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Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response

ABSTRACT: chronic stress activates the GCR-HMGB2-LDLR axis via cortisol release, leading to abnormal cholesterol metabolism and ultimately promoting esophageal carcinogenesis

ORGANISM(S): Homo Sapiens

SUBMITTER: Zigang Dong

PROVIDER: PXD059578 | iProX | Thu Jan 09 00:00:00 GMT 2025

REPOSITORIES: iProX

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Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response.

Wang Ting T Wang Xiangyu X Wang Keke K Yu Mengyuan M Bai Ruihua R Zhang Yiru Y Zhang Zihan Z Liu Feifei F Wang Rui R Shi Xiaodan X Jia Ludan L Liu Kangdong K Li Xiang X Jin Guoguo G Zhao Simin S Dong Zigang Z

Proceedings of the National Academy of Sciences of the United States of America 20250127 5

Recent studies have demonstrated that chronic stress can enhance the development of multiple human diseases, including cancer. However, the role of chronic stress in esophageal carcinogenesis and its underlying molecular mechanisms remain unclear. This study uncovered that dysregulated cholesterol metabolism significantly promotes esophageal carcinogenesis under chronic stress conditions. Our findings indicate that the persistent elevation of glucocorticoids induced by chronic stress stimulates ...[more]

PMID: 39869796

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Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response

Project description:Recent studies have demonstrated that chronic stress can enhance the development of multiple human diseases, including cancer. However, the role of chronic stress in esophageal carcinogenesis and its underlying molecular mechanisms remain unclear. This study uncovered that dysregulated cholesterol metabolism significantly promotes esophageal carcinogenesis under chronic stress conditions. Our findings indicate that the persistent elevation of glucocorticoids induced by chronic stress stimulates cho-lesterol uptake, contributing to esophageal carcinogenesis. The activated glucocor-ticoid receptor (GCR) enrichment at the promoter region of High Mobility Group Box Protein 2 (HMGB2) facilitates its transcription. As a transcription co-activator, HMGB2 enhances Sterol Regulatory Element-Binding Transcription Factor 1 (SREBF1) transcription and regulates cholesterol metabolism through LDL particle uptake into cells via Low-Density Lipoprotein Receptor (LDLR). These results em-phasize the significant impact of chronic stress on esophageal carcinogenesis and establish cholesterol metabolism disorder as a crucial link between chronic stress and the development of ESCC. The implications suggest that effectively managing chronic stress may serve as a viable strategy for preventing and treating ESCC.

2025-01-13 | GSE286200 | GEO

Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response [RNA-Seq]

Project description:This project reported that chronic stress activates the GCR-HMGB2-LDLR axis via cortisol release, leading to abnormal cholesterol metabolism and ultimately promoting esophageal carcinogenesis. Chronic stress is associated with increased ESCC risk, and further exacerbates ESCC progression through HMGB2. Cortisol, by activating GCR, stimulates ESCC cell proliferation. Moreover, GCR activation enhances HMGB2 transcription, which in turn binds to SREBF1, thereby upregulating LDLR transcription and disrupting cholesterol metabolism. Clinical parameters in stressed ESCC patients underscore the relevance of stress management as a pivotal strategy for both the prevention and treatment of this malignancy.

2025-01-14 | GSE286336 | GEO

HMGB2 promote ESCC tumorigenesis and predict neoadjuvant therapy response

2025-01-09 | PXD059616 |

Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response

Project description:Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response

| PRJNA1208109 | ENA

Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response [RNA-Seq]

Project description:Chronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response [RNA-Seq]

| PRJNA1208943 | ENA

Free cholesterol primes the IFN-I response

Project description:we report that free cholesterol in the endolysosomal membrane regulates the IFN-I response in plasmacytoid dendritic cells (pDCs) by facilitating the release of TLR9 from UNC93B1.

2024-04-29 | PXD051868 |

Free cholesterol primes the IFN-I response by facilitating the release of TLR9 from UNC93B1

Project description:Elevated cholesterol is positively associated with autoimmunity. However, it is unclear which mechanism directly link them. Here, we report that free cholesterol in the endolysosomal membrane regulates the IFN-I response in plasmacytoid dendritic cells (pDCs) by facilitating the release of TLR9 from UNC93B1. The cholesterol transporter NPC1 was highly expressed in pDCs, and conditional deletion of Npc1 via Cd11c-Cre (Npc1∆DC) impaired IFNα production by TLR9-stimulated pDCs. Npc1∆DC mice exhibited a weakened IFNα response to HSV-1 infection, and ameliorated anti-DNA autoantibodies and nephritis when crossed to B6.Sle1yaa transgenic lupus model. Mechanistically, through click chemistry-based proteome-wide screening, we found that the TLR chaperone UNC93B1 could bind to free cholesterol. The juxtamembrane cholesterol gradient, mediated by NPC1, promoted TLR9 release from UNC93B1. Increased membrane-bound cholesterol dramatically enhanced IFNα response by murine and human pDCs. Our results suggested that the participation of free cholesterol in TLR9 signaling could directly link elevated cholesterol with autoimmunity.

