Site-Specific HPV18 Integration Facilitates Cervical Carcinogenesis through metabolic reprogramming-Induced dysfunction of the SpHK1/S1P/S1PR1 pathway
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PROVIDER: PRJNA1205690 | ENA |
REPOSITORIES: ENA
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Project description:The integration of high-risk human papillomavirus (HR-HPV) into specific loci of the human genome is a pivotal event in cervical carcinogenesis. However, how HPV integration contributes to malignant transformation remains unclear. Here, we utilized the CRISPR/Cas9 system established an 8q24 site-specific HPV18 gene knock-in cell model. We discovered that HPV18 knock-in resulted in a global alteration of the genome's topologically associating domain (TAD) structure and up-regulation of cancer-related genes in HaCaT cells, leading to malignant transformation. Furthermore, the IL-17 signaling pathway and S100A8/A9 genes were found to be significantly up-regulated in the HPV18 knock-in cell line, as well as K14-HPV transgenic mice and cervical cancer clinical database. Metabolic reprogramming of the HPV18 knock-in cell line, particularly the up-regulation of glycolysis, facilitated glycerolipid synthesis and Sphingosine-1-phospate(S1P) secretion. The increased secretion of S1P and activation of the S1P receptor 1(S1PR1) signaling pathway induced the expression of S100A8/A9 and cytokines. Inhibition of the S1P/S1PR1 signaling pathway down-regulated the expression of S100A8/A9 and suppressed the growth of HPV18 knock-in cell line and cervical cancer patient derived Xenograft. These findings provide novel insights into the molecular mechanisms underlying cervical carcinogenesis and identify potential therapeutic targets for its treatment.
2025-08-06 | GSE285710 | GEO
Project description:The integration of high-risk human papillomavirus (HR-HPV) into specific loci of the human genome is a pivotal event in cervical carcinogenesis. However, how HPV integration contributes to malignant transformation remains unclear. Here, we utilized the CRISPR/Cas9 system established an 8q24 site-specific HPV18 gene knock-in cell model. We discovered that HPV18 knock-in resulted in a global alteration of the genome's topologically associating domain (TAD) structure and up-regulation of cancer-related genes in HaCaT cells, leading to malignant transformation. Furthermore, the IL-17 signaling pathway and S100A8/A9 genes were found to be significantly up-regulated in the HPV18 knock-in cell line, as well as K14-HPV transgenic mice and cervical cancer clinical database. Metabolic reprogramming of the HPV18 knock-in cell line, particularly the up-regulation of glycolysis, facilitated glycerolipid synthesis and Sphingosine-1-phospate(S1P) secretion. The increased secretion of S1P and activation of the S1P receptor 1(S1PR1) signaling pathway induced the expression of S100A8/A9 and cytokines. Inhibition of the S1P/S1PR1 signaling pathway down-regulated the expression of S100A8/A9 and suppressed the growth of HPV18 knock-in cell line and cervical cancer patient derived Xenograft. These findings provide novel insights into the molecular mechanisms underlying cervical carcinogenesis and identify potential therapeutic targets for its treatment.
2025-08-06 | GSE285796 | GEO
Project description:Site-Specific HPV18 Integration Facilitates Cervical Carcinogenesis through metabolic reprogramming-Induced dysfunction of the SpHK1/S1P/S1PR1 pathway-part2
| PRJNA1206104 | ENA
Project description:Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate endothelial cell (EC) regenerative programs and thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Here, we addressed mechanisms of generation of S1PR1+ EC, which may prevent endothelial injury. Studies were made using inducible EC-S1PR1-/- (iEC-S1PR1-/-) mice and S1PR1-GFP reporter mice to trace the generation of S1PR1+ EC. We observed in a mouse model of endotoxemia that S1P generation induced the programming of S1PR1lo to S1PR1+ EC, which comprised 80% of lung EC. The transition of these cells was required for reestablishing the endothelial barrier. We also observed that conditional deletion of S1PR1 in EC increased vascular permeability. RNA-seq analysis of S1PR1+ EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively. The activation of transcription factors EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively, to increase S1P production that served to amplify S1PR1+ EC transition. Transplantation of S1PR1+ EC into injured lung vasculature restored endothelial integrity. Our findings show that generation of a S1PR1+ EC population activates the endothelial regenerative program mediating vascular endothelial repair, thus raising the possibility of harnessing this pathway to restore vascular homeostasis in inflammatory injury.
