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衰老的肝星状细胞的细胞外囊泡有利于非酒精性脂肪性肝炎-肝纤维化进展向肝细胞癌的恶性转化。

Secretome of senescent hepatic stellate cells favors malignant transformation from nonalcoholic steatohepatitis-fibrotic progression to hepatocellular carcinoma.

机构信息

Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

Joint Laboratory of Biomaterials and Translational Medicine, Puheng Technology Co., Ltd, Suzhou 215163, China.

出版信息

Theranostics. 2023 Aug 6;13(13):4430-4448. doi: 10.7150/thno.85369. eCollection 2023.

DOI:10.7150/thno.85369
PMID:37649614
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10465212/
Abstract

Hepatic fibrosis is a premalignant lesion, and how injured hepatocytes transform into malignancy in a fibrotic microenvironment is poorly understood. Senescence is one of major fates of activated hepatic stellate cells (HSCs). Paucity of literature is available regarding the influence of senescent HSCs on behavior of steatotic hepatocytes. Senescent HSCs were identified in a murine model of nonalcoholic steatohepatitis (NASH)-fibrosis-hepatocellular carcinoma (HCC) and human NASH-HCC specimens. Secretome of senescent HSCs was analyzed by label-free mass-spectrum (NanoRPLC-MS/MS) and verified quantitatively. Senescent HSCs were increased along with the progression from nonalcoholic fatty liver (NAFL), NASH to NASH-fibrosis, and reached a peak at the stage of advanced fibrosis and then decreased when hepatocellular dysplasia or HCC was developed. Critical components affecting proliferation, epithelial-mesenchymal transition (EMT) or migration were identified from secretome of senescent HSCs, and may activate morphogenic hedgehog or oncogenic Wnt signaling pathways to accelerate malignant transformation of steatotic or dysplastic hepatocytes. Primary hepatocytes stimulated with conditioned medium from senescent HSCs, in co-culture or co-cultured in 3D spheroids with senescent HSCs exhibited an enhanced proliferating or EMT profile. Senescent HSCs secreted a characterized protein profile favoring malignant transformation of steatotic or dysplastic hepatocytes through activating morphogenic hedgehog or oncogenic Wnt signaling pathways in the progression from NASH to malignancy.

摘要

肝纤维化是一种癌前病变，而在纤维化的微环境中，受损的肝细胞如何转化为恶性肿瘤尚不清楚。衰老是活化的肝星状细胞（HSCs）的主要命运之一。关于衰老的 HSCs 对脂肪变性肝细胞行为的影响，文献报道很少。在非酒精性脂肪性肝炎（NASH）-纤维化-肝细胞癌（HCC）的小鼠模型和人类 NASH-HCC 标本中鉴定出衰老的 HSCs。通过无标记质谱（NanoRPLC-MS/MS）分析衰老的 HSCs 分泌组，并进行定量验证。随着非酒精性脂肪肝（NAFL）、NASH 向 NASH 纤维化的进展，衰老的 HSCs 增加，在晚期纤维化阶段达到高峰，然后在肝细胞发育不良或 HCC 发展时减少。从衰老的 HSCs 分泌组中鉴定出影响增殖、上皮-间充质转化（EMT）或迁移的关键成分，这些成分可能激活形态发生的 hedgehog 或致癌的 Wnt 信号通路，加速脂肪变性或发育不良的肝细胞的恶性转化。用衰老的 HSCs 条件培养基刺激原代肝细胞，在共培养或与衰老的 HSCs 共培养的 3D 球体中，表现出增强的增殖或 EMT 特征。衰老的 HSCs 通过激活形态发生的 hedgehog 或致癌的 Wnt 信号通路，分泌有利于脂肪变性或发育不良的肝细胞恶性转化的特征性蛋白谱，在从 NASH 向恶性肿瘤进展的过程中。

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本文引用的文献

[1]
Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling.

Hepatology. 2023-11-1

[2]
The flavonoid GL-V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells.

Br J Pharmacol. 2023-4

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J Hepatol. 2021-12

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Bromodomain-containing protein 9 promotes hepatocellular carcinoma progression via activating the Wnt/β-catenin signaling pathway.

Exp Cell Res. 2021-9-15

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Direct antiviral agent treatment leads to rapid and significant fibrosis regression after HCV eradication.

J Viral Hepat. 2021-9

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Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis.

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Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma.

Cells. 2021-1-11

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Biosens Bioelectron. 2021-2-15

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Nat Rev Gastroenterol Hepatol. 2021-3

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