Microbial metabolite ammonia disrupts CEACAM1-TGF-β signaling to promote colon cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1184799 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31308172_1.fastq.gz | Fastqsanger.gz | |||
| SRR31308172_2.fastq.gz | Fastqsanger.gz | |||
| SRR31308173_1.fastq.gz | Fastqsanger.gz | |||
| SRR31308173_2.fastq.gz | Fastqsanger.gz | |||
| SRR31308174_1.fastq.gz | Fastqsanger.gz |
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Project description:Colorectal cancer (CRC) incidence is rising globally and anticipated to become the leading cause of cancer death in younger individuals. Potential risk factors are diet induced obesity and altered microbiomes that lead to accumulation of toxic metabolite accumulation. However, how ammonia and other microbial metabolites impact key signaling pathways, such as TGF-β signaling, to promote CRC remains unclear. Our study investigates a critical link between gut microbiome alterations, ammonia, and their toxic effects on the TGF-β signaling pathway, to drive CRC progression. We found that in an obesity induced mouse model of cancer, altered microbial populations and ammonia promote Caspase-3-mediated cleavage of SMAD3 adaptor βII-spectrin (SPTBN1). Cleaved SPTBN1 fragments form adducts with ammonia to induce pro-inflammatory cytokine expression and alter TGF-β signaling driving CRC. Extending on Alphafold docking simulations, we identified that ammonia interacts with six polar residues at SPTBN1 (S553, Y556, S663, Y666, N986, and T1178) of cleaved SPTBN1 fragments to form hydrogen bonds that disrupt downstream SMAD3 signaling, altering TGF-β signaling to a protumorigenic phenotype. Blocking SPTBN1, through an SPTBN1 specific siRNA blocks ammonia toxicity and restore TGF-β signaling by reducing the abundance of SPTBN1 cleaved fragments. Importantly, SPTBN1 siRNA blocks ammonia toxicity and restore normal TGF-β signaling in CRC cells. Moreover, our research establishes crosstalk between TGF-β signaling and a microbial sensor, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is significantly overexpressed in CRC patients. We identified CEACAM1-SPTBN1 interactions at specific residues (E517 and Y520) within the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 cytoplasmic domain, with both molecules playing pivotal roles in CRC progression. Our study identifies mechanistic insights into how microbial metabolites target TGF-β a major signaling pathways to promote CRC.
2024-11-16 | GSE281613 | GEO
Project description:Cleft palate results from a mixture of genetic and environmental factors and occurs when the bilateral palatal shelves fail to fuse. The objective of this study was to search for new genes involved in mouse palate formation. Gene expression of murine embryonic palatal tissue was analyzed at the various developmental stages before, during, and after palate fusion using GeneChip? microarrays. Ceacam1 was one of the highly up-regulated genes during and after fusion in palate formation, and this was confirmed by quantitative real-time PCR. Immunohistochemical staining showed that CEACAM1 was expressed at a very low level in palatal epithelium before fusion, but highly expressed in the midline of the palate during and after fusion. To investigate the developmental role of CEACAM1, function-blocking antibody was added to embryonic mouse palate in organ culture. Palatal fusion was inhibited by this function-blocking antibody. To investigate the subsequent developmental role of CEACAM1, we characterized Ceacam1-deficient (Ceacam1-/-) mice. Epithelial cells persisted abnormally at the midline of the embryonic palate even on day E16.0, and palatal fusion was delayed in Ceacam1-/- mice. TGF?3 expression, apoptosis, and cell proliferation in palatal epithelium were not effected in the palate of Ceacam1-/-mice. CEACAM1 expression was down-regulated in Tgfb3-/- palate. However, exogenous TGF?3 did not induce CEACAM1 expression. These results suggest that CEACAM1 has roles in both the initiation of palate formation via epithelial cell adhesion and TGF signaling has some indirect effect on CEACAM1. Global gene expression profiling of palatal processes before, during and after fusion of palatal shelves We used microarray to investigate the gene expression of palatal tissue during palatal development. Palatal processes were microdissected at the stages of palatal development (before, during and after fusion) for RNA extraction and hybridization on Affymetrix microarrays.
