瑞典卡罗林斯卡学院Eduardo J. Villablanca和Srustidhar Das等人发现，肝脏X受体调控肠道再生并阻止肿瘤发生。相关论文于2024年11月20日发表在《自然》杂志上。

据了解，再生紊乱会导致肿瘤转化。肠上皮细胞需要在稳态和损伤诱导组织更新过程中进行精确调控，以防止肿瘤转化，这表明一定存在将肿瘤发生与再生过程联系起来的途径。

通过挖掘两个肠道损伤模型的RNA序列数据集，并使用药理学、转录组学和遗传学工具，研究人员发现肝脏X受体（LXR）通路激活是组织对损伤的一种适应，其调控肠道再生和肿瘤发生。

利用单细胞RNA测序、肠器官组织以及功能增益和功能缺失实验，研究证明肠上皮细胞中的LXR激活会诱导两性胰岛素（Areg），从而增强再生反应。

这种反应由LXR配体产生酶CYP27A1协调，该酶在受损的肠隐窝中上调。Cyp27a1的缺失会影响肠道再生，而外源LXR激活剂可以挽救肠道再生。

值得注意的是，在肿瘤模型中，Cyp27a1的缺失会导致肿瘤生长加快，而LXR的激活则会引起依赖于适应性免疫的抗肿瘤反应。

同样，人类结直肠癌标本中也存在CYP27A1、LXR靶基因以及B和CD8 T细胞基因特征水平的降低。

因此，该研究发现了一种上皮细胞对损伤的适应机制，LXR在这种机制中发挥着流变调节器的作用，在促进组织修复的同时阻止肿瘤发生。

附：英文原文

Title: Liver X receptor unlinks intestinal regeneration and tumorigenesis

Author: Das, Srustidhar, Parigi, S. Martina, Luo, Xinxin, Fransson, Jennifer, Kern, Bianca C., Okhovat, Ali, Diaz, Oscar E., Sorini, Chiara, Czarnewski, Paulo, Webb, Anna T., Morales, Rodrigo A., Lebon, Sacha, Monasterio, Gustavo, Castillo, Francisca, Tripathi, Kumar P., He, Ning, Pelczar, Penelope, Schaltenberg, Nicola, De la Fuente, Marjorie, Lpez-Kstner, Francisco, Nyln, Susanne, Larsen, Hjalte List, Kuiper, Raoul, Antonson, Per, Hermoso, Marcela A., Huber, Samuel, Biton, Moshe, Scharaw, Sandra, Gustafsson, Jan-ke, Katajisto, Pekka, Villablanca, Eduardo J.

Issue&Volume: 2024-11-20

Abstract: Uncontrolled regeneration leads to neoplastic transformation1,2,3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.

DOI: 10.1038/s41586-024-08247-6

Source: https://www.nature.com/articles/s41586-024-08247-6