Gest Caroline, Sena Sandra, Dif Lydia, Neaud Véronique, Loesch Robin, Dugot-Senant Nathalie, Paysan Lisa, Piquet Léo, Robbe Terezinha, Allain Nathalie, Dembele Doulaye, Guettier Catherine, Bioulac-Sage Paulette, Rullier Anne, Le Bail Brigitte, Grosset Christophe F, Saltel Frédéric, Lagrée Valérie, Colnot Sabine, Moreau Violaine
University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France.
INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC), Paris, France.
JHEP Rep. 2023 Feb 1;5(5):100691. doi: 10.1016/j.jhepr.2023.100691. eCollection 2023 May.
BACKGROUND & AIMS: β-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway.
Using an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APC and β-catenin mice). We used transcriptomic data from mouse and human HB specimens, and used immunohistochemistry to analyse samples.
We highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs.
Fascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB.
The gene, encoding fascin-1, was reported to be a metastasis-related gene in various cancers. Herein, we uncover its expression in poor-prognosis hepatoblastomas, a paediatric liver cancer. We show that fascin-1 expression is driven by the mutated beta-catenin in liver tumour cells. We provide new insights on the impact of fascin-1 expression on tumour cell differentiation. We highlight fascin-1 as a marker of immature cells in mouse and human hepatoblastomas.
β-连环蛋白是Wnt信号通路中一个广为人知的效应分子，也是钙黏蛋白介导的细胞黏附中的关键因子。β-连环蛋白的致癌性突变在儿童肝脏原发性肿瘤中非常常见。这些突变大多是杂合的，这使得野生型（WT）和突变型β-连环蛋白在肿瘤细胞中共同表达。我们研究了肝脏肿瘤细胞中WT和突变型β-连环蛋白之间的相互作用，并寻找β-连环蛋白信号通路的新作用因子。
我们在β-连环蛋白突变的肝母细胞瘤（HB）细胞中采用RNA干扰策略，分别分离了主要由WT和突变蛋白承担的β-连环蛋白的结构和转录活性。利用转录组学和功能分析对它们的影响进行了表征。我们研究了在肝细胞中激活β-连环蛋白后会发生肝脏肿瘤的小鼠（APC和β-连环蛋白小鼠）。我们使用了来自小鼠和人类HB标本的转录组数据，并使用免疫组织化学分析样本。
我们强调了WT和突变型β-连环蛋白在肝细胞分化方面的拮抗作用，这通过肝细胞标志物表达的改变和胆小管的形成得到了证实。我们将细丝蛋白-1鉴定为参与肿瘤细胞分化的突变型β-连环蛋白的转录靶点。利用小鼠模型，我们发现细丝蛋白-1在未分化肿瘤中高度表达。最后，我们发现细丝蛋白-1是人类HBs中包括胚胎细胞和胚基细胞在内的原始细胞的特异性标志物。
细丝蛋白-1的表达与肝细胞分化和极性的丧失有关。我们提出细丝蛋白-1是肝脏中与β-连环蛋白信号通路改变相关的肝细胞分化调节中一个以前未被认识的因子，也是HB中的一个新的潜在靶点。
据报道，编码细丝蛋白-1的基因是各种癌症中的一个转移相关基因。在此，我们揭示了它在预后不良的肝母细胞瘤（一种儿童肝癌）中的表达。我们表明细丝蛋白-1的表达是由肝脏肿瘤细胞中突变的β-连环蛋白驱动的。我们提供了关于细丝蛋白-1表达对肿瘤细胞分化影响的新见解。我们强调细丝蛋白-1是小鼠和人类肝母细胞瘤中未成熟细胞的标志物。
