Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation 1 of NF-κB mediates chemoresistance
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55533 | GEO | 2014/05/19
SECONDARY ACCESSION(S): PRJNA239887
REPOSITORIES: GEO
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Project description:Bone marrow (BM) mesenchymal stromal cells (BM-MSC) upregulate their NF-κB signaling to protect leukemia cells from chemotherapy-induced apoptosis. To elucidate molecular mechanisms by which leukemia-stroma interactions within the BM microenvironment could confer chemoresistance to leukemia cells, we used genome-wide gene expression profiling (GEP) to examine human normal BM-MSC that had been co-cultured with the pre-B ALL REH cells and then separated by flow cytometry (FACS). GEP results for co-cultured cells of each type were compared to GEP results for cells of the corresponding type cultured alone, and taken through the same FACS purification procedure, to identify changes in gene expression profiles caused by co-culture.
2014-05-19 | E-GEOD-55533 | biostudies-arrayexpress
Project description:Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-?B signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-?B target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-?B activation via chemical agents or the overexpression of the mutant form of inhibitor ?B-? (I?B?) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-?B activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-?B in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-?B activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-?B or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.
| S-EPMC3999754 | biostudies-literature
Project description:Adipose tissue (AT) contains mesenchymal stromal cells (MSC) in stages of commitment to becoming specialized tissue cells, including adipocytes and fibroblasts, and immune cells which support tissue homeostasis. How MSC and immune cells interact during infection is poorly understood. We show that during intestinal helminth infection MSC in mesenteric AT (mAT) become enriched in non-differentiated progenitor cells. This is accompanied by MSC-intrinsic metabolic reprogramming supporting increased secretion of extracellular matrix (ECM), IL-33, and TSLP. In parallel, Th2 resident memory (Th2RM) cells populate the mAT and persist after infection is resolved. These cells express Areg, TGFβ and IL-5, and are necessary to promote infection induced changes within mAT, including MSC reprogramming and tissue eosinophilia. In turn, IL-33 and TSLP from MSC facilitate Th2RM activation and maintenance. Our findings link Th2RM cells to mAT remodeling during intestinal infection, underscoring the reciprocal dependence of stroma and resident immune cells for lasting tissue immunity.
2022-08-17 | GSE186160 | GEO
Project description:ObjectivesComplement 1q binding protein (C1QBP/HABP1/p32/gC1qR) has been found to be overexpressed in triple-negative breast cancer (TNBC). However, the underlying mechanisms of high C1QBP expression and its role in TNBC remain largely unclear. Hypoxia is a tumor-associated microenvironment that promotes metastasis and paclitaxel (PTX) chemoresistance in tumor cells. In this study, we aimed to assess C1QBP expression and explore its role in hypoxia-related metastasis and chemoresistance in TNBC.Materials and methodsRNA-sequencing of TNBC cells under hypoxia was performed to identify C1QBP. The effect of hypoxia inducible factor 1 subunit alpha (HIF-1α) on C1QBP expression was investigated using chromatin immunoprecipitation (ChIP) assay. The role of C1QBP in mediating metastasis, chemoresistance to PTX, and regulation of metastasis-linked vascular cell adhesion molecule 1 (VCAM-1) expression were studied using in vitro and in vivo experiments. Clinical tissue microarrays were used to verify the correlation of C1QBP with the expression of HIF-1α, VCAM-1, and RELA proto-oncogene nuclear factor-kappa B subunit (P65).ResultsWe found that hypoxia-induced HIF-1α upregulated C1QBP. The inhibition of C1QBP notably blocked metastasis of TNBC cells and increased their sensitivity to PTX under hypoxic conditions. Depletion of C1QBP decreased VCAM-1 expression by reducing the amount of P65 in the nucleus and suppressed the activation of hypoxia-induced protein kinase C-nuclear factor-kappa B (PKC-NF-κB) signaling.immunohistochemistry (IHC) staining of the tissue microarray showed positive correlations between the C1QBP level and those of HIF-1α, P65, and VCAM-1.ConclusionTargeting C1QBP along with PTX treatment might be a potential treatment for TNBC patients.
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Project description:Easily developed chemoresistance is a major characteristic of multiple myeloma (MM) and the main obstacle in curing MM in the clinic, but the key regulators have not been fully identified. In the current study, we find that PPFIA Binding Protein 1 (PPFIBP1) is highly expressed in the plasma cells from MM patients, and higher PPFIBP1 expression predicts poorer outcomes. PPFPIBP1 enhances chemoresistance of MM cells to the treatment of bortezomib (BTZ), a proteasome inhibitor, and manipulation of PPFPIBP1 can alter chemosensitivity of MM cells to BTZ. Mechanistic studies reveal that PPFPIBP1 directly binds and stabilizes RelA, promotes the cyto-nuclear translocation of RelA, and activates NF-κB signaling pathway. Targeting PPFPIBP1 in a xenograft mouse model of MM prohibits tumor growth and prolongs overall survival of mice. Taken together, our findings suggest that PPFIBP1 is a crucial regulator of chemoresistance to PIs in MM cells, and shed light on developing therapeutic strategies to overcome chemoresistance by targeting PPFIBP1.
