• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

PROX1对细胞命运可塑性的主动抑制可维护肝细胞特性并预防肝脏肿瘤发生。

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

作者信息

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, Böse 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, Mäkinen Taija, Tschaharganeh Darjus F, Heikenwalder Mathias, Zaugg Judith B, Mall Moritz

机构信息

Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.

HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany.

出版信息

Nat Genet. 2025 Mar;57(3):668-679. doi: 10.1038/s41588-025-02081-w. Epub 2025 Feb 13.

DOI:10.1038/s41588-025-02081-w
PMID:39948437
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11906372/
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.

摘要

细胞命运可塑性推动了发育进程，然而不受控制的可塑性却是癌症的一个标志。虽然转录主调控因子会诱导谱系特异性基因来限制可塑性，但目前尚不清楚可塑性是否受到谱系特异性阻遏物的主动抑制。在此，我们通过计算预测了18种细胞类型中所谓的保障阻遏物，它们终身阻断表型可塑性。我们利用重编程验证了肝细胞特异性候选物，发现prospero同源框蛋白1（PROX1）通过直接抑制替代命运主调控因子来增强肝细胞特性。在小鼠中，Prox1是损伤后高效肝细胞再生所必需的，并且足以预防肝脏肿瘤发生。与患者数据一致，Prox1缺失在体内导致肝细胞命运丧失，并使肝细胞癌转变为胆管癌。相反，过表达促进胆管癌向肝细胞癌的转分化。我们的研究结果为PROX1作为肝细胞特异性保障提供了证据，并支持一种模型，即细胞类型特异性阻遏物在整个生命过程中主动抑制可塑性，以保障谱系特性从而预防疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/b1f75150dd4e/41588_2025_2081_Fig17_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/a870f967d9e5/41588_2025_2081_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/99fd74ba2b5d/41588_2025_2081_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/dc4cc0ef77ff/41588_2025_2081_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/12b45db51282/41588_2025_2081_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/db6822328306/41588_2025_2081_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/0e042c97eac6/41588_2025_2081_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/5ab52a0b762e/41588_2025_2081_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/d7d8117e5c54/41588_2025_2081_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/f070d2240bbd/41588_2025_2081_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/e8706fc1df4f/41588_2025_2081_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/e286b30c3405/41588_2025_2081_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/230ac0cb4857/41588_2025_2081_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/ca19c2e1e39f/41588_2025_2081_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/831da10c4055/41588_2025_2081_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/1b89cf761116/41588_2025_2081_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/9dd14e073245/41588_2025_2081_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/b1f75150dd4e/41588_2025_2081_Fig17_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/a870f967d9e5/41588_2025_2081_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/99fd74ba2b5d/41588_2025_2081_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/dc4cc0ef77ff/41588_2025_2081_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/12b45db51282/41588_2025_2081_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/db6822328306/41588_2025_2081_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/0e042c97eac6/41588_2025_2081_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/5ab52a0b762e/41588_2025_2081_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/d7d8117e5c54/41588_2025_2081_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/f070d2240bbd/41588_2025_2081_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/e8706fc1df4f/41588_2025_2081_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/e286b30c3405/41588_2025_2081_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/230ac0cb4857/41588_2025_2081_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/ca19c2e1e39f/41588_2025_2081_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/831da10c4055/41588_2025_2081_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/1b89cf761116/41588_2025_2081_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/9dd14e073245/41588_2025_2081_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13cb/11906372/b1f75150dd4e/41588_2025_2081_Fig17_ESM.jpg

