Loss of colonic primary cilia promotes inflammation and carcinogenesis.
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ABSTRACT:
PROVIDER: PRJNA857563 | ENA |
REPOSITORIES: ENA
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Project description:Primary cilia (PC) are important signaling hubs in cells and we explored their role in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts and exposure of mice to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced acute colitis decreased PC numbers. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Secretome and immunohistochemical analyses of DSS-treated mice displayed an elevated production of the pro-inflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminished PC presence in primary fibroblast cultures. This was triggered by IL-6 as identified by RNAseq analysis together with blocking experiments, suggesting an activation loop between IL-6 production and PC loss. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.
2022-11-29 | PXD033440 | Pride
Project description:Primary cilia (PC) are important signaling hubs and their deregulation is associated with various diseases. The 2P-CF cultures plus starvation mimic the in vivo proportion of PC on colonic fibroblasts (CF) in an intact colon and thus allow to explore the biology of PC. We generated conditioned starvation medium from colons of DSS treated (termed inflammatory conditioned medium, i.e. inf-CM) and untreated control animals (termed co-CM) and cultured 2P-CF in those media for 24 hours. 30-40% of 2P-CF starved in control medium displayed PC, whereas PC number on 2P-CF starved in inf-CM was consistently lower. We performed RNAseq analysis of 2P-CF starved in inf-CM or in co-CM to gain insight in the molecular traits of those cell cultures.
2022-10-01 | GSE207877 | GEO
Project description:Primary cilia (PC) are important signaling hubs, and we here explored their role in colonic pathology. In the colon, PC are mostly present on fibroblasts, and exposure of mice to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced acute colitis decreases PC numbers. We generated conditional knockout mice with reduced numbers of PC on colonic fibroblasts. These mice show increased susceptibility to CAC, as well as DSS-induced colitis. Secretome and immunohistochemical analyses of DSS-treated mice display an elevated production of the proinflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminishes PC presence in primary fibroblast cultures, which is triggered by IL-6 as identified by RNA-seq analysis together with blocking experiments. These findings suggest an activation loop between IL-6 production and PC loss. An analysis of PC presence on biopsies of patients with ulcerative colitis or colorectal cancer (CRC) reveals decreased numbers of PC on colonic fibroblasts in pathological compared with surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.
| S-EPMC9724674 | biostudies-literature
Project description:miR-181 regulates colonic inflammation
| PRJNA859816 | ENA
Project description:Effect of Smox deletion and spermidine supplementation on colonic gene expression during carcinogenesis
2021-10-01 | GSE158826 | GEO
Project description:Inflammation-Driven Carcinogenesis is Mediated through STING
| PRJNA246777 | ENA
Project description:Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naïve tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoi-resistant BCCs possess an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared to naive or Gorlin patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature reveals increased Ras/MAPK pathway activation. Tissue analysis confirms an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiates Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines confers resistance to both canonical (vismodegib) and non-canonical (aPKC and MRTF inhibitors) HH pathway inhibitors, while conferring sensitivity to MAPK inhibitors. Our results provide new insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH to Ras/MAPK pathway switching.
2018-10-10 | GSE120954 | GEO
Project description:Inflammatory conditions can contribute to tumor formation. However, any clear marker predicting progression to cancer are still lacking. The aim of our study was to analyze microRNA modulations accompanying inflammation-induced tumor development to determine whether these microRNA may jointly affect the expression of genes involved in cancer. For this purpose, we used the well-established azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model of colitis-associated cancer. We performed a microRNA microarray to establish microRNA expression profiles in mouse whole colon at early and late time points during inflammation and/or tumor growth. Chronic inflammation and carcinogenesis were associated with distinct changes in microRNA expression. Nevertheless, prediction algorithms of microRNA-mRNA interactions and computational analyses based on ranked microRNA lists consistently identified putative target genes that play essential roles in tumor growth or belong to key carcinogenesis-related networks or signaling pathways. Hence, inflammation, through microRNA, may affect unexpected genes or signaling pathways, thereby contributing to carcinogenesis. The present method can lead to the identification of novel genes or signaling pathways involved in cancer development. miRNA microarray profiling in whole mouse colon at 4 time points during AOM/DSS treatment. Controls : PBS, DSS alone or AOM alone, at two time points; 10 experimental conditions, 5 replicates per experimental conditions, one replicate per array hybridized in dual color with a commercial reference (Universal Reference, Miltenyi Biotec GmbH)
2013-12-31 | E-GEOD-38443 | biostudies-arrayexpress
Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Conclusions/significance: Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia plays a significant role in the pathogenesis of smoking-induced lung disease.
2012-12-13 | E-GEOD-16696 | biostudies-arrayexpress
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
2014-05-31 | E-GEOD-57604 | biostudies-arrayexpress