{"title":"G-LERP/miR-374i-b减轻IRI并抑制肝细胞癌进展","authors":"Chang Xie, Nasha Qiu, Chao Wang, Jun Chen, Hui Zhang, Xinfeng Lu, Siyu Chen, Yiyang Sun, Zhengxing Lian, Haitao Hu, Hengkai Zhu, Xiao Xu","doi":"10.1097/TP.0000000000005412","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Liver transplantation (LT) is the most effective therapeutic strategy for late-stage hepatocellular carcinoma (HCC), but it is prone to ischemia-reperfusion injury (IRI), leading to poor prognosis. Previous articles have reported that miR-374b-5p expression is increased in HCC tissues, and its relationship with IRI and HCC carcinoma progression is unclear.</p><p><strong>Methods: </strong>Previous reports have shown that miR-374b-5p expression is significantly upregulated in HCC tissues. The effect of miR-374b-5p on patient symptoms and prognosis were analyzed from The Cancer Genome Atlas database and liver specimens from LT patients. To further explore its therapeutic potential, a liver-targeted esterase-responsive gene delivery system (G-LERP/miR-374i-b) was developed to downregulate miR-374b-5p expression in the mouse hepatic IRI (HIRI) model. An orthotopic HCC model was further established to mimic the postoperative recurrence of HCC.</p><p><strong>Results: </strong>In this study, we found that miR-374b-5p expression correlates with tumor size and microvascular invasion based on patients' clinical information. Patients with low miR-374b-5p expression had a higher Milan criteria score and a lower Model for End-stage Liver Disease score. We verified the positive correlation between miR-374b-5p expression and the proliferation and invasion of HCC cells. Effective downregulation of miR-374b-5p simultaneously alleviated HIRI and reduced tumor burden by 56%, whereas miR-374b-5p upregulation promoted HCC progression. Furthermore, we found G-LERP/miR-374i-b attenuated hepatic inflammation by downregulating the nuclear factor kappa-B pathway, thereby reducing HIRI and the risk of HCC recurrence.</p><p><strong>Conclusions: </strong>This research is the first to demonstrate miR-374b-5p as a dual therapeutic target during LT and postoperative recurrence of HCC. Preintervention of miR-374b-5p using an esterase-responsive gene delivery system during the preoperative period simultaneously alleviates IRI and suppresses HCC progression.</p>","PeriodicalId":23316,"journal":{"name":"Transplantation","volume":" ","pages":"e469-e483"},"PeriodicalIF":5.0000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"G-LERP/miR-374i-b Attenuates IRI and Suppresses Hepatocellular Carcinoma Progression.\",\"authors\":\"Chang Xie, Nasha Qiu, Chao Wang, Jun Chen, Hui Zhang, Xinfeng Lu, Siyu Chen, Yiyang Sun, Zhengxing Lian, Haitao Hu, Hengkai Zhu, Xiao Xu\",\"doi\":\"10.1097/TP.0000000000005412\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Liver transplantation (LT) is the most effective therapeutic strategy for late-stage hepatocellular carcinoma (HCC), but it is prone to ischemia-reperfusion injury (IRI), leading to poor prognosis. Previous articles have reported that miR-374b-5p expression is increased in HCC tissues, and its relationship with IRI and HCC carcinoma progression is unclear.</p><p><strong>Methods: </strong>Previous reports have shown that miR-374b-5p expression is significantly upregulated in HCC tissues. The effect of miR-374b-5p on patient symptoms and prognosis were analyzed from The Cancer Genome Atlas database and liver specimens from LT patients. To further explore its therapeutic potential, a liver-targeted esterase-responsive gene delivery system (G-LERP/miR-374i-b) was developed to downregulate miR-374b-5p expression in the mouse hepatic IRI (HIRI) model. An orthotopic HCC model was further established to mimic the postoperative recurrence of HCC.</p><p><strong>Results: </strong>In this study, we found that miR-374b-5p expression correlates with tumor size and microvascular invasion based on patients' clinical information. Patients with low miR-374b-5p expression had a higher Milan criteria score and a lower Model for End-stage Liver Disease score. We verified the positive correlation between miR-374b-5p expression and the proliferation and invasion of HCC cells. Effective downregulation of miR-374b-5p simultaneously alleviated HIRI and reduced tumor burden by 56%, whereas miR-374b-5p upregulation promoted HCC progression. Furthermore, we found G-LERP/miR-374i-b attenuated hepatic inflammation by downregulating the nuclear factor kappa-B pathway, thereby reducing HIRI and the risk of HCC recurrence.