南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (11): 2416-2426.doi: 10.12122/j.issn.1673-4254.2025.11.14

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高表达YEATS2通过激活Wnt/β-catenin通路促进胃癌细胞上皮-间质转化进程

姜雪凝1(), 黄晴晴2, 徐盈2, 王舜印2, 张小凤2, 王炼1, 王月月2, 左芦根1,2()   

  1. 1.蚌埠医科大学第一附属医院胃肠外科,安徽 蚌埠 233004
    2.炎症相关性疾病基础与转化研究安徽省重点实验室,安徽 蚌埠 233030
  • 收稿日期:2025-05-06 出版日期:2025-11-20 发布日期:2025-11-28
  • 通讯作者: 左芦根 E-mail:jiangxn1202@163.com;zuolugen@126.com
  • 作者简介:姜雪凝,在读硕士研究生,E-mail: jiangxn1202@163.com
  • 基金资助:
    国家自然科学基金(82370534);安徽省卫生健康科研项目(AHWJ2022a019);安徽省高校杰出青年科研项目(2022AH020085);安徽省临床医学研究转化专项(202427b10020099)

High YEATS2 expression promotes epithelial-mesenchymal transition in gastric cancer cells by activating the Wnt/β-catenin signaling pathway

Xuening JIANG1(), Qingqing HUANG2, Ying XU2, Shunyin² WANG2, Xiaofeng² ZHANG2, Lian¹ WANG1, Yueyue² WANG2, Lugen ZUO1,2()   

  1. 1.Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China
    2.Anhui Provincial Key Laboratory of Basic and Translational Research on Inflammation-related Diseases, Bengbu 233030, China
  • Received:2025-05-06 Online:2025-11-20 Published:2025-11-28
  • Contact: Lugen ZUO E-mail:jiangxn1202@163.com;zuolugen@126.com
  • Supported by:
    National Natural Science Foundation of China(82370534)

摘要:

目的 探究YEATS2在胃癌组织中的表达水平及其临床预后价值,并揭示其对胃癌细胞EMT进程的作用和机制。 方法 基于TIMER2.0、GEPIA等公共数据库预测YEATS2在胃癌中的表达水平;纳入100例在本院接受胃癌根治术的患者,通过免疫组化检测胃癌及癌旁组织中YEATS2表达,分析其与临床病理参数和Ki67的相关性;采用Kaplan-Meier生存分析、Cox回归和ROC曲线评估YEATS2的预后价值;通过生物富集分析预测YEATS2对胃癌可能的作用和机制,构建YEATS2敲低与过表达的胃癌细胞系(HGC-27与AGS),设shNC、shYEATS2、Vector和OE-YEATS2组,分别采用shRNA阴性对照慢病毒和YEATS2特异性干扰慢病毒、空载对照慢病毒载体及YEATS2过表达慢病毒进行转染。结合细胞划痕、Transwell和Western blotting检测YEATS2对胃癌细胞迁移、侵袭及EMT的作用。 结果 YEATS2在胃癌组织中表达显著高于癌旁组织且与Ki67表达呈正相关(P<0.05)。YEATS2高表达组中CEA≥5 μg/L、CA19-9≥37 kU/L、T3-4期及N2-3期的患者比例高于低表达组(P<0.05)。生存分析显示YEATS2高表达患者术后5年生存率降低(P<0.001),ROC曲线分析表明YEATS2评估胃癌患者根治术后5年生存率的敏感性为80.00%,特异性为66.67%(P<0.05)。Cox回归显示YEATS2高表达是胃癌患者术后5年生存率低的独立危险因素(HR:1.675,95%CI:1.013~2.771,P=0.045)。富集分析提示YEATS2可能与胃癌EMT过程和Wnt/β-catenin通路有关。体外实验表明,YEATS2高表达可促进胃癌细胞迁移、侵袭,同时上调Vimentin、N-cadherin、Wnt和Active β-catenin,并下调E-cadherin的表达(P<0.05)。经XAV-939(Wnt/β-catenin抑制剂)处理后,YEATS2过表达导致的EMT相关蛋白表达变化(N-cadherin、Vimentin上调和E-cadherin下调)被显著削弱(P<0.05)。 结论 YEATS2高表达可能激活Wnt/β-catenin通路促进胃癌细胞EMT进程,并与患者预后不良有关。

关键词: 胃癌, YEATS2, 预后, 上皮-间质转化, Wnt/β-catenin

Abstract:

Objective To investigate YEATS2 expression in gastric cancer (GC), its prognostic value, and its regulatory role in epithelial-mesenchymal transition (EMT) of GC cells. Methods YEATS2 expression in GC was analyzed using publicly available databases. Paired GC and adjacent tissues were collected from 100 patients undergoing radical surgery for immunohistochemical detection of YEATS2 expression, and its correlations with the patients' clinicopathological parameters and Ki67 expression were analyzed. The prognostic value of YEATS2 was assessed using Kaplan-Meier analysis, Cox regression and ROC curves, and its regulatory mechanisms were analyzed using KEGG enrichment analysis. In cultured GC cell lines (HGC-27 and AGS), the effect of YEATS2 knockdown and overexpression on migration, invasion and EMT of the cells were examined with scratching assay, Transwell assay and Western blotting. Results YEATS2 was significantly overexpressed in GC tissues with a positive correlation with Ki67 (P<0.05). High YEATS2 expression was associated with elevated CEA (≥5 μg/L), CA19-9 (≥37 kU/L), T3-4 stage, and N2-3 stage (all P<0.05). Patients with high YEATS2 expression had significantly reduced 5-year survival (P<0.001); ROC analysis showed that YEATS2 expression levels had a sensitivity of 80.00% and a specificity of 66.67% for predicting patient survival (P<0.05). Cox regression identified high YEATS2 as an independent risk factor for poor postoperative 5-year survival outcome of GC patients (HR: 1.675, 95%CI: 1.013-2.771; P=0.045). KEGG enrichment analysis suggested involvement of YEATS2 in EMT in GC and Wnt/β-catenin signaling. In cultured GC cells, YEATS2 overexpression significantly promoted cell migration and invasion, upregulated the expressions of vimentin, N-cadherin, Wnt and active β-catenin, and downregulated E-cadherin expression, and these changes were obviously suppressed by treatment with XAV-939 (a Wnt/β-catenin inhibitor). Conclusion High YEATS2 expression activates Wnt/β-catenin signaling to promote EMT in GC and is correlated with poor prognosis of GC patients.

Key words: Gastric cancer, YEATS2, prognosis, epithelial-mesenchymal transition, Wnt/β-catenin