Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice
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ABSTRACT:
PROVIDER: PRJNA549162 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9309410_1.fastq.gz | Fastqsanger.gz | |||
| SRR9309410_2.fastq.gz | Fastqsanger.gz | |||
| SRR9309411_1.fastq.gz | Fastqsanger.gz | |||
| SRR9309411_2.fastq.gz | Fastqsanger.gz | |||
| SRR9309412_1.fastq.gz | Fastqsanger.gz |
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Project description:The helicase-like transcription factor (HLTF) gene – a tumor suppressor in human colorectal cancer (CRC) - is regulated by alternative splicing and promoter hypermethylation. The detection of hypermethylated HLTF DNA in fecal occult blood tests is an indicator of disease recurrence and poor survival. Hltf-deficiency in the ApcMin/+ mouse strain increased the formation of intestinal adenocarcinoma with a high incidence of gross chromosomal instabilities. To investigate Hltf-deletion effects in CRC without cross-breeding into a tumorigenic strain, Hltf-deletion was studied in mice treated with the carcinogen azoxymethane (AOM) and the proinflammatory agent dextran sulfate (DSS). Hltf-deletion resulted in weight loss beginning at treatment week 6, and poor survival (Kaplan-Meier survival plot). Hltf-deletion increased tumor multiplicity compared to controls, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis of lesions from control mice revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present (3:1.8 ratio) during adenocarcinoma formation. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway (p=0.006; p value correction: Bonferroni) perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p=0.0176). Upregulation of gene expression, as validated with qRT-PCR, was accompanied by a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics. The distal shift in tumorigenesis indicates the detection of hypermethylated HLTF DNA in human stool samples might be a prognostic biomarker for distal (left-sided) colorectal cancer rather than proximal (right-sided) colon cancer.
2019-06-18 | GSE132814 | GEO
Project description:The helicase-like transcription factor (HLTF) gene-a tumor suppressor in human colorectal cancer (CRC)-is regulated by alternative splicing and promoter hypermethylation. In this study, we used the AOM/DSS-induced mouse model to show Hltf-deletion caused poor survival concomitant with increased tumor multiplicity, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present during adenocarcinoma formation in controls. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p = 0.0062). Upregulation of gene expression, as validated with qRT-PCR, accompanied a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics.
| S-EPMC6713344 | biostudies-literature
Project description:The tumor suppressor, helicase-like transcription factor (HLTF), is expressed in tumor cells but not in the tumor microenvironment (TME) in early stage colorectal cancer (CRC). With disease progression, epigenetic silencing of HLTF in primary CRC tumors coincides with negligible HLTF expression in the TME. Cell line-derived xenograft (CDX) models were developed to test the hypothesis that HLTF-deletion in cancer cells with resultant metabolic reprogramming—a hallmark of metastasis—is a prototypical example of cancer cells modifying their metabolic requirements in response to HLTF-deletion in the TME. The two metabolic pathways that derive energy from glucose—glycolysis and oxidative phosphorylation (OXPHOS)—are variously utilized by cancer cells depending upon the TME. HIF-1α, a master regulator of glycolysis, was eliminated from a role in reprogramming metabolism to satisfy CDX energetic requirements by RNAseq and spatial transcriptomics. Variability in the gut microbiome, with a putative role in altered metabolism, was also eliminated. In contrast, HLTF-deleted cancer cells recovered from DNA damage at a transcriptomic level induction of DNA repair and OXPHOS genes linked to an amoeboid-associated phenotype at the tumor border (confocal microscopy). HLTF-deleted cancer and endothelial cells of the intravascular niche in the TME share a site-specific protein S-glutathionylation signature (2D DIGE, MALDI-TOF/TOF mass spectrometry) for three glycolytic enzymes (PGK1 Cys379/380, PGAM1 Cys55, ENOA1 Cys119) that diverted glycolysis in support of continued glutathione biosynthesis. The collective absence of HLTF/Hltf from tumor and TME maintained redox homeostasis throughout the CDX and promoted metastasis.
2023-09-13 | GSE234517 | GEO
Project description:The tumor suppressor, helicase-like transcription factor (HLTF), is expressed in tumor cells but not in the tumor microenvironment (TME) in early stage colorectal cancer (CRC). With disease progression, epigenetic silencing of HLTF in primary CRC tumors coincides with negligible HLTF expression in the TME. Cell line-derived xenograft (CDX) models were developed to test the hypothesis that HLTF-deletion in cancer cells with resultant metabolic reprogramming—a hallmark of metastasis—is a prototypical example of cancer cells modifying their metabolic requirements in response to HLTF-deletion in the TME. The two metabolic pathways that derive energy from glucose—glycolysis and oxidative phosphorylation (OXPHOS)—are variously utilized by cancer cells depending upon the TME. HIF-1α, a master regulator of glycolysis, was eliminated from a role in reprogramming metabolism to satisfy CDX energetic requirements by RNAseq and spatial transcriptomics. Variability in the gut microbiome, with a putative role in altered metabolism, was also eliminated. In contrast, HLTF-deleted cancer cells recovered from DNA damage at a transcriptomic level induction of DNA repair and OXPHOS genes linked to an amoeboid-associated phenotype at the tumor border (confocal microscopy). HLTF-deleted cancer and endothelial cells of the intravascular niche in the TME share a site-specific protein S-glutathionylation signature (2D DIGE, MALDI-TOF/TOF mass spectrometry) for three glycolytic enzymes (PGK1 Cys379/380, PGAM1 Cys55, ENOA1 Cys119) that diverted glycolysis in support of continued glutathione biosynthesis. The collective absence of HLTF/Hltf from tumor and TME maintained redox homeostasis throughout the CDX and promoted metastasis.
