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Brahma‐Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion
Author(s) -
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
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31780
Subject(s) - progenitor cell , cancer research , wnt signaling pathway , fibrosis , cirrhosis , liver regeneration , transcription factor , bile duct , medicine , stem cell , chemistry , microbiology and biotechnology , pathology , gene , biology , signal transduction , regeneration (biology) , biochemistry
Background and Aims 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. Approach and Results 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. Conclusions 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.