Ontology highlight
ABSTRACT:
PROVIDER: PRJNA912744 | ENA |
REPOSITORIES: ENA
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Project description:The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in cross-linking and stabilising fibrillar collagens, and its known role in tumour desmoplasia. Using small-molecule drug design approaches, we generated and validated PXS-5505, a first-in-class, highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, whilst also demonstrating anti-fibrotic effects in human PDX models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of the first pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.
2023-05-18 | GSE186748 | GEO
Project description:Human placental development is characterized by invasion of extravillous cytotrophoblasts (EVCTs) into the uterine wall during the first trimester of pregnancy. Peroxisome proliferator-activated receptor gamma (PPARG) plays a major role in placental development, and activation of PPARG by its agonists results in inhibition of EVCT invasion in vitro. To identify PPARG target genes, microarray analysis was performed using GeneChip technology on EVCT primary cultures obtained from first-trimester human placentas. Gene expression was compared in EVCTs treated with the PPARG agonist rosiglitazone versus control. A total of 139 differentially regulated genes were identified, and changes in the expression of the following 8 genes were confirmed by reverse transcription-quantitative polymerase chain reaction: a disintegrin and metalloproteinase domain12 (ADAM12), connexin 43 (CX43), deleted in liver cancer 1 (DLC1), dipeptidyl peptidase 4 (DPP4), heme oxygenase 1 (HMOX-1), lysyl oxidase (LOX), plasminogen activator inhibitor 1 (PAI-1) and PPARG. Among the upregulated genes, lysyl oxidase (LOX) was further analyzed. In the LOX family, only LOX, LOXL1 and LOXL2 mRNA expression was significantly upregulated in rosiglitazone-treated EVCTs. RNA and protein expression of the subfamily members LOX, LOXL1 and LOXL2 were analyzed by absolute RT-qPCR and western blotting, and localized by immunohistochemistry and immunofluorescence-confocal microscopy. LOX protein was immunodetected in the EVCT cytoplasm, while LOXL1 was found in the nucleus and nucleolus. No signal was detected for LOXL2 protein. Specific inhibition of LOX activity by beta-aminopropionitrile in cell invasion assays led to an increase in EVCT invasiveness. These results suggest that LOX, LOXL1 and LOXL2 are downstream PPARG targets and that LOX activity is a negative regulator of trophoblastic cell invasion. Microarray analysis was performed using GeneChip technology in EVCTs isolated from first trimester human placentae. Gene expression in rosiglitazone-treated primary EVCT cultures was compared with matched untreated controls. A total of 175 probe sets identified differentially regulated genes. One of these genes, lysyl oxidase (LOX) which was up-regulated, was further analyzed. Expression of the LOX family was determined by real time Q-PCR, Western blotting, immunohistochemistry and immunofluorescence. LOX, LOXL and LOXL2 mRNA expression was significantly upregulated in PPARg-activated EVCTs. LOX and LOXL2 protein were present throughout the trophoblast cytoplasm, while LOXL was localized to the nucleus and nucleolus. Cell invasion assays on Matrigel Transwells showed that specific inhibition of LOX activity by M-CM-^_-aminopropionitrile led to an increase in EVCT invasiveness, showing the basal inhibitory effect of LOX and LOX-like in the trophoblastic cells invasion process. Together these results show that LOX family as PPARg-target genes participate to the regulation of trophoblast invasion. Total RNA from EVCT were labelled according to the standard Affymetrix protocol. Five independent targets per treatment vs control were generated and hybridized on a GeneChip.
2013-12-04 | E-GEOD-28426 | biostudies-arrayexpress
Project description:Primary murine lung fibroblasts were transfected with either control (scrambled) or sequence-specific siRNA against Lysyl oxidase (Lox), Lysyl oxidase-like (Loxl1) or Lysyl oxidase-like 2 (Loxl2) genes. Cells were harvested 48 hours after the transfection. Multiple changes in gene expression were found in the corrected p values in this microarray study.
