TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis.
TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis.
复制标题
DOI：
10.1002/advs.202300350
复制
发表时间：
2023-06
期刊：
影响因子：
15.1
通讯作者：
Han, Zhipeng
中科院分区：
文献类型：
--
作者：
Liu, Wenting;Gao, Lu;Hou, Xiaojuan;Feng, Shiyao;Yan, Haixin;Pan, Hongyu;Zhang, Shichao;Yang, Xue;Jiang, Jinghua;Ye, Fei;Zhao, Qiudong;Wei, Lixin;Han, Zhipeng
关键词：
肝祖细胞在炎症微环境中的恶性转化是肝癌发生的根本原因。然而，潜在的分子机制仍然难以捉摸。通过单细胞RNA（scRNA）测序鉴定HPC亚组，并在原发性HCC模型中研究HPC的表型。还对HPC衍生的类器官进行批量RNA测序（RNA-seq）和蛋白质组学分析。在肝癌模型中发现，在第16周，肿瘤由癌周组织中的HPC形成。此外，证实了巨噬细胞来源的TWEAK/Fn 14通过NF-κB信号促进HPC中分化抑制因子1（ID 1）的表达，并且高水平的ID 1诱导HPC的异常分化。ID 1通过抑制HNF 4 α和Rap 1GAP的转录，抑制HPCs的分化，促进其增殖。最后，对HCC患者的scRNA测序和对临床标本的调查也证实了ID 1的表达与HPC向癌干细胞的异常分化相关，HPC中ID 1高水平的患者预后较差。本研究为肝癌的临床诊断和治疗提供了重要的干预靶点和理论依据。在肝癌发生发展过程中，观察到了炎症微环境下HPCs从活化到恶变的动态过程。作者证明，巨噬细胞源性TWEAK促进ID 1表达，ID 1通过抑制HNF 4 α和Rap 1GAP转录抑制HPC的分化并促进细胞增殖。本研究结果有助于了解炎症微环境诱导肝癌发生的可能机制。
The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single‐cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA‐seq) and proteomic analyses are also performed on HPC‐derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage‐derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation‐1 (ID1) in HPCs via NF‐κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC. The dynamic process of HPCs under the inflammatory microenvironment from activation to malignant transformation is observed during hepatocarcinogenesis. The authors prove that macrophage‐derived TWEAK promotes ID1 expression, which suppresses differentiation and promotes cell proliferation in HPCs through inhibition of HNF4α and Rap1GAP transcription. The results may be facilitated to understand the potential mechanism of hepatocarcinogenesis induced by the inflammatory microenvironment.
登录
查看更多内容
影响因子：
82.9
作者：
通讯作者：
--
铥(III)-胂III复合物对鲱鱼精子DNA的药物作用
影响因子：
3
作者：
Li, Hongbo;Lei, Shutao;Wang, Suqin
通讯作者：
Wang, Suqin
影响因子：
48
作者：
Browaeys, Robin;Saelens, Wouter;Saeys, Yvan
通讯作者：
Saeys, Yvan
影响因子：
2.9
作者：
Gao WL;Ye GC;Liu LW;Wei L
通讯作者：
Wei L
DOI：
10.1142/s0219720005001375
发表时间：
2005-08-01
影响因子：
1
作者：
Futschik, Matthias E.;Carlisle, Bronwyn
通讯作者：
Carlisle, Bronwyn