Zhou Yongjie, Chen Yuwei, Zhang Xiaoyun, Xu Qing, Wu Zhenru, Cao Xiaoyue, Shao Mingyang, Shu Yuke, Lv Tao, Lu Changli, Xie Mingjun, Wen Tianfu, Yang Jiayin, Shi Yujun, Bu Hong
Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina.
Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina.
Hepatology. 2021 Aug;74(2):797-815. doi: 10.1002/hep.31780. Epub 2021 May 22.
Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma-related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up-regulated in both HPCs and iCCA; however, its role in this correlation remains undefined.
A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the β-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/β-catenin signaling.
We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/β-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.
肝内胆管癌（iCCA）与肝祖细胞（HPC）扩增及肝纤维化密切相关。Brahma相关基因1（Brg1）是开关/蔗糖非发酵复合物的一个酶亚基，在干细胞维持和肿瘤进展中起关键作用，在HPC和iCCA中均显著上调；然而，其在这种关联中的作用仍不明确。
一项回顾性队列研究表明，Brg1高表达提示iCCA患者预后不良。在由0.1% 3,5 - 二乙氧羰基 - 1,4 - 二氢可力丁饮食或胆管结扎手术诱导的慢性损伤肝脏中，HPC被显著激活，表现为Brg1及一部分干细胞标志物的表达增强；然而，HPC中Brg1的缺失强烈抑制了HPC扩增和肝纤维化。此外，在化学诱导的iCCA模型中，用特异性抑制剂抑制Brg1或进行诱导性基因敲除可显著改善组织学并抑制iCCA生长。机制上，除了转录促进Wnt受体基因和靶基因外，还发现Brg1与β - 连环蛋白/转录因子4转录复合物结合，提示了一种调节Wnt/β - 连环蛋白信号通路的可能途径。
我们已经证明了Brg1在促进慢性损伤肝脏中HPC扩增、肝硬化以及最终iCCA发生发展中的作用，这在很大程度上依赖于Wnt/β - 连环蛋白信号通路。我们的数据表明针对表达Brg1的HPC的治疗方法在肝硬化和iCCA治疗方面具有前景。
