Background The effect of metformin on gut microbiota has been reported, but whether metformin can suppress colorectal cancer (CRC) by affecting gut microbiota composition and rescue F. nucleatum -induced tumourigenicity remains unclear. Methods To identify microbiota associated with both CRC occurrence and metformin treatment, first, we reanalyzed the gut microbiome of our previous data on two human cohorts of normal and CRC individuals. Subsequently, we summarized microbiota altered by metformin from published literatures. Several taxa, including Fusobacterium , were associated with both CRC occurrence and metformin treatment. We investigated the effect of metformin on APC Min/+ mice given with or without F. nucleatum . 16S rRNA gene sequencing was performed. Findings We summarized 131 genera altered by metformin from 18 published literatures . Five genera reported to be changed by metformin, including Bacteroides, Streptococcus, Achromobacter, Alistipes and Fusobacterium , were associated with CRC in both of our human cohorts. Metformin relieved the symptoms caused by F. nucleatum administration in APC Min/+ mice, and showed promise in suppressing intestinal tumour formation and rescuing F. nucleatum -induced tumourigenicity. Administration of F. nucleatum and/or metformin had effect on gut microbiome structure, composition and functions of APC Min/+ mice. Interpretation This study pioneers in predicting critical CRC-associated taxa contributing to the antitumour effect of metformin, and correlating gut microbiome with the antitumour effect of metformin in experimental animals. We presented a basis for future investigations into metformin's potential effect on suppressing F. nucleatum -induced tumor formation in vivo . Funding This work was supported by grants from the National Natural Science Foundation of China (31701250).

Most colorectal cancer (CRC) are characterized by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the tumor suppressor p53 gene. Although important, p53 is not the only driver of chromosome 17p loss. In this study, we explored the biological and prognostic significance of genes around p53 on 17p13.1 in CRC. The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes located between 1000 kb upstream and downstream of p53 gene. The function of CLDN7 was evaluated by both in vitro and in vivo experiments. Quantitative real-time PCR, western blot, and promoter luciferase activity, immunohistochemistry were used to explore the molecular drivers responsible for the development and progression of CRC. The results showed that CLDN7, located between 1000 kb upstream and downstream of p53 gene, were remarkably differentially expressed in tumor and normal tissues. CLDN7 expression also positively associated with p53 level in different stages of the adenoma-carcinoma sequence. Both in vitro and in vivo assays showed that CLDN7 inhibited cell proliferation in p53 wild type CRC cells, but had no effects on p53 mutant CRC cells. Mechanistically, p53 could bind to CLDN7 promoter region and regulate its expression. Clinically, high CLDN7 expression was negatively correlated with tumor size, invasion depth, lymphatic metastasis and AJCC III/IV stage, but was positively associated with favorable prognosis of CRC patients. Collectively, our work uncovers the tumor suppressive function for CLDN7 in a p53-dependent manner, which may mediate colorectal tumorigenesis induced by p53 deletion or mutation.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40–50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild‐type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild‐type p53 and suppresses tumor growth only in p53‐wild‐type (p53‐WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM‐induced CRC growth in mouse models with the intestinal epithelial cell‐specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53‐WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6A‐YTHDF2‐dependent pri‐miR‐6769b/pri‐miR‐499a processing. Biosynthetic mature miR‐6769b‐3p and miR‐499a‐3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53‐WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53‐dependent cancer growth inhibition, which could be targeted for therapy in p53‐WT CRC.