2023-09-13 | GSE234725 | GEO
Project description:To find out which miRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed miRNA microarray as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation. 5-7 weeks female BALB/c mice, (1) AOM/DSS group: AOM 12.5mg/kg i.p. at day 1, DSS drinking 5d/21dx3circles from day 5; (2) AOM group: AOM 10mg/kg i.p. 1/weekx6 from day 1; (3) DSS group: DSS drinking 5d/21dx3circles from day 5. The distal colon epithelial tissues were collected at day100 when tumor formed in AOM/DSS bearing mice. The miRNA microarray experiments were performed together.
2013-05-10 | E-GEOD-44983 | biostudies-arrayexpress
Project description:To find out which mRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation. 5-7 weeks female BALB/c mice, (1) AOM/DSS group: AOM 12.5mg/kg i.p. at day 1, DSS drinking 5d/21dx3circles from day 5; (2) AOM group: AOM 10mg/kg i.p. 1/weekx6 from day 1; (3) DSS group: DSS drinking 5d/21dx3circles from day 5. The distal colon epithelial tissues were collected at day100 when tumor formed in AOM/DSS bearing mice. The whole genome microarray expression profiling experiments were performed together.
2013-05-10 | E-GEOD-44904 | biostudies-arrayexpress
Project description:To find out which miRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed miRNA microarray as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation.
2013-05-10 | GSE44983 | GEO
Project description:To find out which mRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation.
2013-05-10 | GSE44904 | GEO
Project description:Epigenetic mechanisms are integral to pancreatic β cell function. Promoter hypermethylation of the helicase like-transcription factor (HLTF) gene—a component of the cellular DNA damage response that contributes to genome stability—has been implicated in age-associated changes in β cells. To study HLTF, we generated global and β cell-specific (β) Hltf knockout (KO) immune competent (IC) and immune deficient (ID) Rag2-/IL2- mice. IC global and β Hltf KO mice were neonatal lethal whereas ID global and β Hltf KO newborn mice had normal survival. This focused our investigation on the effects of Rag2 interruption with common gamma chain interruption on β cell function/survival. Three-way transcriptomic (RNAseq) analyses of whole pancreata from IC and ID newborn β Hltf KO and wild type (Hltf +/+) controls combined with spatially resolved transcriptomic analysis of formalin fixed paraffin embedded tissue, immunohistochemistry and laser scanning confocal microscopy showed DNA damage caused by β Hltf KO in IC mice upregulated the Hmgb1-Rage axis and a gene signature for innate immune cells. Perforin-delivered granzyme A (GzmA) activation of DNase, Nme1, showed damaged nuclear single-stranded DNA (γH2AX immunostaining). This caspase-independent method of cell death was supported by transcriptional downregulation of Serpinc1 gene that encodes a serine protease inhibitor of GzmA. Increased transcriptional availability of complement receptors C3ar1 and C5ar1 likely invited crosstalk with Hmgb1 to amplify inflammation. This study explores the complex dialog between β cells and immune cells during development. It has implications for the initiation of type I diabetes in utero when altered gene expression that compromises genome stability invokes a localized inflammatory response.
2023-05-01 | GSE137060 | GEO
Project description:The tumor microenvironment plays a key role in the pathogenesis of colorectal tumors and contains various cell types including epithelial, immune, and mesenchymal cells. Characterization of the interactions between these cell types is necessary for revealing the complex nature of tumors. In this study, we used single-cell RNA-seq (scRNA-seq) to compare the tumor microenvironments between a mouse model of sporadic colorectal adenoma (Lrig1CreERT2/+;Apc2lox14/+) and a mouse model of inflammation-driven colorectal cancer induced by azoxymethane and dextran sodium sulfate (AOM/DSS). While both models develop tumors in the distal colon, we found that the two tumor types have distinct microenvironments. AOM/DSS tumors have an increased abundance of two populations of cancer-associated fibroblasts (CAFs) compared with APC tumors, and we revealed their divergent spatial association with tumor cells using multiplex immunofluorescence (MxIF) imaging. We also identified a unique squamous cell population in AOM/DSS tumors, whose origins were distinct from anal squamous epithelial cells. These cells were in higher proportions upon administration of a chemotherapy regimen of 5-Fluorouracil/Irinotecan. We used computational inference algorithms to predict cell-cell communication mediated by ligand-receptor interactions and downstream pathway activation, and identified potential mechanistic connections between CAFs and tumor cells, as well as CAFs and squamous epithelial cells. This study provides important preclinical insight into the microenvironment of two distinct models of colorectal tumors and reveals unique roles for CAFs and squamous epithelial cells in the AOM/DSS model of inflammation-driven cancer. This series comprises the drug treatment set as well as the fibroblast enrichment set.
2022-04-27 | GSE199999 | GEO