腸道微生物組可將突變型p53從抑制腫瘤轉變為致癌
作者：
小柯機器人發布時間：2020/7/31 23:07:13
以色列希伯來大學-哈達薩醫學院Yinon Ben-Neriah研究組近日取得一項新成果。他們發現腸道微生物組可將突變型p53從抑制腫瘤轉變為致癌。相關論文發表在2020年7月29日出版的《自然》雜誌上。
他們研究了由Csnk1a1缺失或ApcMin突變引起的WNT驅動的腸癌小鼠模型中Trp53（在小鼠中編碼p53的基因）中的熱點功能突變的影響。已知這些模型中的癌症可通過p53的丟失而促進。他們發現p53突變體在腸道的不同部位具有對比作用：在遠端腸道中，p53突變體具有預期的致癌作用；然而，在近端腸道和腫瘤類器官中，它具有顯著的腫瘤抑制作用。
在腫瘤抑制模型下，突變體p53消除了Csnk1a1缺陷和ApcMin / +小鼠的不典型增生和腫瘤發生，並促進了這些小鼠來源的類器官的正常生長和分化。在這些情況下，突變型p53在抑制腫瘤形成方面比野生型p53更有效。從機制上講，突變型p53的腫瘤抑制作用是通過阻止WNT途徑（通過阻止TCF4與染色質的結合）來驅動的。
值得注意的是，腸道微生物組完全消除了這種腫瘤抑制作用。此外，源自腸道菌群的單一代謝物-沒食子酸可以重現微生物組的全部作用。給予腸道無菌菌的p53突變小鼠和p53突變類器官沒食子酸，可恢復TCF4-染色質相互作用和WNT的過度活化，從而賦予類器官和整個腸道以惡性表型。他們的研究證明了癌症突變的可塑性，並強調了微環境在決定其功能預後方面的作用。
此外，源自腸道菌群的單一代謝物-沒食子酸可以重現微生物組的全部作用。用沒食子酸補充經腸道滅菌的p53突變小鼠和p53突變類器官，可恢復TCF4-染色質相互作用和WNT的過度活化，從而賦予類器官和整個腸道以惡性表型。他們的研究表明癌症突變的持續可塑性，並強調微環境在決定其功能的作用。
據介紹，p53中的體細胞突變會導致其喪失腫瘤抑制功能，並通常賦予癌症功能獲得特性，在癌症中非常常見。
附：英文原文
Title: The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic
Author: Eliran Kadosh, Irit Snir-Alkalay, Avanthika Venkatachalam, Shahaf May, Audrey Lasry, Ela Elyada, Adar Zinger, Maya Shaham, Gitit Vaalani, Marco Mernberger, Thorsten Stiewe, Eli Pikarsky, Moshe Oren, Yinon Ben-Neriah
Issue&Volume: 2020-07-29
Abstract: Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer1,2. Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion3,4 or ApcMin mutation5. Cancer in these models is known to be facilitated by loss of p533,6. We found that mutant versions of p53 had contrasting effects in different segments of the gut: in the distal gut, mutant p53 had the expected oncogenic effect; however, in the proximal gut and in tumour organoids it had a pronounced tumour-suppressive effect. In the tumour-suppressive mode, mutant p53 eliminated dysplasia and tumorigenesis in Csnk1a1-deficient and ApcMin/+ mice, and promoted normal growth and differentiation of tumour organoids derived from these mice. In these settings, mutant p53 was more effective than wild-type p53 at inhibiting tumour formation. Mechanistically, the tumour-suppressive effects of mutant p53 were driven by disruption of the WNT pathway, through preventing the binding of TCF4 to chromatin. Notably, this tumour-suppressive effect was completely abolished by the gut microbiome. Moreover, a single metabolite derived from the gut microbiota—gallic acid—could reproduce the entire effect of the microbiome. Supplementing gut-sterilized p53-mutant mice and p53-mutant organoids with gallic acid reinstated the TCF4–chromatin interaction and the hyperactivation of WNT, thus conferring a malignant phenotype to the organoids and throughout the gut. Our study demonstrates the substantial plasticity of a cancer mutation and highlights the role of the microenvironment in determining its functional outcome.
DOI: 10.1038/s41586-020-2541-0
Source: https://www.nature.com/articles/s41586-020-2541-0