WNT/PI3K-mTOR 轴与 APC 驱动的结直肠癌变中的微生物组的相互作用：来自一项初步研究的数据及其对 CRC 预防的可能影响。

Interplay between WNT/PI3K-mTOR axis and the microbiota in APC-driven colorectal carcinogenesis: data from a pilot study and possible implications for CRC prevention.

机构信息

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

出版信息

J Transl Med. 2024 Jul 5;22(1):631. doi: 10.1186/s12967-024-05305-5.

DOI:10.1186/s12967-024-05305-5

PMID:38970018

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11227240/

Abstract

BACKGROUND

Wnt/β-catenin signalling impairment accounts for 85% of colorectal cancers (CRCs), including sporadic and familial adenomatous polyposis (FAP) settings. An altered PI3K/mTOR pathway and gut microbiota also contribute to CRC carcinogenesis. We studied the interplay between the two pathways and the microbiota composition within each step of CRC carcinogenesis.

METHODS

Proteins and target genes of both pathways were analysed by RT-qPCR and IHC in tissues from healthy faecal immunochemical test positive (FIT+, n = 17), FAP (n = 17) and CRC (n = 15) subjects. CRC-related mutations were analysed through NGS and Sanger. Oral, faecal and mucosal microbiota was profiled by 16 S rRNA-sequencing.

RESULTS

We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. Wnt/β-catenin molecular markers positively correlated with Clostridium_sensu_stricto_1 and negatively with Bacteroides in FAP faecal microbiota. Alistipes, Lachnospiraceae, and Ruminococcaceae were enriched in FAP stools and adenomas, the latter also showing an overabundance of Lachnoclostridium, which positively correlated with cMYC. In impaired-mTOR-mutated CRC tissues, p-S6R correlated with Fusobacterium and Dialister, the latter also confirmed in the faecal-ecosystem.

CONCLUSIONS

Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment.

摘要

背景

Wnt/β-catenin 信号通路的损伤占结直肠癌（CRC）的 85%，包括散发性和家族性腺瘤性息肉病（FAP）。改变的 PI3K/mTOR 通路和肠道微生物群也有助于 CRC 的癌变。我们研究了两条通路之间以及 CRC 癌变每个步骤中微生物群组成之间的相互作用。

方法

通过 RT-qPCR 和 IHC 分析了来自健康粪便免疫化学试验阳性（FIT+，n=17）、FAP（n=17）和 CRC（n=15）患者组织中两条通路的蛋白质和靶基因。通过 NGS 和 Sanger 分析 CRC 相关突变。通过 16S rRNA 测序分析口腔、粪便和黏膜微生物群。

结果

我们发现 FAP 病变中的 Wnt/β-catenin 和 PI3K/mTOR 通路同时过度激活，与 CRC 相比。Wnt/β-catenin 分子标志物与 Clostridium_sensu_stricto_1 呈正相关，与 FAP 粪便微生物群中的 Bacteroides 呈负相关。Alistipes、Lachnospiraceae 和 Ruminococcaceae 在 FAP 粪便和腺瘤中富集，后者也显示出 Lachnoclostridium 的过度丰富，与 cMYC 呈正相关。在受损的 mTOR 突变的 CRC 组织中，p-S6R 与 Fusobacterium 和 Dialister 相关，后者在粪便生态系统中也得到了证实。