2023-01-15 | GSE165000 | GEO
Project description:The study analyzes analyzes gene expression changes in the ankle joint in mouse TNFa overexpression models with or without sphingosine kinase 1 activity. SphK1 is a sphingolipid enzyme that converts sphingosine to bioactive sphingosine-1-phosphate (S1P). Recent data suggest a potential relationship between SphK1 and TNFα and have implicated SphK1/S1P in the development and progression of inflammation. Here we further study the relationship of TNFα and SphK1 using an in vivo model. Transgenic hTNFα mice, which develop a spontaneous arthritis (limited to paws) at 20 weeks, were crossed with SphK1 activity null mice (SphK1-/-) to study the development of inflammatory arthritis in the functional absence of SphK1. Results show that hTNF/SphK1-/- have significantly less severity and progression of arthritis and bone erosions as measured through micro-CT images. Additionally, less COX-2 protein, mTNFα transcript levels and fewer Th 17 cells were detected in the joints of hTNF/SphK1-/- compared to hTNF/SphK1+/+ mice. Microarray analysis of the ankle joint showed that hTNF/SphK1-/- mice have increased transcript levels of IL-6 and SOCS3 compared to hTNF/SphK1+/+ mice. Finally, fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1-/- mice compared to hTNF/SphK1+/+ mice. These data show that SphK1 plays a role in hTNFα induced inflammatory arthritis, potentially through a novel pathway involving IL-6 and SOCS3. Two wild-type replicates; three replicates of human TNFa transgene overexpression and normal sphingosine kinase 1; three replicates of human TNFa transgene overexpression and sphingosine kinase 1 null.
2011-01-15 | E-GEOD-20152 | biostudies-arrayexpress
Project description:The study analyzes analyzes gene expression changes in the ankle joint in mouse TNFa overexpression models with or without sphingosine kinase 1 activity. SphK1 is a sphingolipid enzyme that converts sphingosine to bioactive sphingosine-1-phosphate (S1P). Recent data suggest a potential relationship between SphK1 and TNFα and have implicated SphK1/S1P in the development and progression of inflammation. Here we further study the relationship of TNFα and SphK1 using an in vivo model. Transgenic hTNFα mice, which develop a spontaneous arthritis (limited to paws) at 20 weeks, were crossed with SphK1 activity null mice (SphK1-/-) to study the development of inflammatory arthritis in the functional absence of SphK1. Results show that hTNF/SphK1-/- have significantly less severity and progression of arthritis and bone erosions as measured through micro-CT images. Additionally, less COX-2 protein, mTNFα transcript levels and fewer Th 17 cells were detected in the joints of hTNF/SphK1-/- compared to hTNF/SphK1+/+ mice. Microarray analysis of the ankle joint showed that hTNF/SphK1-/- mice have increased transcript levels of IL-6 and SOCS3 compared to hTNF/SphK1+/+ mice. Finally, fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1-/- mice compared to hTNF/SphK1+/+ mice. These data show that SphK1 plays a role in hTNFα induced inflammatory arthritis, potentially through a novel pathway involving IL-6 and SOCS3.
2011-01-15 | GSE20152 | GEO
Project description:Background: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates immune cell trafficking by signaling via five G protein-coupled receptors (S1PRs). We investigated the role of S1P in the RTM of aortic intimal MCs. Methods: Intravenous injection of lipopolysaccharide (LPS) was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. Results: In wild-type C57BL/6 mice, LPS induced intimal cell expression of S1pr1, S1pr3, and sphingosine kinase 1 (Sphk1, a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked LPS-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked LPS-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima and blunted LPS-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and LPS-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1 +/+ and -/- bone marrow. Stimulation with LPS increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. Conclusions: Functional and expression studies support a novel role for S1P signaling in the regulation of LPS-induced RTM as well as the homeostatic maintenance of aortic intimal MCs. Our data provides insight into how circulating plasma mediators help orchestrate intimal MC dynamics.
