Xie Chang, Qiu Nasha, Wang Chao, Chen Jun, Zhang Hui, Lu Xinfeng, Chen Siyu, Sun Yiyang, Lian Zhengxing, Hu Haitao, Zhu Hengkai, Xu Xiao
School of Clinical Medicine, Hangzhou Normal University, Zhejiang Province, Hangzhou, China.
Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang Province, Hangzhou, China.
Transplantation. 2025 Sep 1;109(9):e469-e483. doi: 10.1097/TP.0000000000005412. Epub 2025 May 8.
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.
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.
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.
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.
肝移植（LT）是晚期肝细胞癌（HCC）最有效的治疗策略，但它易发生缺血再灌注损伤（IRI），导致预后不良。既往文章报道miR-374b-5p在HCC组织中表达增加，但其与IRI及HCC癌进展的关系尚不清楚。
既往报道显示miR-374b-5p在HCC组织中显著上调。从癌症基因组图谱数据库及LT患者的肝脏标本分析miR-374b-5p对患者症状和预后的影响。为进一步探索其治疗潜力，开发了一种肝脏靶向酯酶响应基因递送系统（G-LERP/miR-374i-b），以在小鼠肝缺血再灌注损伤（HIRI）模型中下调miR-374b-5p表达。进一步建立原位HCC模型以模拟HCC术后复发。
在本研究中，基于患者的临床信息，我们发现miR-374b-5p表达与肿瘤大小和微血管侵犯相关。miR-374b-5p低表达的患者有更高的米兰标准评分和更低的终末期肝病模型评分。我们验证了miR-374b-5p表达与HCC细胞增殖和侵袭之间的正相关。有效下调miR-374b-5p同时减轻了HIRI并使肿瘤负荷降低了56%，而miR-374b-5p上调促进了HCC进展。此外，我们发现G-LERP/miR-374i-b通过下调核因子κB途径减轻肝脏炎症，从而降低HIRI和HCC复发风险。
本研究首次证明miR-374b-5p是LT及HCC术后复发期间的双重治疗靶点。术前使用酯酶响应基因递送系统对miR-374b-5p进行干预可同时减轻IRI并抑制HCC进展。
