The pivotal role of SFRP2 in promoting glycolysis and progression in the high-risk group based on the glycometabolism prognostic model for colorectal cancer.

IF 5.5 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Feng Du, Xu Ji, Jiayi Su, Chuntao Liu, Junxiong Wang, Tingting Ning, Nan Zhang, Junxuan Xu, Si-An Xie, Si Liu, Li Min, Jing Wu, Shutian Zhang, Shuilong Guo, Shengtao Zhu, Peng Li
{"title":"The pivotal role of SFRP2 in promoting glycolysis and progression in the high-risk group based on the glycometabolism prognostic model for colorectal cancer.","authors":"Feng Du, Xu Ji, Jiayi Su, Chuntao Liu, Junxiong Wang, Tingting Ning, Nan Zhang, Junxuan Xu, Si-An Xie, Si Liu, Li Min, Jing Wu, Shutian Zhang, Shuilong Guo, Shengtao Zhu, Peng Li","doi":"10.1007/s00535-025-02281-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Reprogramming glucose metabolism is a hallmark of human cancer during its occurrence and development. However, the comprehensive glycometabolism signature and underlying mechanism in CRC prognosis and immune response remind to be elucidated.</p><p><strong>Methods: </strong>A prognostic model derived from 297 glycometabolism-related genes (GRGs) was developed using LASSO-Cox and nomogram algorithms. Immune dysfunction between high-risk (Risk<sup>H</sup>) and low-risk (Risk<sup>L</sup>) groups was compared using CIBERSORT, TIMER, and TIDE analyses. The expression and function of key genes, including secreted frizzled-related protein 2 (SFRP2), were validated using PCR, western blotting, immunohistochemistry, transwell assays, and metastatic model in mice. Luciferase reporter and chromatin immunoprecipitation were used to determine the transcription regulation of ENO2 by TCF4.</p><p><strong>Results: </strong>More than half of the GRGs (152 out of 297) showed differential expression, mainly those associated with glycolysis and biosynthesis. The GRG-risk score outperformed other clinical indicators (AUC = 0.810) and served as an independent risk predictor (P < 0.001, HR = 3.180). The Risk<sup>H</sup> group showed increased infiltration of immune cells and higher immune checkpoint expression. Mechanistically, SFRP2, a key gene in Risk<sup>H</sup>, promoted CRC glycolysis and metastasis via enolase 2 (ENO2) activation through the TCF4/β-catenin axis. Inhibiting ENO2 reversed SFRP2-induced metastasis. Coexpression of SFRP2 and ENO2 correlated with poorer survival and higher recurrence.</p><p><strong>Conclusion: </strong>The Risk<sup>H</sup> group is characterized by glycolysis overactivation and immune exclusion. SFRP2 and ENO2 have emerged as promising treatment targets for high-risk CRC patients.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.5000,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-025-02281-5","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Reprogramming glucose metabolism is a hallmark of human cancer during its occurrence and development. However, the comprehensive glycometabolism signature and underlying mechanism in CRC prognosis and immune response remind to be elucidated.

Methods: A prognostic model derived from 297 glycometabolism-related genes (GRGs) was developed using LASSO-Cox and nomogram algorithms. Immune dysfunction between high-risk (RiskH) and low-risk (RiskL) groups was compared using CIBERSORT, TIMER, and TIDE analyses. The expression and function of key genes, including secreted frizzled-related protein 2 (SFRP2), were validated using PCR, western blotting, immunohistochemistry, transwell assays, and metastatic model in mice. Luciferase reporter and chromatin immunoprecipitation were used to determine the transcription regulation of ENO2 by TCF4.

Results: More than half of the GRGs (152 out of 297) showed differential expression, mainly those associated with glycolysis and biosynthesis. The GRG-risk score outperformed other clinical indicators (AUC = 0.810) and served as an independent risk predictor (P < 0.001, HR = 3.180). The RiskH group showed increased infiltration of immune cells and higher immune checkpoint expression. Mechanistically, SFRP2, a key gene in RiskH, promoted CRC glycolysis and metastasis via enolase 2 (ENO2) activation through the TCF4/β-catenin axis. Inhibiting ENO2 reversed SFRP2-induced metastasis. Coexpression of SFRP2 and ENO2 correlated with poorer survival and higher recurrence.

Conclusion: The RiskH group is characterized by glycolysis overactivation and immune exclusion. SFRP2 and ENO2 have emerged as promising treatment targets for high-risk CRC patients.

基于糖代谢预后模型的结直肠癌高危人群中,SFRP2在促进糖酵解和进展中的关键作用
背景:糖代谢重编程是人类癌症发生发展过程中的一个标志。然而,糖代谢在结直肠癌预后和免疫应答中的综合特征和潜在机制仍有待阐明。方法:采用LASSO-Cox和nomogram算法建立297个糖代谢相关基因(GRGs)的预后模型。采用CIBERSORT、TIMER和TIDE分析比较高危组(RiskH)和低危组(RiskL)之间的免疫功能障碍。通过PCR、western blotting、免疫组织化学、transwell实验和小鼠转移模型验证了关键基因(包括分泌卷曲相关蛋白2 (SFRP2))的表达和功能。采用荧光素酶报告基因法和染色质免疫沉淀法测定TCF4对ENO2的转录调控作用。结果:297个GRGs中有152个存在差异表达,主要与糖酵解和生物合成相关。grg风险评分优于其他临床指标(AUC = 0.810),可作为独立的风险预测指标(P H组免疫细胞浸润增加,免疫检查点表达升高)。从机制上讲,RiskH的关键基因SFRP2通过TCF4/β-catenin轴通过烯醇化酶2 (ENO2)激活促进CRC糖酵解和转移。抑制ENO2可逆转sfrp2诱导的转移。SFRP2和ENO2的共表达与较差的生存率和较高的复发率相关。结论:RiskH组以糖酵解过度激活和免疫排斥为特征。SFRP2和ENO2已成为高危CRC患者有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Gastroenterology
Journal of Gastroenterology 医学-胃肠肝病学
CiteScore
12.20
自引率
1.60%
发文量
99
审稿时长
4-8 weeks
期刊介绍: The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信