Journal of Hepatology

Journal Information
ISSN / EISSN : 0168-8278 / 0168-8278
Published by: Elsevier BV (10.1016)
Total articles ≅ 45,578
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Published: 1 July 2021
Journal of Hepatology, Volume 75, pp 7-9; doi:10.1016/j.jhep.2021.04.032

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Published: 1 July 2021
Journal of Hepatology, Volume 75, pp 10-11; doi:10.1016/j.jhep.2021.04.007

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Qian Wang, Ning Liang, Tao Yang, Yuedan Li, Jing Li, Qian Huang, Chen Wu, Ligang Sun, Xile Zhou, Xiaobin Cheng, et al.
Published: 1 July 2021
Journal of Hepatology; doi:10.1016/j.jhep.2021.06.025

Background & Aims Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) exhibit remarkable cancer stem cell (CSCs) features. Moreover, the development of both diseases is closely associated with the presence of CSCs. We investigated the role of brain-expressed X-linked protein 1 (BEX1) in regulating CSC properties of HB, and a subtype of HCC with high CSC features (CSC-HCC). Methods Stemness scores were analyzed in five murine HCC models. A subpopulation of BEX1-positive cells and BEX1-negative cells were sorted from HCC cell lines, and subjected to transcriptome analysis. The expression and function of BEX1 was examined via western blotting, sphere formation assays, and xenograft tumor models. Results We identified BEX1 as a novel CSC marker that was required for the self-renewal maintenance of liver CSCs. Furthermore, zebularine, a potent DNMT1 inhibitor, can induce the reactivation of BEX1 by removing epigenetic inhibition. Notably, BEX1 was highly expressed in HB and CSC-HCC patients, but exhibited a low expression in non-CSC HCC patients (non-CSC-HCC). Moreover, DNMT1-mediated methylation of the BEX1 promoter resulted in differential BEX1 expression patterns in HB, CSC-HCC, and non-CSC-HCC patients. Mechanistically, BEX1 established interaction with RUNX3 to block its inhibition of β-catenin transcription, which led to the activation of Wnt/β-catenin signaling, and stemness maintenance in both HB and CSC-HCC. In contrast, downregulated BEX1 expression released RUNX3 and inhibited the activation of Wnt/β-catenin signaling in non-CSC-HCC. Conclusion BEX1, under the regulation of DNMT1, is necessary for the self-renewal ability and maintenance of liver CSCs through activation of Wnt/β-catenin signaling, rendering BEX1 a valuable therapeutic target for both HB and CSC-HCC. Lay summary Cancer stem cells (CSCs) contribute to a high rate of cancer recurrence, as well as resistance to conventional therapies. However, the regulatory mechanisms underlying their self-renewal remains elusive. Here, we have reported that BEX1 plays a key role in regulating CSC properties in different types of liver cancer. Targeting BEX1-mediated Wnt/β-catenin signaling may help to address the high rate of recurrence, and heterogeneity of liver cancer.
Published: 1 July 2021
Journal of Hepatology, Volume 75, pp 16-18; doi:10.1016/j.jhep.2021.03.002

Published: 1 July 2021
Journal of Hepatology, Volume 75; doi:10.1016/s0168-8278(21)00317-2

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