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缺乏RAD51的肝细胞中病理性多倍体化和细胞衰老的早期发生会产生促纤维化和促肿瘤发生的炎症微环境。

Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment.

作者信息

Bu Wenqing, Sun Xue, Xue Xiaotong, Geng Shengmiao, Yang Tingting, Zhang Jia, Li Yanan, Feng Chao, Liu Qiao, Zhang Xiyu, Li Peishan, Liu Zhaojian, Shi Yufang, Shao Changshun

机构信息

The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China.

Key Laboratory of Experimental Teratology, Ministry of Education, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

出版信息

Hepatology. 2025 Feb 1;81(2):491-508. doi: 10.1097/HEP.0000000000000821. Epub 2024 Mar 11.

DOI:10.1097/HEP.0000000000000821
PMID:38466833
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11737125/
Abstract

BACKGROUND AND AIMS

RAD51 recombinase (RAD51) is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development.

APPROACH AND RESULTS

RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated a hepatocyte-specific Rad51 deletion mouse model using Alb -Cre ( Rad51 -conditional knockout (CKO)) and Adeno-associated virus 8-thyroxine-binding globulin-cyclization recombination enzyme to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51 -CKO mice is dependent on CRE dosage, with Rad51fl/fl ; Alb -Cre +/+ manifesting a more severe phenotype than the Rad51fl/fl ; Alb -Cre +/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl ; Alb -Cre +/+ mice. While liver regeneration is compromised in Rad51 -CKO mice, they are more tolerant of carbon tetrachloride-induced hepatic injury and resistant to diethylnitrosamine/carbon tetrachloride-induced HCC. A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction the transdifferentiation of cholangiocytes to hepatocytes. The newly derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC.

CONCLUSIONS

Our results demonstrate a novel function of RAD51 in liver development, homeostasis, and tumorigenesis. The Rad51 -CKO mice represent a unique genetic model for premature liver senescence, fibrosis, and hepatocellular carcinogenesis.

摘要

背景与目的

RAD51重组酶（RAD51）是一种高度保守的DNA修复蛋白，对胚胎存活至关重要。因此，RAD51在肝脏发育和功能中的作用尚不清楚。我们的目的是阐明RAD51在出生后肝脏发育中的功能。

方法与结果

RAD51在肝脏发育过程中以及肝切除和肝损伤后的再生过程中高度表达，在慢性肝病中也升高。我们使用Alb-Cre（Rad51条件性敲除（CKO））和腺相关病毒8-甲状腺素结合球蛋白-环化重组酶构建了肝细胞特异性Rad51缺失小鼠模型，以评估RAD51在肝脏发育和再生中的功能。Rad51-CKO小鼠的表型取决于CRE剂量，Rad51fl/fl;Alb-Cre +/+表现出比Rad51fl/fl;Alb-Cre +/-小鼠更严重的表型。出生后肝细胞中RAD51的缺失导致有丝分裂中止和病理性多倍体化的早期发生，这与氧化应激和细胞衰老有关。早在3个月大的Rad51fl/fl;Alb-Cre +/+小鼠中就自发出现明显的肝纤维化。虽然Rad51-CKO小鼠的肝脏再生受损，但它们对四氯化碳诱导的肝损伤更耐受，对二乙基亚硝胺/四氯化碳诱导的肝癌有抗性。衰老肝细胞产生的慢性炎症微环境似乎激活了胆管反应，即胆管细胞向肝细胞的转分化。新衍生的RAD51功能不成熟肝细胞大量增殖，恶性程度增加，最终导致肝癌。

结论

我们的结果证明了RAD51在肝脏发育、稳态和肿瘤发生中的新功能。Rad51-CKO小鼠代表了一种独特的遗传模型，用于研究肝脏早衰、纤维化和肝细胞癌发生。

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