近日，德国德堡大学教授Moritz Mall及其研究团队的最新研究提出了PROX1积极抑制细胞命运可塑性，保护肝细胞身份，防止肝肿瘤发生。这一研究成果发表在2025年2月13日出版的国际学术期刊《自然—遗传学》上。

在这里，课题组人员通过计算预测了18种细胞类型的所谓保护性抑制因子，这些抑制因子可以终身阻断表型可塑性。课题组验证了肝细胞特异性候选主题重编程，揭示普洛斯彼罗同源盒蛋白1 （PROX1）通过直接抑制替代命运主调控因子来增强肝细胞的身份。

在小鼠中，Prox1是损伤后肝细胞有效再生所必需的，并且足以防止肝肿瘤的发生。与患者数据一致，Prox1缺失在体内引导肝细胞命运丧失，并使肝细胞癌向胆管癌转变。相反，过表达可促进胆管癌向肝细胞癌的转分化。他们的发现为PROX1作为肝细胞特异性保护提供了证据，并支持细胞类型特异性抑制因子在整个生命过程中积极抑制可塑性以保护谱系身份并预防疾病的模型。

研究人员表示，细胞命运的可塑性促进了发育，但未解锁的可塑性是癌症的标志。虽然转录主调控因子诱导谱系特异性基因限制可塑性，但尚不清楚可塑性是否受到谱系特异性抑制因子的积极抑制。

附：英文原文

Title: Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis

Author: Lim, Bryce, Kamal, Aryan, Gomez Ramos, Borja, Adrian Segarra, Juan M., Ibarra, Ignacio L., Dignas, Lennart, Kindinger, Tim, Volz, Kai, Rahbari, Mohammad, Rahbari, Nuh, Poisel, Eric, Kafetzopoulou, Kanela, Bse, Lio, Breinig, Marco, Heide, Danijela, Gallage, Suchira, Barragan Avila, Jose E., Wiethoff, Hendrik, Berest, Ivan, Schnabellehner, Sarah, Schneider, Martin, Becker, Jonas, Helm, Dominic, Grimm, Dirk, Mkinen, Taija, Tschaharganeh, Darjus F., Heikenwalder, Mathias, Zaugg, Judith B., Mall, Moritz

Issue&Volume: 2025-02-13

Abstract: Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.

DOI: 10.1038/s41588-025-02081-w

Source: https://www.nature.com/articles/s41588-025-02081-w