Dantzer Camille, Dif Lydia, Vaché Justine, Basbous Sara, Billottet Clotilde, Moreau Violaine
University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France.
Br J Cancer. 2024 Dec;131(12):1871-1880. doi: 10.1038/s41416-024-02849-7. Epub 2024 Sep 11.
CTNNB1, encoding the ß-catenin protein, is a key oncogene contributing to liver carcinogenesis. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in adult, representing the third leading cause of cancer-related death. Aberrant activation of the Wnt/ß-catenin pathway, mainly due to mutations of the CTNNB1 gene, is observed in a significant subset of HCC. In this review, we first resume the major recent advances in HCC classification with a focus on CTNNB1-mutated HCC subclass. We present the regulatory mechanisms involved in β-catenin stabilisation, transcriptional activity and binding to partner proteins. We then describe specific phenotypic characteristics of CTNNB1-mutated HCC thanks to their unique gene expression patterns. CTNNB1-mutated HCC constitute a full-fledged subclass of HCC with distinct pathological features such as well-differentiated cells with low proliferation rate, association to cholestasis, metabolic alterations, immune exclusion and invasion. Finally, we discuss therapeutic approaches to target ß-catenin-mutated liver tumours and innovative perspectives for future drug developments.
编码β-连环蛋白的CTNNB1是导致肝癌发生的关键癌基因。肝细胞癌（HCC）是成人原发性肝癌最常见的形式，是癌症相关死亡的第三大主要原因。在相当一部分HCC中观察到Wnt/β-连环蛋白通路的异常激活，主要是由于CTNNB1基因的突变。在本综述中，我们首先回顾了HCC分类的主要最新进展，重点是CTNNB1突变的HCC亚类。我们介绍了参与β-连环蛋白稳定、转录活性以及与伴侣蛋白结合的调控机制。然后，我们通过其独特的基因表达模式描述了CTNNB1突变的HCC的特定表型特征。CTNNB1突变的HCC构成了一个成熟的HCC亚类，具有独特的病理特征，如低增殖率的高分化细胞、与胆汁淤积的关联、代谢改变、免疫排斥和侵袭。最后，我们讨论了针对β-连环蛋白突变的肝肿瘤的治疗方法以及未来药物开发的创新前景。