2016-10-25 | GSE89121 | GEO
Project description:Human placental development is characterized by invasion of extravillous cytotrophoblasts (EVCTs) into the uterine wall during the first trimester of pregnancy. Peroxisome proliferator-activated receptor gamma (PPARG) plays a major role in placental development, and activation of PPARG by its agonists results in inhibition of EVCT invasion in vitro. To identify PPARG target genes, microarray analysis was performed using GeneChip technology on EVCT primary cultures obtained from first-trimester human placentas. Gene expression was compared in EVCTs treated with the PPARG agonist rosiglitazone versus control. A total of 139 differentially regulated genes were identified, and changes in the expression of the following 8 genes were confirmed by reverse transcription-quantitative polymerase chain reaction: a disintegrin and metalloproteinase domain12 (ADAM12), connexin 43 (CX43), deleted in liver cancer 1 (DLC1), dipeptidyl peptidase 4 (DPP4), heme oxygenase 1 (HMOX-1), lysyl oxidase (LOX), plasminogen activator inhibitor 1 (PAI-1) and PPARG. Among the upregulated genes, lysyl oxidase (LOX) was further analyzed. In the LOX family, only LOX, LOXL1 and LOXL2 mRNA expression was significantly upregulated in rosiglitazone-treated EVCTs. RNA and protein expression of the subfamily members LOX, LOXL1 and LOXL2 were analyzed by absolute RT-qPCR and western blotting, and localized by immunohistochemistry and immunofluorescence-confocal microscopy. LOX protein was immunodetected in the EVCT cytoplasm, while LOXL1 was found in the nucleus and nucleolus. No signal was detected for LOXL2 protein. Specific inhibition of LOX activity by beta-aminopropionitrile in cell invasion assays led to an increase in EVCT invasiveness. These results suggest that LOX, LOXL1 and LOXL2 are downstream PPARG targets and that LOX activity is a negative regulator of trophoblastic cell invasion. Microarray analysis was performed using GeneChip technology in EVCTs isolated from first trimester human placentae. Gene expression in rosiglitazone-treated primary EVCT cultures was compared with matched untreated controls. A total of 175 probe sets identified differentially regulated genes. One of these genes, lysyl oxidase (LOX) which was up-regulated, was further analyzed. Expression of the LOX family was determined by real time Q-PCR, Western blotting, immunohistochemistry and immunofluorescence. LOX, LOXL and LOXL2 mRNA expression was significantly upregulated in PPARg-activated EVCTs. LOX and LOXL2 protein were present throughout the trophoblast cytoplasm, while LOXL was localized to the nucleus and nucleolus. Cell invasion assays on Matrigel Transwells showed that specific inhibition of LOX activity by ß-aminopropionitrile led to an increase in EVCT invasiveness, showing the basal inhibitory effect of LOX and LOX-like in the trophoblastic cells invasion process. Together these results show that LOX family as PPARg-target genes participate to the regulation of trophoblast invasion.
2013-12-04 | GSE28426 | GEO
Project description:The transcription factor GATA3 is essential for luminal cell differentiation during mammary gland development and critical for formation of the luminal subtypes of breast cancer. Ectopic expression of GATA3 promoted global alterations of the transcriptome of basal triple-negative breast cancer cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix protein that affects cell proliferation, cross-linking of extracellular collagen types, and establishment of the metastatic niche. There are 2 samples sent in triplicates.
2011-08-31 | E-GEOD-24249 | biostudies-arrayexpress
Project description:Lysyl oxidase is an extracellular enzyme essential for crosslinking elastin and collagen. Mice that do not express Lox have 60% and 40% reductions in elastin-specific and collagen-specific crosslinks, respectively. Mutations in LOX are associated with thoracic aortic aneurysm and dissection (TAAD). Lysyl oxidase knockout mice dye perinatally with ruptured diaphragm, tortuous arteries, and TAAD This is the first study to analyze the mechanical and genetic changes induced by the absence of lysyl oxidase in the thoracic aorta, and may provide new therapeutic targets relevant for the pathogenesis of thoracic aortic aneurysms and dissections
2016-10-28 | GSE89227 | GEO
Project description:The transcription factor GATA3 is essential for luminal cell differentiation during mammary gland development and critical for formation of the luminal subtypes of breast cancer. Ectopic expression of GATA3 promoted global alterations of the transcriptome of basal triple-negative breast cancer cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix protein that affects cell proliferation, cross-linking of extracellular collagen types, and establishment of the metastatic niche.
2011-09-01 | GSE24249 | GEO
Project description:Lysyl oxidase (LOX) is an copper dependent amine oxidase enzyme involved in cross linking of collagens and elastins. Lysyl oxidase propeptide (LOX-PP) is 18 kDa region cleaved during maturation of LOX and its anti-tumorigenic role were studied in various cancers. The effect of LOX-PP overexpression in retinoblastoma cancer cells (Y79) using transient transfection of LOX-PP gene accessed for global gene deregulations. The analysis resulted in RB cancer cell death through deregulation of retinoblastoma in cancer, cell cycle, apoptosis, focal adhesion-PI3K-AKT signaling and DNA repair mechanism pathway. Further validations were done using RT-PCR and western blot analysis. Our results provide evidence that inducing apoptosis through AKT-NFκB signaling.
2019-09-01 | GSE119413 | GEO
Project description:In this study, we assessed the effects of lysyl oxidase (LOX/LOXL) inhibition on the composition of extracellular matrix (ECM) produced by in vitro expanded bone marrow derived mesenchymal stromal cells (MSCs) of n=3 patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN).
2023-02-17 | PXD031217 | Pride
Project description:NF1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing FoxF1. Forkhead Box F1 promotes breast cancer cell migration by upregulating lysyl oxidase and suppressing Smad2/3 signaling
2016-02-04 | GSE77551 | GEO