Unveiling Immune Metabolic Mechanisms in Bladder Cancer: Spatial Profiling Identifies ZFP36 as a Therapeutic Target
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1205694 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Treatment of bladder cancer (BLCA) is currently facing formidable challenges due to its high heterogeneity and immune evasion. In this study, we utilize spatial metabolomics (SM) and spatial transcriptomics (ST) to systematically analyze and visualize metabolic and transcriptional landscapes of BLCA. Correlation analysis reveals significant metabolic and transcriptional differences among tumor regions, shedding light on the heterogeneity and immune-related metabolic reprogramming mechanisms in BLCA. Further studies identify ZFP36 as a potential immunotherapeutic marker, with its higher expression correlating with poor prognosis in BLCA patients. Mechanistically, ZFP36 mediates the mRNA decay of key immune regulatory genes, including C1QBP, thereby suppressing T-cell activation and cytotoxicity. Notably, the combination of ZFP36 knockout and anti-PD-1 therapy demonstrated synergistic antitumor effects, suggesting that targeting ZFP36 may offer a promising therapeutic strategy for BLCA treatment. In summary, this study, through integrated multi-omics analysis, unveils the immune metabolic regulatory mechanisms of BLCA and provides crucial molecular targets for immunotherapy.
2025-07-09 | GSE285715 | GEO
Project description:Platelet-derived growth factor (PDGF-BB) released from the injured intima induces the proliferation and migration of vascular smooth muscle cells (VSMCs), which is the key mechanism of neointimal hyperplasia. Zinc finger 36 (ZFP36), a widespread RNA-binding protein, is important for pathological processes in many diseases. In this study we investigated the role of ZFP36 in VSMCs proliferation, migration and neointimal hyperplasia in mice. We generated smooth muscle-specific Zfp36 knockout (Zfp36SMKO) mice, and established restenosis mouse models by ligation of left carotid artery in Zfp36SMKO mice. We showed that the expression levels of ZFP36 were significantly decreased in human atherosclerotic coronary arteries and murine injured carotid arteries compared with controls. Compared to control Zfp36fl/fl mice, Zfp36SMKO mice displayed accelerated neointimal hyperplasia. In cultured mouse VSMCs, PDGF-BB (20 ng/mL) significantly downregulated ZFP36 expression through KLF4 binding site in Zfp36 promoter. We revealed that ZFP36 could bind to the mRNA of cell migration-inducing protein (CEMIP) and promoted its degradation in VSMCs, thereby reducing the expression of CEMIP protein. Knockdown of Cemip inhibited VSMCs proliferation and migration induced by Zfp36 knockout, thereby suppressing neointimal hyperplasia in Zfp36SMKO mice. We conclude that vascular smooth muscle ZFP36 has a protective effect against neointimal hyperplasia by reducing CEMIP expression. ZFP36 is downregulated by vascular injury and PDGF-BB treatment, which promotes VSMCs proliferation and migration and neointima formation. The results suggest that targeting ZFP36 may represent a novel therapeutic strategy for preventing or treating neointimal hyperplasia and related cardiovascular diseases.
2025-05-29 | GSE286906 | GEO
Project description:Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer
| PRJNA1126301 | ENA
Project description:Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3M-bM-^@M-^Y UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins. Five biological replicates for each of the four sample classes -> Parental and EGFP-ZFP36 HEK293 cells treated with either doxycycline or water.
2013-12-24 | E-GEOD-53183 | biostudies-arrayexpress
Project description:Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3M-bM-^@M-^Y UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins. FLAG-HA ZFP36
2013-12-24 | E-GEOD-53184 | biostudies-arrayexpress
Project description:ATM Loss and Therapeutic Vulnerabilities in Bladder Cancer
| PRJNA974064 | ENA
Project description:Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3’ UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins.
2013-12-24 | GSE53183 | GEO
Project description:Tristetraprolin/ZFP36/TTP and ELAVL1/HuR are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embyonic kidney cells and examined combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. Among the targets ZFP36 binds and negatively regulates the mRNA of genes encoding proteins necessary for immune function and cancer, and other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance from ZFP36 overexpression independent of effects from confounding features, such as 3’ UTR length. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes. ZFP36 preferentially interacts with and regulates AU-rich sequences while ELAVL1 prefers predominantly U- and CU-rich sequences. RNA target specificity identified by global in vivo ZFP36-mRNA interactions were quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 both bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to untangle the in vivo combinatorial regulation by RNA-binding proteins.
2013-12-24 | GSE53184 | GEO
Project description:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in T-cells, which confirmed regulation of cytokine expression and revealed unanticipated actions in regulating T-cell activation and proliferation. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, most robustly through a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics by attenuating activation marker expression, limiting T-cell expansion, and promoting apoptosis in a cell autonomous manner. Strikingly, loss of ZFP36 in vivo accelerated T-cell responses to acute viral infection, and enhanced anti-viral immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T-cell expansion and effector functions, and suggest ZFP36 inhibition as a novel strategy to enhance immune-based therapies.
2018-03-01 | GSE96074 | GEO
Project description:We used Xenium In Situ assay with a custom probe panel to visualize a human bladder cross-section. The custom probe panel contains probe sets against bladder cell type marker genes and RNA isoforms to enable cell identification. We detected 33 distinct cell groups consisted of urothelial cell states, immune cells, and various stromal cell types.
2025-12-19 | GSE297459 | GEO