相似文献

1
Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis.PROX1对细胞命运可塑性的主动抑制可维护肝细胞特性并预防肝脏肿瘤发生。
Nat Genet. 2025 Mar;57(3):668-679. doi: 10.1038/s41588-025-02081-w. Epub 2025 Feb 13.
2
and Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma.并且突变导致胆管细胞和肝细胞衍生的胆管癌。
Cancer Res. 2018 Aug 15;78(16):4445-4451. doi: 10.1158/0008-5472.CAN-17-1123. Epub 2018 Jun 5.
3
The homeobox transcription factor Prox1 inhibits proliferation of hepatocellular carcinoma cells by inducing p53-dependent senescence-like phenotype.同源盒转录因子 Prox1 通过诱导 p53 依赖性衰老样表型抑制肝癌细胞的增殖。
Cancer Biol Ther. 2013 Mar;14(3):222-9. doi: 10.4161/cbt.23293. Epub 2013 Jan 4.
4
Gene regulation by homeobox transcription factor Prox1 in murine hepatoblasts.同源框转录因子Prox1对小鼠肝母细胞的基因调控
Cell Tissue Res. 2007 Nov;330(2):209-20. doi: 10.1007/s00441-007-0477-4. Epub 2007 Sep 9.
5
Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis.Yap-Sox9 信号通路决定了肝细胞的可塑性和谱系特异性肝癌发生。
J Hepatol. 2022 Mar;76(3):652-664. doi: 10.1016/j.jhep.2021.11.010. Epub 2021 Nov 15.
6
A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma.一种同源框蛋白Prox1参与肝细胞癌的分化、增殖及预后过程。
Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6005-11. doi: 10.1158/1078-0432.CCR-06-0712.
7
Altered regulation of Prox1-gene-expression in liver tumors.肝脏肿瘤中Prox1基因表达的调控改变。
BMC Cancer. 2008 Apr 9;8:92. doi: 10.1186/1471-2407-8-92.
8
Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus.Prox1 在海马体中通过指定颗粒细胞身份来决定齿状回细胞，从而在后mitotic 期定义齿状回细胞，而不是 CA3 锥体神经元的命运。
Development. 2012 Aug;139(16):3051-62. doi: 10.1242/dev.080002. Epub 2012 Jul 12.
9
Liver-specific Prox1 inactivation causes hepatic injury and glucose intolerance in mice.肝脏特异性Prox1失活导致小鼠肝损伤和葡萄糖不耐受。
FEBS Lett. 2017 Feb;591(4):624-635. doi: 10.1002/1873-3468.12570. Epub 2017 Feb 16.
10
Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice.p53 基因敲除小鼠中转分化和去分化产生的肝细胞胆管细胞癌。
Cancer Sci. 2021 Aug;112(8):3111-3124. doi: 10.1111/cas.14996. Epub 2021 Jun 27.

引用本文的文献

1
Identification and structural insights into RNA motifs targeted by a CAG repeat DNA-binding small molecule.对CAG重复序列DNA结合小分子靶向的RNA基序的鉴定及结构洞察。
Chem Sci. 2025 Aug 21. doi: 10.1039/d5sc05255f.
2
PROX1 Expression in Resected Non-Small Cell Lung Cancer: Immunohistochemical Profile and Clinicopathological Correlates.PROX1在切除的非小细胞肺癌中的表达：免疫组织化学特征及临床病理相关性
Med Sci (Basel). 2025 Aug 17;13(3):140. doi: 10.3390/medsci13030140.

本文引用的文献

1
Progressive plasticity during colorectal cancer metastasis.结直肠癌转移过程中的渐进性可塑性。
Nature. 2025 Jan;637(8047):947-954. doi: 10.1038/s41586-024-08150-0. Epub 2024 Oct 30.
2
Canalizing cell fate by transcriptional repression.通过转录抑制来调控细胞命运。
Mol Syst Biol. 2024 Mar;20(3):144-161. doi: 10.1038/s44320-024-00014-z. Epub 2024 Feb 1.
3
GRaNIE and GRaNPA: inference and evaluation of enhancer-mediated gene regulatory networks.GRaNIE 和 GRaNPA：增强子介导的基因调控网络的推断和评估。
Mol Syst Biol. 2023 Jun 12;19(6):e11627. doi: 10.15252/msb.202311627. Epub 2023 Apr 19.
4
Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers.库普弗细胞衍生的白细胞介素-6通过激活损伤特异性增强子中的祖细胞基因，被重新用于肝细胞去分化。
Cell Stem Cell. 2023 Mar 2;30(3):283-299.e9. doi: 10.1016/j.stem.2023.01.009. Epub 2023 Feb 13.
5
MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention.人类神经元和小鼠中 MYT1L 杂合不足导致自闭症相关表型，这种表型可以通过遗传和药物干预来逆转。
Mol Psychiatry. 2023 May;28(5):2122-2135. doi: 10.1038/s41380-023-01959-7. Epub 2023 Feb 14.
6
PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression.PRRX1 是成纤维细胞中肌成纤维细胞谱系进展的主转录因子。
Nat Commun. 2022 May 19;13(1):2793. doi: 10.1038/s41467-022-30484-4.
7
Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages.整合蛋白质基因组学分析肝癌的病因和分期特征。
Nat Commun. 2022 May 4;13(1):2436. doi: 10.1038/s41467-022-29960-8.
8
Pioneer factors as master regulators of the epigenome and cell fate.先驱因子作为表观基因组和细胞命运的主要调节因子。
Nat Rev Mol Cell Biol. 2022 Jul;23(7):449-464. doi: 10.1038/s41580-022-00464-z. Epub 2022 Mar 9.
9
Ex vivo and in vivo suppression of SARS-CoV-2 with combinatorial AAV/RNAi expression vectors.用组合型 AAV/RNAi 表达载体进行 SARS-CoV-2 的离体和体内抑制。
Mol Ther. 2022 May 4;30(5):2005-2023. doi: 10.1016/j.ymthe.2022.01.024. Epub 2022 Jan 14.
10
Hallmarks of Cancer: New Dimensions.癌症的特征：新视角。
Cancer Discov. 2022 Jan;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059.