2013-01-23 | E-GEOD-43651 | biostudies-arrayexpress
Project description:In this experiment, we used advanced proteomics techniques to discern differences in energy allocation between three strains of ammonia oxidizing bacteria: Nitrosomonas europaea, Nitrosomonas ureae, and Nitrosospira multiformis, during ammonia starved and ammonia replete conditions. Replicate cultures in late log phase from the three strains were starved of ammonia for 24 hours and compared to replicate control cultures grown for the same period. All three species were grown with three biological replicates for each condition and species with the exception of two replicates from the N. ureae starved cultures due to sample processing loss. This study has, to our knowledge, produced the first complete proteomes of Nitrosospira multiformis and Nitrosomonas ureae.
2018-05-16 | PXD008954 | Pride
Project description:Cleft palate results from a mixture of genetic and environmental factors and occurs when the bilateral palatal shelves fail to fuse. The objective of this study was to search for new genes involved in mouse palate formation. Gene expression of murine embryonic palatal tissue was analyzed at the various developmental stages before, during, and after palate fusion using GeneChip? microarrays. Ceacam1 was one of the highly up-regulated genes during and after fusion in palate formation, and this was confirmed by quantitative real-time PCR. Immunohistochemical staining showed that CEACAM1 was expressed at a very low level in palatal epithelium before fusion, but highly expressed in the midline of the palate during and after fusion. To investigate the developmental role of CEACAM1, function-blocking antibody was added to embryonic mouse palate in organ culture. Palatal fusion was inhibited by this function-blocking antibody. To investigate the subsequent developmental role of CEACAM1, we characterized Ceacam1-deficient (Ceacam1-/-) mice. Epithelial cells persisted abnormally at the midline of the embryonic palate even on day E16.0, and palatal fusion was delayed in Ceacam1-/- mice. TGF?3 expression, apoptosis, and cell proliferation in palatal epithelium were not effected in the palate of Ceacam1-/-mice. CEACAM1 expression was down-regulated in Tgfb3-/- palate. However, exogenous TGF?3 did not induce CEACAM1 expression. These results suggest that CEACAM1 has roles in both the initiation of palate formation via epithelial cell adhesion and TGF signaling has some indirect effect on CEACAM1. Global gene expression profiling of palatal processes before, during and after fusion of palatal shelves We used microarray to investigate the gene expression of palatal tissue during palatal development.
2013-01-23 | GSE43651 | GEO
Project description:Rhizobium leguminosarum biovar viciae strain 3841 was grown on acetate ammonia AMS and glucose ammonia AMS and gene expression between the two cultures compared
2009-06-11 | E-MEXP-1964 | biostudies-arrayexpress
Project description:Ammonia oxidizer community structure were examined in a depth profile from 20 to 2000 m at the Bermuda Atlantic Time-series Study using a functional gene microarray to look at amoA diversity
2012-11-15 | GSE42287 | GEO
Project description:Free-living bacteria were grown on succinae ammonia AMS and gene expression was compared to free-living bacteria grown on glucose ammonia AMS.
2008-11-30 | E-MEXP-1919 | biostudies-arrayexpress
Project description:The abundance of bacterial (AOB) and archaeal (AOA) ammonia oxidisers, assessed using quantitative PCR measurements of their respective a-subunit of the ammonia monooxygenase (amoA) genes, and ammonia oxidation rates were measured in four contrasting coastal sediments in the Western English Channel. Sediment was sampled bimonthly from July 2008 to May 2011, and measurements of ammonia oxidiser abundance and activity compared to a range of environmental variables including salinity, temperature, water column nutrients and sediment carbon and nitrogen content. Despite a higher abundance of AOA amoA genes within all sediments, and at all time-points, rates of ammonia oxidation correlated with AOB and not AOA amoA gene abundance. Other than ammonia oxidation rate, sediment particle size was the only variable that correlated with the spatial and temporal patterns of AOB amoA gene abundance, implying a preference of the AOB for larger sediment particles. This is possibly due to deeper oxygen penetration into the sandier sediments, increasing the area available for ammonia oxidation to occur, higher concentrations of inhibitory sulphide with pore waters of muddier sediments or a combination of both oxygen and sulphide concentrations. Similar to many other temporal studies of nitrification within estuarine and coastal sediments, decreases in AOB amoA gene abundance were evident during summer and autumn, with maximum abundance and ammonia oxidation rates occurring in winter and early spring. The lack of correlation between AOA amoA gene abundance and ammonium oxidation rate suggests an alternative role for amoA-carrying AOA within these sediments.
2013-08-24 | GSE50163 | GEO