核蛋白支持WNT驱动的过度增殖和肿瘤起始，这一成果由英国苏格兰癌症研究所Owen J. Sansom团队经过不懈努力而取得。2025年12月18日出版的《自然—遗传学》发表了这项成果。

课题组人员证明，在WNT应答组织中APC丢失后，Npm1上调，并支持WNT驱动的肠道和肝脏肿瘤发生。在机制上，NPM1缺失诱导核糖体在编码序列的5'端进行寻路和积累，触发蛋白质合成应激反应和p53激活，介导这种抗肿瘤作用。总的来说，他们的数据确定NPM1是一个关键的WNT效应物，通过减弱综合应激反应和p53激活来维持WNT驱动的过度增殖和肿瘤发生。值得注意的是，在人类结直肠癌（CRC）中，NPM1的表达与WNT信号的升高和增殖相关，而含有NPM1缺失的CRC表现出优先的TP53失活，强调了他们的研究结果的临床相关性。NPM1对于成人上皮稳态来说是必不可少的，在p53精通的WNT驱动的肿瘤中，包括难治性KRAS突变型CRC和肝癌，NPM1是一个有希望的治疗靶点。

研究人员表示，核磷蛋白（NPM1）是一种在造血恶性肿瘤中经常发生突变的核仁蛋白，在几种实体肿瘤中过度表达，其功能作用尚不清楚。

附：英文原文

Title: Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation

Author: Kanellos, Georgios, Giacomelli, Chiara, Raven, Alexander, Vlahov, Nikola, Jin, Hu, Herviou, Pauline, Malla, Sudhir B., Nasreddin, Nadia, Centeno, Patricia P., Alexandrou, Constantinos, Gilroy, Kathryn, Baird, Rachel L., Pennel, Kathryn, Munro, June, Waldron, Joseph A., Hall, Holly, Officer-Jones, Leah, Bryson, Sheila, Strathdee, Douglas, Lilla, Sergio, Zanivan, Sara, Morrison, Vivienne, Nixon, Colin, Ridgway, Rachel A., Miller, Crispin, Knight, John R. P., Campbell, Andrew D., Dunne, Philip D., Le Quesne, John, Edwards, Joanne, Park, Peter J., Bushell, Martin, Sansom, Owen J.

Issue&Volume: 2025-12-18

Abstract: Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5’-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.

DOI: 10.1038/s41588-025-02408-7

Source: https://www.nature.com/articles/s41588-025-02408-7