pLKO.1载体的KYSE-30细胞作为阴性对照组（NC）组，通过CCK-8、流式细胞术、Transwell及划痕实验系统评估IGFBP7敲低对细胞增殖、凋亡、迁移与侵袭的影响。结果：多组学整合分析共鉴定出9个候选关键基因。受试者工作特征（ROC）曲线分析进一步筛选出3个关键基因（INHBA、PITX1和IGFBP7），其在TCGA队列中均显示出优异的诊断效能（曲线下面积>0.75）。富集分析显示，上调基因显著富集于细胞外基质组织、趋化及细胞因子-细胞因子受体相互作用等通路，而下调基因则与膜电位调节、表皮发育及cAMP信号通路等相关。免疫浸润分析显示，ESCC肿瘤微环境呈现免疫抑制特征，表现为活化CD4记忆T细胞、中性粒细胞及M0型巨噬细胞浸润增加，而静息CD4记忆T细胞、静息树突状细胞等抗肿瘤免疫细胞减少。CCK-8实验显示，与NC组相比，sh-IGFBP7组在24、48和72h的细胞增殖活力均显著降低（t=4.148，P<0.05；t=4.377，P<0.05；t=5.124，P<0.01），且抑制作用随时间延长而增强。划痕实验显示，与NC组相比，培养24h后sh-IGFBP7组的细胞迁移能力显著降低。Transwell迁移与侵袭实验显示，与NC组相比，sh-IGFBP7组穿过滤膜的细胞数量显著减少（迁移t=17.573，P<0.001；侵袭t=13.473，P<0.0001）。此外，流式细胞术检测显示，与NC组相比，sh-IGFBP7组的总细胞凋亡率显著升高（t=23.491，P<0.0001）。以上功能实验结果表明，IGFBP7敲低能显著抑制ESCC细胞的增殖、迁移和侵袭能力，并诱导细胞凋亡。结论：筛选出3个受表观遗传与染色质状态协同调控的ESCC关键基因。通过系统功能实验补充并扩展了IGFBP7在ESCC中发挥致癌基因的作用。

Abstract:

Objective： To systematically identify key genes in esophageal squamous cell carcinoma（ESCC） under the coordinated re-gulation of epigenetic and transcriptional mechanisms by integrating multi-omics data， and to experimentally validate the representa-tive gene insulin-like growth factor-binding protein 7（IGFBP7）. Methods： Transcriptomic（GSE149609）， methylation（GSE157807）， and chromatin accessibility（GSE167488） data for ESCC were obtained from the Gene Expression Omnibus（GEO） database. Differ-ential expression genes， differentially methylated regions， and differential open chromatin regions between tumor and normal tissues were identified. Key candidate genes were screened through multi-omics intersection and further validated for survival and diagnostic value using the ESCC cohort from The Cancer Genome Atlas（TCGA）. For the key gene IGFBP7， a stable IGFBP7-knockdown KYSE-30 cell model （designated as the sh-IGFBP7 group） was constructed， with KYSE-30 cells transfected with the empty pLKO.1 vector serving as the negative control（NC） group. The impact of IGFBP7 knockdown on cell proliferation， apoptosis， migration， and inva-sion was systematically evaluated through CCK-8 assay， flow cytometry， Transwell assay， and wound healing assay. Results： Inte-grated multi-omics analysis identified nine candidate key genes. Receiver operating characteristic（ROC） curve analysis further pin-pointed three key genes（INHBA， PITX1， and IGFBP7）， all of which showed excellent diagnostic performance（AUC>0.75） in the TCGA cohort. Enrichment analysis revealed that upregulated genes were significantly enriched in pathways such as extracellular ma-trix organization， chemotaxis， and cytokine-cytokine receptor interaction， while downregulated genes were related to regulation of membrane potential， epidermis development， and the cAMP signaling pathway. Immune infiltration analysis indicated an immunosup-pressive tumor microenvironment in ESCC， characterized by increased infiltration of activated CD4 memory T cells， neutrophils， and M0 macrophages， and decreased levels of anti-tumor immune cells such as resting CD4 memory T cells and resting dendritic cells. CCK-8 assay showed that cell proliferation viability of the sh-IGFBP7 group was markedly reduced at 24， 48， and 72 hours com-pared to the negative control （NC） group （t=4.148， P<0.05； t=4.377， P<0.05； t=5.124， P<0.01）， with the inhibitory effect in-tensifying over time. Wound healing showed that compared with the NC group， the cell migration ability of the sh-IGFBP7 group was significantly reduced after 24 hours of cultivation. Transwell migration and invasion experiments showed that compared with the NC group， the number of cells passing through the filter membrane in the sh-IGFBP7 group was significantly reduced（migration： t=17.573， P<0.001； invasion： t=13.473， P<0.000 1）. Furthermore， flow cytometry analysis showed a significant increase in the total apoptosis rate upon IGFBP7 knockdown compared to the NC group（t=23.491，P<0.000 1）. Functional experiments demonstrated that IGFBP7 knockdown significantly inhibited the proliferation， migration， and invasion ability of ESCC cells， and induced cell apoptosis. Conclu-sion： Three key genes（INHBA， PITX1， and IGFBP7）are identified in ESCC potentially co-regulated by epigenetic and chromatin states. Systematic functional validation substantiates and extends the oncogenic role of IGFBP7 in ESCC cells.

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备注/Memo

备注/Memo:

作者简介 李心悦（2000-），女，硕士在读，研究方向：表观遗传学；通信作者：赵倩，E-mail：zhaoq@tmu.edu.cn。
（2025-11-14收稿）

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更新日期/Last Update: 2026-05-25