Shijie Yao, Siming Chen, Shimeng Wan, Anjin Wang, Ziyan Liang, Xuelian Liu, Yang Gao, Hongbing Cai
{"title":"LAG3作为宫颈癌的肿瘤抑制因子和免疫调节因子：从功能验证到治疗策略","authors":"Shijie Yao, Siming Chen, Shimeng Wan, Anjin Wang, Ziyan Liang, Xuelian Liu, Yang Gao, Hongbing Cai","doi":"10.1002/cam4.71278","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Cervical cancer remains a significant health burden for women worldwide, with persistent high-risk HPV infection being a major etiological factor. Despite treatment advances, prognosis for recurrent or metastatic disease remains poor. Pyroptosis, a form of programmed cell death, plays a dual role in tumor immunity, but its implications in cervical cancer are not fully elucidated. This study aims to systematically characterize pyroptosis-related genes (PRGs) in cervical cancer and explore their prognostic and therapeutic relevance.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Multi-omics data from TCGA and GEO databases were integrated to analyze genetic variations, expression patterns, and prognostic significance of 52 PRGs in cervical cancer. Consensus clustering was used to identify PRG subtypes. A prognostic risk score model was constructed using LASSO-Cox regression based on differentially expressed genes (DEGs). Functional validation was performed via in vitro and in vivo experiments, including Western blot, CCK-8, colony formation, transwell assays, and a subcutaneous tumor model. Single-cell RNA sequencing data (GSE171894, GSE168652) were analyzed to explore LAG3 expression in the tumor immune microenvironment.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Two distinct PRG subtypes were identified, with subtype A showing immune activation features. A five-gene prognostic signature (GNAZ, LAG3, IL-1β, CA2, SPRR3) effectively stratified patients into high- and low-risk groups. Low LAG3 expression was associated with poor prognosis. Functional experiments demonstrated that LAG3 overexpression suppressed cervical cancer cell proliferation, migration, and tumor growth, while its knockdown promoted malignant phenotypes. Single-cell analysis revealed high LAG3 expression in Treg and CD8⁺ T cells, suggesting its role in immune regulation.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>This study establishes a novel PRG-based prognostic model and highlights LAG3 as a key tumor suppressor and immune regulator in cervical cancer. These findings provide insights into the interplay between pyroptosis and antitumor immunity, supporting LAG3 as a potential therapeutic target for cervical cancer immunotherapy.</p>\n </section>\n </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"14 19","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481447/pdf/","citationCount":"0","resultStr":"{\"title\":\"LAG3 as a Tumor Suppressor and Immune Regulator in Cervical Cancer: From Functional Validation to Therapeutic Strategy\",\"authors\":\"Shijie Yao, Siming Chen, Shimeng Wan, Anjin Wang, Ziyan Liang, Xuelian Liu, Yang Gao, Hongbing Cai\",\"doi\":\"10.1002/cam4.71278\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Cervical cancer remains a significant health burden for women worldwide, with persistent high-risk HPV infection being a major etiological factor. Despite treatment advances, prognosis for recurrent or metastatic disease remains poor. Pyroptosis, a form of programmed cell death, plays a dual role in tumor immunity, but its implications in cervical cancer are not fully elucidated. This study aims to systematically characterize pyroptosis-related genes (PRGs) in cervical cancer and explore their prognostic and therapeutic relevance.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Multi-omics data from TCGA and GEO databases were integrated to analyze genetic variations, expression patterns, and prognostic significance of 52 PRGs in cervical cancer. Consensus clustering was used to identify PRG subtypes. A prognostic risk score model was constructed using LASSO-Cox regression based on differentially expressed genes (DEGs). Functional validation was performed via in vitro and in vivo experiments, including Western blot, CCK-8, colony formation, transwell assays, and a subcutaneous tumor model. Single-cell RNA sequencing data (GSE171894, GSE168652) were analyzed to explore LAG3 expression in the tumor immune microenvironment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Two distinct PRG subtypes were identified, with subtype A showing immune activation features. A five-gene prognostic signature (GNAZ, LAG3, IL-1β, CA2, SPRR3) effectively stratified patients into high- and low-risk groups. Low LAG3 expression was associated with poor prognosis. Functional experiments demonstrated that LAG3 overexpression suppressed cervical cancer cell proliferation, migration, and tumor growth, while its knockdown promoted malignant phenotypes. 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LAG3 as a Tumor Suppressor and Immune Regulator in Cervical Cancer: From Functional Validation to Therapeutic Strategy
Background
Cervical cancer remains a significant health burden for women worldwide, with persistent high-risk HPV infection being a major etiological factor. Despite treatment advances, prognosis for recurrent or metastatic disease remains poor. Pyroptosis, a form of programmed cell death, plays a dual role in tumor immunity, but its implications in cervical cancer are not fully elucidated. This study aims to systematically characterize pyroptosis-related genes (PRGs) in cervical cancer and explore their prognostic and therapeutic relevance.
Methods
Multi-omics data from TCGA and GEO databases were integrated to analyze genetic variations, expression patterns, and prognostic significance of 52 PRGs in cervical cancer. Consensus clustering was used to identify PRG subtypes. A prognostic risk score model was constructed using LASSO-Cox regression based on differentially expressed genes (DEGs). Functional validation was performed via in vitro and in vivo experiments, including Western blot, CCK-8, colony formation, transwell assays, and a subcutaneous tumor model. Single-cell RNA sequencing data (GSE171894, GSE168652) were analyzed to explore LAG3 expression in the tumor immune microenvironment.
Results
Two distinct PRG subtypes were identified, with subtype A showing immune activation features. A five-gene prognostic signature (GNAZ, LAG3, IL-1β, CA2, SPRR3) effectively stratified patients into high- and low-risk groups. Low LAG3 expression was associated with poor prognosis. Functional experiments demonstrated that LAG3 overexpression suppressed cervical cancer cell proliferation, migration, and tumor growth, while its knockdown promoted malignant phenotypes. Single-cell analysis revealed high LAG3 expression in Treg and CD8⁺ T cells, suggesting its role in immune regulation.
Conclusion
This study establishes a novel PRG-based prognostic model and highlights LAG3 as a key tumor suppressor and immune regulator in cervical cancer. These findings provide insights into the interplay between pyroptosis and antitumor immunity, supporting LAG3 as a potential therapeutic target for cervical cancer immunotherapy.
期刊介绍：
Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas:
Clinical Cancer Research
Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations
Cancer Biology:
Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery.
Cancer Prevention:
Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach.
Bioinformatics:
Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers.
Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.
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