Dataset Information

Prognostic relevance of the hexosamine biosynthesis pathway activation in leiomyosarcoma.

ABSTRACT: Metabolic reprogramming of tumor cells and the increase of glucose uptake is one of the hallmarks of cancer. In order to identify metabolic pathways activated in leiomyosarcoma (LMS), we analyzed transcriptomic profiles of distinct subtypes of LMS in several datasets. Primary, recurrent and metastatic tumors in the subtype 2 of LMS showed consistent enrichment of genes involved in hexosamine biosynthesis pathway (HBP). We demonstrated that glutamine-fructose-6-phosphate transaminase 2 (GFPT2), the rate-limiting enzyme in HBP, is expressed on protein level in a subset of LMS and the expression of this enzyme is frequently retained in patient-matched primary and metastatic tumors. In a new independent cohort of 327 patients, we showed that GFPT2 is associated with poor outcome of uterine LMS but not extra-uterine LMS. Based on the analysis of a small group of patients studied by ¹⁸F-FDG-PET imaging, we propose that strong expression of GFPT2 in primary LMS may be associated with high metabolic activity. Our data suggest that HBP is a potential new therapeutic target in one of the subtypes of LMS.

SUBMITTER: Tolwani A

PROVIDER: S-EPMC8093268 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Prognostic relevance of the hexosamine biosynthesis pathway activation in leiomyosarcoma.

Tolwani Angela A Matusiak Magdalena M Bui Nam N Forgó Erna E Varma Sushama S Baratto Lucia L Iagaru Andrei A Lazar Alexander J AJ van de Rijn Matt M Przybyl Joanna J

NPJ genomic medicine 20210503 1

Metabolic reprogramming of tumor cells and the increase of glucose uptake is one of the hallmarks of cancer. In order to identify metabolic pathways activated in leiomyosarcoma (LMS), we analyzed transcriptomic profiles of distinct subtypes of LMS in several datasets. Primary, recurrent and metastatic tumors in the subtype 2 of LMS showed consistent enrichment of genes involved in hexosamine biosynthesis pathway (HBP). We demonstrated that glutamine-fructose-6-phosphate transaminase 2 (GFPT2), t ...[more]

PMID: 33941787

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Project description:BackgroundNucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart.MethodsNDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs).ResultsNDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E' wave, and in the ratios of E/A and E'/A' in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB-/- mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation.ConclusionsDeficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.

Project description:Background: Urinary bladder cancer (UBC) is one of the common urological malignancies, lacking reliable biomarkers to predict clinical outcomes in UBC patients. Thus, it is needed to identify the novel diagnostic/prognostic biomarkers to stratify the high-risk UBC patients. As a shunt pathway of glycolysis, the hexosamine biosynthesis pathway (HBP) has been implicated in carcinogenesis. However, its prognostic value in UBC remains unclear. Methods: The RNA sequencing and mRNA microarray datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus databases. The expression levels of five HBP genes were analyzed in normal and UBC samples, and their associations with stage, grade and survival were plotted. The performance of HBP risk group was evaluated by receiver-operating characteristics (ROC) curve. The HBP signature was generated by Gene Set Variation Analysis (GSVA) and its association with clinicopathological parameters and survival were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to examine the potential biological functions of HBP using DAVID online tool. The infiltration estimation fraction of immune cells was performed using CIBERSORT-ABS algorithm. Gene set enrichment analysis (GSEA) was used to explore the potential function of HBP in tumor immunoregulation. Results: Four HBP genes were upregulated in UBCs compared to normal tissues in TCGA-BLCA dataset. The upregulation of all five HBP genes was significantly associated with tumor grade and stage of UBC in three independent UBC datasets. The expression of HBP genes predicted poor clinical outcomes in UBC patients in both TCGA-BLCA and GSE13507 datasets. The high-risk group based on HBP genes showed a poor prognosis. Furthermore, HBP signature was positively associated with tumor grade and stage in TCGA-BLCA dataset and with tumor grade, stage, distal metastasis and poor survival in GSE13507 dataset. Interestingly, high-HBP signature group exhibited a high infiltration of immune cells, particularly the macrophage population. Conclusion: We identified that HBP was a promising prognostic biomarker in UBC patients and strongly associated with immune infiltration.

Project description:Background: Endothelial cells (ECs) use glycolysis to produce energy. In pre-clinical models of peripheral arterial disease (PAD), the further activation of EC glycolysis was ineffective and/or deleterious in promoting hypoxia-dependent angiogenesis while pentose phosphate pathway (PPP) activation was effective. Hexosamine biosynthesis pathway (HBP), PPP, and glycolysis are closely linked. Glucosamine directly activates HBP.Methods:Hind-limb ischemia (HLI)ineNOS-/-and Balb/c mice was used. Glucosamine (600 ug/g/day) was injected intraperitoneally. Blood flow recovery was assessed using laser Doppler perfusion imaging (LDPI), angiogenesis was studied by CD31immunostaining.In-vitro: human umbilical vein ECs (HUVECs) and mouse microvascular EC with glucosamine, L-glucose or vascular endothelial growth factor (VEGF165a), were tested underhypoxiaand serum starvation (HSS). Cell counting kit-8 (CCK-8), tube formation, intracellular reactive oxygen species (ROS), Electric Cell-substrate Impedance Sensing (ECIS) and FITC dextran permeability were assessed. Glycolysis and oxidative phosphorylation were assessed by seahorse assay. Gene expression was assessed using RNA sequencing, real-time qPCR, and western blot. Human muscle biopsies from patients with PAD were assessed for EC O-GlcNAcylation before and after supervised exercise vs. standard medical care. Results: Day-3 post-HLI,glucosamine vs. control-treated eNOS-/-had less necrosis.Beginning Day-7 post-HLI, glucosamine vs. control-treated Balb/chad higherblood flowthat persisted to Day-21whereischemic musclesshowed greaterCD31 staining/muscle fiber. In-vitro,glucosamine vs. L-glucoseshowedimproved EC survival and tube formation. RNA-sequencing of glucosamine vs. L-glucose showed increased amino acid metabolism. That resulted in increased oxidative phosphorylation and serine biosynthesis pathway (SBP) without an increase in glycolysis or PPP genes. This was associated with better barrier function and less ROS compared to activating glycolysis by VEGF165a. These effects were mediated by activating transcription factor 4 (ATF4); a driver of exercise-induced angiogenesis. Finally, in muscle biopsies from humans with PAD,EC/O-GlcNAcylation was increased by 12 weeks of supervised exercise vs. standard medical care. Conclusion: In-cells, mice, and humans activation of HBP by glucosamine in PAD inducesan “exercise-like” angiogenesis and offers a promising novel therapeutic pathway to treat this challenging disorder.

Dataset Information

Prognostic relevance of the hexosamine biosynthesis pathway activation in leiomyosarcoma.

Publications

Prognostic relevance of the hexosamine biosynthesis pathway activation in leiomyosarcoma.

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