肝分区决定突变β-连环蛋白的致瘤潜能，这一成果由英国苏格兰癌症研究所Owen J. Sansom研究团队经过不懈努力而取得。2025年11月19日出版的《自然》杂志发表了这项成果。

在这里，该团队研究了在肝肿瘤发生过程中，WNT驱动的带状肝细胞群生长和分化之间的拮抗相互作用。课题组发现β-连环蛋白突变与外源性MYC表达合作，驱动增殖翻译体。肝细胞分化到极端的3区命运抑制了这种增殖翻译体。

此外，GLUL和Lgr5阳性的3区肝细胞周围亚群对WNT诱导和MYC诱导的肿瘤发生具有难治性。

然而，当突变的CTNNB1和MYC等位基因在肝小叶中零星地被激活时，一部分突变的肝细胞变得增殖和致瘤性。这些早期病变的特征是WNT通路激活减少和MAPK信号升高，这抑制了3区分化。增殖性病变还依赖于IGFBP2–mTOR–cyclin D1信号通路，其中抑制IGFBP2或mTOR均可抑制增殖和肿瘤发生。因此，该课题组人员提出，区域特性决定了肝细胞对WNT驱动的肿瘤发生的易感性，而逃避WNT诱导的分化对肝癌至关重要。

据介绍，表型正常组织中的致癌突变在成人器官中很常见。这表明，多个事件需要汇聚在一起才能驱动肿瘤发生，许多过程如组织分化，可能会防止癌变。WNT -β-catenin信号传导在肝脏稳态过程中维持区向分化。然而，编码β-catenin的CTNNB1癌基因在肝细胞癌中也经常发生突变，导致异常的WNT信号传导促进细胞生长。

附：英文原文

Title: Hepatic zonation determines tumorigenic potential of mutant β-catenin

Author: Raven, Alexander, Gilroy, Kathryn, Jin, Hu, Waldron, Joseph A., Leslie, Holly, Munro, June, Hall, Holly, Ridgway, Rachel A., Ford, Catriona A., Gulhan, Doga C., Vlahov, Nikola, Mills, Megan L., Hartley, Andrew, Anderson, Eve, Bryson, Sheila, Sphyris, Nathalie, Mller, Miryam, May, Stephanie, Cadden, Barbara, Nixon, Colin, Waddell, Scott H., Guest, Rachel, Boulter, Luke, Barker, Nick, Clevers, Hans, Zhu, Hao, Ivaska, Johanna, Strathdee, Douglas, Miller, Crispin J., Jamieson, Nigel B., Bushell, Martin, Park, Peter J., Bird, Thomas G., Sansom, Owen J.

Issue&Volume: 2025-11-19

Abstract: Oncogenic mutations in phenotypically normal tissue are common across adult organs1,2. This suggests that multiple events need to converge to drive tumorigenesis and that many processes such as tissue differentiation may protect against carcinogenesis. WNT–β-catenin signalling maintains zonal differentiation during liver homeostasis3,4. However, the CTNNB1 oncogene—encoding β-catenin—is also frequently mutated in hepatocellular carcinoma, resulting in aberrant WNT signalling that promotes cell growth5,6. Here we investigated the antagonistic interplay between WNT-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. We found that β-catenin mutations co-operate with exogenous MYC expression to drive a proliferative translatome. Differentiation of hepatocytes to an extreme zone 3 fate suppressed this proliferative translatome. Furthermore, a GLUL and Lgr5-positive perivenous subpopulation of zone 3 hepatocytes were refractory to WNT-induced and MYC-induced tumorigenesis. However, when mutant CTNNB1 and MYC alleles were activated sporadically across the liver lobule, a subset of mutant hepatocytes became proliferative and tumorigenic. These early lesions were characterized by reduced WNT pathway activation and elevated MAPK signalling, which suppresses zone 3 differentiation. The proliferative lesions were also dependent on IGFBP2–mTOR–cyclin D1 pathway signalling, in which inhibition of either IGFBP2 or mTOR suppressed proliferation and tumorigenesis. Therefore, we propose that zonal identity dictates hepatocyte susceptibility to WNT-driven tumorigenesis and that escaping WNT-induced differentiation is essential for liver cancer.

DOI: 10.1038/s41586-025-09733-1

Source: https://www.nature.com/articles/s41586-025-09733-1