2024-02-22 | GSE252674 | GEO
Project description:Sphingosine 1-phosphate (S1P), a pro-tumor survival bioactive lysophospholipid, generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via transducing S1P receptor 1 (S1PR1) signalling, and also plays a role in the differentiation of regulatory T cells and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1/S1P signallng regulates anti-tumor T cell activity remain unknown. Using melanoma antigen gp100 reactive T cells deficient in Sphk1, we found that Pmel-Sphk1-/- T cells maintained central memory phenotype, showed higher mitochondrial respiration, and exhibited resistance to TGF-β mediated suppression. Mechanistically, we discovered a direct correlation between SphK1 generated intracellular S1P and PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulate lipolysis in T cells. Genetic, molecular or pharmacologic inhibition of SphK1 or PPARγ improved metabolic fitness and anti-tumor activity of T cells. Further, inhibition of SphK1 and PD1 together led to long-term control of melanoma. Overall, these data highlight the clinical potential of targeting SphK1/S1P for improved anti-cancer adoptive T cell immunotherapy.
2019-07-31 | GSE129489 | GEO
Project description:Sphingosine 1-phosphate (S1P) is a lysosphingolipid with anti-atherogenic properties, but mechanisms underlying its effects remain unclear. We here analyzed the consequences of overexpressing the S1P receptor type 1 (S1pr1) on peritoneal macrophage gene expression. To amplify S1pr1 signaling in macrophages, double transgenic mice expressing mouse S1pr1 in mononuclear cells were constructed by crossing two lines. The S1pr1-KI line carries a transgenic cassette in the Rosa 26 locus harboring the mouse S1P1 cDNA and separated from the CAG promoter by a lox-Stop-lox insert. S1pr1-KI mice were then crossed to LysMCre mice expressing Cre recombinase under the control of the lysozyme M promoter, which drives macrophage expression. In the offspring the lox-Stop-lox insert is excised in Cre-expressing cells (macrophages), which induces cDNA expression driven by the CAG promoter. At 12 weeks of age, peritoneal leukocytes were isolated from S1pr1-LysMCre mice and control mice (S1pr1-KI) by peritoneal lavage and seeded in cell culture plates. After 2 h non-adherent cells were removed, total RNA was isolated from the remaining macrophages and subjected to microarray gene expression analysis.
2024-11-07 | E-MTAB-14469 | biostudies-arrayexpress
Project description:Sphingosine 1-phosphate (S1P), a lipid chemoattractant, guides immune cells from the low-S1P environment of tissues into the high-S1P environment of circulatory fluids. Most notably, S1P directs T cell exit from lymph nodes (LN), where T cells are initially activated to fight pathogens, into lymph, from which T cells flow into blood and ultimately reach inflamed tissues. T cells follow these gradients primarily using S1P receptor 1 (S1PR1). The drugs Gilenya and Siponimod, both FDA-approved for the autoimmune disease multiple sclerosis, target S1PR1. They blind self-reactive T cells to S1P gradients, block them from exiting LN, and thus prevent them from infiltrating the central nervous system. While recent work has revealed key aspects of how S1P gradients are established at steady-state, very little is known about S1P distribution in disease, and in turn how changing S1P gradients may affect the immune response. Here, we find that LN S1P increases during an immune response, which prolongs the time T cells spend in the LN before exiting into lymph. Inflammatory monocytes, which had not previously been implicated in shaping S1P gradients, are an important source of this S1P. Inflammatory monocytes must express the early activation marker CD69 to supply S1P to T cells; CD69 represses transcription of S1P receptor 5 (S1pr5), enabling monocytes to infiltrate the LN T zone and efficiently release S1P. Here we compared RNA sequencing of inflammatory monocytes WT or CD69-KO infiltrating the draining lymph node.$
2020-12-23 | GSE139006 | GEO