RESUMEN
Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.
RESUMEN
OBJECTIVE: Branched-chain amino acid (BCAA) metabolism is involved in the development of colorectal cancer (CRC); however, the underlying mechanism remains unclear. Therefore, this study investigates the role of BCAA metabolism in CRC progression. METHODS: Dietary BCAA was administered to both azoxymethane-induced and azoxymethane/dextran sodium sulfate-induced CRC mouse models. The expression of genes related to BCAA metabolism was determined using RNA sequencing. Adjacent tissue samples, obtained from 58 patients with CRC, were subjected to quantitative real-time PCR and immunohistochemical analysis. Moreover, the suppressive role of branched-chain aminotransferase 2 (BCAT2) in cell proliferation, apoptosis, and xenograft mouse models was investigated. Alterations in BCAAs and activation of downstream pathways were also assessed using metabolic analysis and western blotting. RESULTS: High levels of dietary BCAA intake promoted CRC tumorigenesis in chemical-induced CRC and xenograft mouse models. Both the mRNA and protein levels of BCAT2 were decreased in tumor tissues of patients with CRC compared to those in normal tissues. Proliferation assays and xenograft models confirmed the suppressive role of BCAT2 in CRC progression. Furthermore, the accumulation of BCAAs caused by BCAT2 deficiency facilitated the chronic activation of mTORC1, thereby mediating the oncogenic effect of BCAAs. CONCLUSION: BCAT2 deficiency promotes CRC progression through inhibition of BCAAs metabolism and chronic activation of mTORC1.
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Neoplasias Colorrectales , Proteínas Gestacionales , Humanos , Ratones , Animales , Aminoácidos de Cadena Ramificada/metabolismo , ARN Mensajero , Diana Mecanicista del Complejo 1 de la Rapamicina , Azoximetano , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Transaminasas/genética , Transaminasas/metabolismo , Proteínas Gestacionales/metabolismo , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismoRESUMEN
Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
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Neoplasias Colorrectales , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Limosilactobacillus reuteri , Microbiota , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Triptófano , Estudios Retrospectivos , Neoplasias Colorrectales/prevención & controlRESUMEN
Chronic inflammation and gut microbiota dysbiosis are risk factors for colorectal cancer. In clinical practice, patients with inflammatory bowel disease (IBD) have a greatly increased risk of developing colitis-associated colorectal cancer (CAC). However, the underlying mechanism of the initiation of CAC remains unknown. Systematic analyses using an existing genome-wide association study (GWAS) and conditional deletion of Zfp90 (encoding zinc finger protein 90 homolog) in a CAC mouse model indicated that Zfp90 is a putative oncogene in CAC development.Strikingly, depletion of the gut microbiota eliminated the tumorigenic effect of Zfp90 in the CAC mouse model. Moreover, fecal microbiota transplantation demonstrated that Zfp90 promoted CAC dependent on the gut microbiota. Analysis of 16s rDNA sequences in fecal specimens from the CAC mouse model allowed us to speculate that a Prevotella copri-defined microbiota might mediate the oncogenic role of Zfp90 in the development of CAC. Mechanistic studies revealed Zfp90 accelerated CAC development through the TLR4-PI3K-AKT-NF-κB pathway. Our findings revealed the crucial role of the Zfp90-microbiota-NF-κB axis in creating a tumor-promoting environment and suggested therapeutic targets for CAC prevention and treatment.
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Neoplasias Asociadas a Colitis/metabolismo , Microbioma Gastrointestinal , Proteínas Represoras/metabolismo , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/microbiología , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Represoras/genéticaRESUMEN
OBJECTIVES: Shotgun metagenomic sequencing of human fecal samples has shown that Saccharomyces cerevisiae (S. cerevisiae) is significantly suppressed in colorectal cancer (CRC) and probably plays an important role in CRC progression. However, these results need to be validated. Here we aimed to confirm the results of high-throughput sequencing and demonstrate the mechanisms mediating the effect of S. cerevisiae on progression from colorectal adenoma (CRA) to CRC. METHODS: We used a quantitative polymerase chain reaction (qPCR) assay to examine the relative abundance of S. cerevisiae in 281 fecal samples collected from 106 healthy controls, 108 patients with CRA and 67 with CRC. C57BL/6 and APCMin/+ mouse models and in vitro cell assays were subsequntly used for additional analyses. The mouse models were treated or not treated with broad-spectrum antibiotics and given an S. cerevisiae gavage for 8 weeks. Western blot, 16S rRNA sequencing, qPCR, immunohistochemistry, RNA sequencing, cell counting kit-8 assay, colony formation assay and flow cytometry were performed. RESULTS: S. cerevisiae was 2.68-fold and 3.94-fold less abundant in patients with CRA and CRC, respectively, than in the controls. In vivo experiments showed that S. cerevisiae reduced colorectal tumor progression by promoting epithelial cell apoptosis and modulated gut microbial structure and intestinal immunity. S. cerevisiae downregulated nuclear factor kappa light chain enhancer of activated B cells and the mechanistic target of rapamycin signaling pathways. Cell assays confirmed the pro-apoptotic effect of S. cerevisiae. CONCLUSIONS: S. cerevisiae may play a probiotic role in CRC by promoting cancer cell apoptosis. It can reduce CRC progression by modulating the mucosal microbial structure.
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Apoptosis , Neoplasias Colorrectales , Probióticos , Saccharomyces cerevisiae , Animales , Proliferación Celular , Neoplasias Colorrectales/terapia , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16SRESUMEN
The rapid development of microbiota research has remolded our view of human physiological and pathological processes. Among all the gastrointestinal microorganisms, Helicobacter pylori (H pylori) is probably the most notorious constituent. Although half of the adults worldwide are infected with H pylori, their clinical manifestations vary widely, suggesting other microorganisms beyond H pylori may play a role in determining clinical outcomes. Recently, many studies have put effort into elucidating the crosstalk within the human microbiota, some of which specifically explored the interplay between H pylori and other gastrointestinal microbial members. In this work, we reviewed these potential interactions. Meanwhile, the impacts of H pylori eradication therapy on gastrointestinal microbial homeostasis were summarized in terms of diversity, composition, functional capacity, and antibiotic resistance.
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Microbioma Gastrointestinal , Infecciones por Helicobacter , Adulto , Antibacterianos/uso terapéutico , Farmacorresistencia Microbiana , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Helicobacter pylori , HumanosRESUMEN
Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.