2025-01-18 | GSE253771 | GEO

Deletions in the ATAD3 gene cluster cause cerebellar developmental defects with mitochondrial DNA abnormalities owing to local cholesterol insufficiency

Project description:The DNA in mitochondria is associated with the inner of two membranes and it co-fractionates with the limited amount of cholesterol in the organelles. However, the effects of mitochondrial cholesterol deficiency are largely unknown, and mitochondrial disorders relating to this area of cell metabolism have not been reported hitherto. Using detailed SNP array analysis we have identified patients with impaired cerebellar development and neurological dysfunction who have large deletions in the locus encoding the ATAD3A, ATAD3B and ATAD3C genes. Patient cells with inherited ATAD3 defects display aberrant mitochondrial DNA organization and synthesis associated with disrupted cholesterol metabolism. Moreover drug-induced perturbations of cholesterol metabolism cause mitochondrial DNA disorganization in control cells. The interdependence of mitochondria and cholesterol homeostasis is further corroborated by the presence of mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann Pick type C disease. Thus, we conclude, mitochondria are fully integrated in the circuitry of cellular cholesterol homeostasis, in which ATAD3 plays a critical role, and the dual problem of perturbed cholesterol homeostasis and mitochndrila dysfunction may be widespread in neurological and neurodegenerative diseases.

2017-06-23 | GSE86550 | GEO

MiRNA expression arrays from esophageal squamous cell carcinomas with different neoadjuvant chemoradiotherapy response

Project description:Preoperative chemoradiotherapy (CRT) followed by surgery has been proved to improve esophageal squamous cell carcinoma (ESCC) patients’ survival in comparison with surgery alone. However, the outcomes of CRT are heterogeneous, and no clinical or pathological method could predict CRT response. We aim to identify miRNA markers for ESCC CRT-response prediction through miRNA expression analyses. MiRNA expression analyses were performed on pretreatment cancer biopsies from 28 ESCCs who received neoadjuvant CRT and surgery using Agilent human miRNA microarrays based on miRBase (release 18.0) GeneChip®.

2015-07-27 | E-GEOD-59974 | biostudies-arrayexpress

Molecular mechanisms vascular smooth muscle cell (VSMC) acquisition of macrophage features in response to cholesterol loading

Project description:In this study, murine primary aortic smooth muscle cells (SMCs) were transcriptionally profiled at baseline, after 3 d of cholesterol loading, and after 3 d of subsequent cholesterol unloading with HDL treatment, to identify vascular SMC genes that are transcripionally dysregulated in response to cholesterol loading and/or unloading. Mouse aortic SMCs were isolated from thoracic aortas of 8 week-old C57BL/6 mice (as described in Rong et al., Proc Nat Acad Sci USA, v100, pp13531M-bM-^@M-^S13536, 2003) and subconfluent cell preparations were harvested and transcriptionally profiled (baseline group) or treated with 10 M-NM-<g/mL cholesterol:methyl-M-NM-2-cyclodextrin complex (1:6 molar ratio) for 72 h for cholesterol loading. Of the cholesterol-loaded cells, samples were transcriptionally profiled (cholesterol samples) or treated for an additional 72 h with 100 M-NM-<g/mL human HDL and then transcriptionally profiled (HDL treatment). For all transcriptional profiling, RNA was isolated from cells using TRIzol, and labeled aRNA was prepared for hybridization to Affymetrix Mouse Genome 430 2.0 microarrays according to the manufacturer's protocol. Probe-level intensities were background-adjusted and normalized (in two separate analyses, one with baseline and cholesterol-treated samples, and the other analysis with all three sample groups) using Robust Multichip Average and combined into probesets using probe-to-probeset mappings from the University of Michigan CustomCDF project based on Ensembl Gene identifiers (release 59). Using the data from the analysis that combined the baseline and cholesterol-loaded samples, log2 probeset intensities were compared the between baseline and cholesterol sample groups using a one-way ANOVA with a P value cutoff determined by a Benjamini-Hochberg false discovery rate threshold of 0.05. Analysis (I): baseline and cholesterol-treated sample groups. Analysis (II): all three sample groups.

2015-02-06 | E-GEOD-47744 | biostudies-arrayexpress

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