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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
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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
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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
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Journal Article
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
2024
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,BMC
Subject
Adenomatous Polyposis Coli - genetics
/ Adenomatous Polyposis Coli - microbiology
/ Adenomatous Polyposis Coli Protein - genetics
/ Adenomatous Polyposis Coli Protein - metabolism
/ Adult
/ Aged
/ Biomedical and Life Sciences
/ Colorectal Neoplasms - microbiology
/ Familial adenomatous polyposis
/ Female
/ Humans
/ Male
/ Microbiota (Symbiotic organisms)
/ Phosphatidylinositol 3-Kinases - metabolism
/ Testing
/ TOR Serine-Threonine Kinases - metabolism