| S-EPMC10458954 | biostudies-literature
Project description:Vascular cell adhesion molecule 1 (VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesion and extravasation. However, its expression in renal carcinomas inversely correlates with tumor malignancy. Our experiments in clear cell renal cell carcinoma (ccRCC) cell lines demonstrated that von Hippel Lindau (VHL) loss, hypoxia, or PHD (for prolyl hydroxylase domain-containing proteins) inactivation decreased VCAM-1 levels through a transcriptional mechanism that was independent of the hypoxia-inducible factor and dependent on the nuclear factor κB signaling pathway. Conversely, VHL expression leads to high VCAM-1 levels in ccRCC, which in turn leads to better outcomes, possibly by favoring antitumor immunity through VCAM-1 interaction with the α4β1 integrin expressed in immune cells. Remarkably, in ccRCC human samples with VHL nonmissense mutations, we observed a negative correlation between VCAM-1 levels and ccRCC stage, microvascular invasion, and symptom presentation, pointing out the clinical value of VCAM-1 levels as a marker of ccRCC progression.
| S-EPMC5350518 | biostudies-literature
Project description:Targeting nuclear factor-kappa B (NF-κB) represents a highly viable strategy against chemoresistance in cancers as well as cell death. Ubiquitination, including linear ubiquitination mediated by the linear ubiquitin chain assembly complex (LUBAC), is emerging as a crucial mechanism of overactivated NF-κB signaling. Ovarian tumor family deubiquitinase OTULIN is the only linear linkage-specific deubiquitinase; however, the molecular mechanisms of how it counteracts LUBAC-mediated NF-κB activation have been largely unknown. Here, we identify Lys64/66 of OTULIN for linear ubiquitination facilitated in a LUBAC-dependent manner as a necessary event required for OTULIN-LUBAC interaction under unstressed conditions, which becomes deubiquitinated by OTULIN itself in response to genotoxic stress. Furthermore, this self-deubiquitination of OTULIN occurs intermolecularly, mediated by OTULIN dimerization, resulting in the subsequent dissociation of OTULIN from the LUBAC complex and NF-κB overactivation. Oxidative stress induces OTULIN dimerization via cysteine-mediated covalent disulfide bonds. Our study reveals that the status of the physical interaction between OTULIN and LUBAC is a crucial determining factor for the genotoxic NF-κB signaling, as measured by cell survival and proliferation, while OTULIN loss of function resulting from its dimerization and deubiquitination leads to a dissociation of OTULIN from the LUBAC complex. Of note, similar molecular mechanisms apply to the inflammatory NF-κB signaling in response to tumor necrosis factor α. Hence, a fuller understanding of the detailed molecular mechanisms underlying the disruption of the OTULIN-LUBAC interaction will be instrumental for developing future therapeutic strategies against cancer chemoresistance and necroptotic processes pertinent to numerous human diseases.
| S-EPMC9388121 | biostudies-literature
Project description:RationaleHuman and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown.ObjectiveDetermine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene.Methods and resultsHomologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions.ConclusionsThis study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.
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Project description:While extensive efforts have been on understanding bone marrow (BM) niche contribution to normal and malignant hematopoiesis, the role of extramedullary niches has been largely ignored. Evidence suggests a BM mesenchymal stem cell (MSC) counterpart exists in skin. However, their native identity and role in hematopoiesis remain unexplored. Here, we demonstrated that mouse skin harbors MSC subsets that are phenotypically and molecularly similar to BM MSCs, including a primitive MSC population marked by Early B-cell Factor 2 (Ebf2) and downstream MSCs lacking Ebf2. Functionally, skin MSCs not only support acute myeloid leukemia (AML) stem cells but also protect them from chemotherapy. This persistence of AML cells in skin were further amplified in AML-promoting microenvironment lacking Lama4. Our study demonstrated the features of extramedullary niches in skin and their previously unrecognized role in supporting AML stem cells during chemotherapy, opening a new path for understanding the extramedullary manifestation of AML in patients.
2023-07-16 | GSE167562 | GEO
Project description:Twenty natural remedies traditionally used against different inflammatory diseases were probed for their potential to suppress the expression of the inflammatory markers E-selectin and VCAM-1 in a model system of IL-1 stimulated human umbilical vein endothelial cells (HUVEC). One third of the tested extracts showed in vitro inhibitory effects comparable to the positive control oxozeaenol, an inhibitor of TAK1. Among them, the extract derived from the roots and rhizomes of Peucedanum ostruthium (i.e., Radix Imperatoriae), also known as masterwort, showed a pronounced and dose-dependent inhibitory effect. Reporter gene analysis demonstrated that inhibition takes place on the transcriptional level and involves the transcription factor NF-κB. A more detailed analysis revealed that the P. ostruthium extract (PO) affected the phosphorylation, degradation, and resynthesis of IκBα, the activation of IKKs, and the nuclear translocation of the NF-κB subunit RelA. Strikingly, early effects on this pathway were less affected as compared to later ones, suggesting that PO may act on mechanism(s) that are downstream of nuclear translocation. As the majority of cognate NF-κB inhibitors affect upstream events such as IKK2, these findings could indicate the existence of targetable signaling events at later stages of NF-κB activation.
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