</p><p><strong>Conclusions: </strong>This research is the first to demonstrate miR-374b-5p as a dual therapeutic target during LT and postoperative recurrence of HCC. Preintervention of miR-374b-5p using an esterase-responsive gene delivery system during the preoperative period simultaneously alleviates IRI and suppresses HCC progression.</p>\",\"PeriodicalId\":23316,\"journal\":{\"name\":\"Transplantation\",\"volume\":\" \",\"pages\":\"e469-e483\"},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Transplantation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/TP.0000000000005412\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Transplantation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/TP.0000000000005412","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/8 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：肝移植（Liver transplantation， LT）是治疗晚期肝细胞癌（HCC）最有效的治疗策略，但其易发生缺血再灌注损伤（ischemia-reperfusion injury， IRI），预后差。先前的文章报道了miR-374b-5p在HCC组织中的表达升高，其与IRI和肝癌进展的关系尚不清楚。方法：先前的报道表明，miR-374b-5p在HCC组织中表达显著上调。通过The Cancer Genome Atlas数据库和LT患者肝脏标本分析miR-374b-5p对患者症状和预后的影响。为了进一步探索其治疗潜力，研究人员开发了一种肝脏靶向酯酶反应性基因传递系统（G-LERP/miR-374i-b），以下调小鼠肝脏IRI （HIRI）模型中miR-374b-5p的表达。进一步建立原位肝细胞癌模型，模拟肝细胞癌术后复发。结果：在本研究中，我们根据患者的临床信息发现miR-374b-5p表达与肿瘤大小和微血管侵袭相关。miR-374b-5p低表达的患者米兰标准评分较高，终末期肝病模型评分较低。我们验证了miR-374b-5p的表达与HCC细胞的增殖和侵袭呈正相关。miR-374b-5p的有效下调同时缓解了HIRI并减少了56%的肿瘤负担，而miR-374b-5p的上调促进了HCC的进展。此外，我们发现G-LERP/miR-374i-b通过下调核因子κ b通路来减轻肝脏炎症，从而降低HIRI和HCC复发的风险。结论：本研究首次证明miR-374b-5p在肝细胞癌肝移植和术后复发期间具有双重治疗作用。在术前使用酯酶反应性基因传递系统预先干预miR-374b-5p，同时缓解IRI并抑制HCC进展。
G-LERP/miR-374i-b Attenuates IRI and Suppresses Hepatocellular Carcinoma Progression.
Background: Liver transplantation (LT) is the most effective therapeutic strategy for late-stage hepatocellular carcinoma (HCC), but it is prone to ischemia-reperfusion injury (IRI), leading to poor prognosis. Previous articles have reported that miR-374b-5p expression is increased in HCC tissues, and its relationship with IRI and HCC carcinoma progression is unclear.
Methods: Previous reports have shown that miR-374b-5p expression is significantly upregulated in HCC tissues. The effect of miR-374b-5p on patient symptoms and prognosis were analyzed from The Cancer Genome Atlas database and liver specimens from LT patients. To further explore its therapeutic potential, a liver-targeted esterase-responsive gene delivery system (G-LERP/miR-374i-b) was developed to downregulate miR-374b-5p expression in the mouse hepatic IRI (HIRI) model. An orthotopic HCC model was further established to mimic the postoperative recurrence of HCC.
Results: In this study, we found that miR-374b-5p expression correlates with tumor size and microvascular invasion based on patients' clinical information. Patients with low miR-374b-5p expression had a higher Milan criteria score and a lower Model for End-stage Liver Disease score. We verified the positive correlation between miR-374b-5p expression and the proliferation and invasion of HCC cells. Effective downregulation of miR-374b-5p simultaneously alleviated HIRI and reduced tumor burden by 56%, whereas miR-374b-5p upregulation promoted HCC progression. Furthermore, we found G-LERP/miR-374i-b attenuated hepatic inflammation by downregulating the nuclear factor kappa-B pathway, thereby reducing HIRI and the risk of HCC recurrence.
Conclusions: This research is the first to demonstrate miR-374b-5p as a dual therapeutic target during LT and postoperative recurrence of HCC. Preintervention of miR-374b-5p using an esterase-responsive gene delivery system during the preoperative period simultaneously alleviates IRI and suppresses HCC progression.
期刊介绍：
The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year.
Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal.
Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed.
The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.
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