High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma

Wang, Zhigang; Chen, Hongsai; Xue, Lu; He, Weiwei; Shu, Wenying; Wu, Hao; Wang, Zhaoyan

doi:10.1016/j.tranon.2021.101146

Cited by 9 publications

(8 citation statements)

References 48 publications

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“…34 Succinate dehydrogenase (SDH), a formidable constituent of the respiratory chain complex II and a vanguard of energy metabolism, assumes a dual mantle as a cardinal component within both the tricarboxylic acid cycle and the mitochondrial respiratory chain’s complex II, thereby orchestrating oxidative phosphorylation. 35 Under the ambience of hypoxia, the genetic malformations bedecking the SDH subunit-encoding genes engender an accrual of succinate, thereby prompting the restraint of HIF-1 prolyl hydroxylases, thereby perpetuating the stabilizing trajectory of HIF-1. Supplementary to this, the aberrant functioning of SDH precipitates the generation of reactive oxygen species (ROS), a cardinal consequence of SDH inhibition’s dual identity within the respiratory chain’s complex II, an outcome imbued with the potency of directly potentiating the stabilization of HIF-1.…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of carotid body tumor revealed potential mechanisms and molecular differences among Shamblin classifications

Lv,

Gu,

Zeng

et al. 2023

Exp Biol Med (Maywood)

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Carotid body tumors (CBTs) are a rare type of paraganglioma, and surgical resection is the only effective treatment. Because of the proximity of CBTs to the carotid artery, jugular vein, and cranial nerve, surgery is extremely difficult, with high risks of hemorrhage and neurovascular injury. The Shamblin classification is used for CBT clinical evaluation; however, molecular mechanisms underlying classification differences remain unclear. This study aimed to investigate pathogenic mechanisms and molecular differences between CBT types. In Shamblin I, II, and III tumors, differentially expressed proteins (DEPs) were identified using direct data-independent acquisition (DIA). DEPs were validated using immunohistochemistry. Proteomics profiling of three Shamblin subtypes differed significantly. Bioinformatics analysis showed that adrenomedullin signaling, protein kinase A signaling, vascular endothelial growth factor (VEGF) signaling, ephrin receptor signaling, gap junction signaling, interleukin (IL)-1 signaling, actin cytoskeleton signaling, endothelin-1 signaling, angiopoietin signaling, peroxisome proliferator–activated receptor (PPAR) signaling, bone morphogenetic protein (BMP) signaling, hypoxia-inducible factor 1-alpha (HIF-1α) signaling, and IL-6 signaling pathways were significantly enriched. Furthermore, 60 DEPs changed significantly with tumor progression. Immunohistochemistry validated several important DEPs, including aldehyde oxidase 1 (AOX1), mediator complex subunit 22 (MED22), carnitine palmitoyltransferase 1A (CPT1A), and heat shock transcription factor 1 (HSF1). To our knowledge, this is the first application of proteomics quantification in CBT. Our results will deepen the understanding of CBT-related pathogenesis and aid in identifying therapeutic targets for CBT treatment.

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Section: Discussionmentioning

confidence: 99%

Proteomics analysis of carotid body tumor revealed potential mechanisms and molecular differences among Shamblin classifications

Lv,

Gu,

Zeng

et al. 2023

Exp Biol Med (Maywood)

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“…ND-UFA2 and NDUFB9 are auxiliary subunits of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Zhigang Wang et al [20] demonstrated through mutational analysis of 14 patients that significant up-regulations of NDUFA2, NDUFA10 and NDUFA4 were involved in the development of head and neck paragangliomas (HNPGLs). NDUFA2 has been found to be frequently targeted by tumorigenic microRNAs in colorectal cancer (CRC) [21].…”

Section: Discussionmentioning

confidence: 99%

Identification of an immune-related metabolic gene signature to predict possible prognosis in endometrial cancer and reveals immune landscape feature

2023

European Journal of Gynaecological Oncology

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The immunotherapy of endometrial cancer (EC) has gradually attracted attention and metabolic reprogramming is associate with tumor immune infiltration. Our goal was to use proteome analysis to examine the role of immune-related metabolic genes (IRMGs) in EC. Data-independent acquisition mass spectrometry (DIA-MS) was performed on 20 EC patients, consisting of 10 high-grade and 10 low-grade cancer tissues. IRMGs were screened using Spearman correlation, and an immune-related metabolic prognosis signature (IRMPS) was constructed based on the Cancer Genome Atlas-Uterine Corpus Endometrioid Carcinoma (TCGA-UCEC) cohort using the least absolute shrinkage and selection operator (LASSO) regression analysis. We also investigated differences between different risk groups in terms of prognostic value, clinical potency, immune characteristics and therapy response. In total, 285 differentially expressed genes (DEGs) were acquired via DIA-MS. Subsequently, metabolic-DEGs and immune-DEGs were analyzed by Spearman correlation to identify 41 IRMGs. Finally, seven IRMGs, including NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2 (NDUFA2), AMPK-alpha2 (PRKAA2), syntaxin binding protein 1 (STXBP1), NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9 (NDUFB9), ribosomal protein S27-like (RPS27L), lysolecithin acyltransferase 2 (LPCAT2) and uridine monophosphate synthetase (UMPS) were identified to establish a prognosis signature. The risk score was determined as an independent prognostic indicator, and patients in the IRMPS-high group was strong linked with adverse prognosis for EC. Additionally, IRMPS was closely related with tumor immune infiltration. Notably, the IRMPS-low group had better immune checkpoint inhibitors (ICI) treatment response and more sensitive to chemotherapy drugs. In conclusion, IRMPS can serve as a precise prognostic tool to guide the personalized treatment of EC patients.

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“…Similar observations have been suggested by Hujber et al regarding human glioma cells containing IDH mutation [ 20 ]. Interestingly, Wang et al showed that SDHx tumors present decreased complex II activity, associated with increased activity of the rest of OXPHOS complexes (I, III and IV), suggesting a compensatory effect [ 21 ]. The decrease in OXPHOS gene expression has been shown earlier in SDHx mutated PCCs/PGLs [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS

Tabebi

Dutta

Skoglund

et al. 2022

IJMS

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Background: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis. Methods: Using the human pheochromocytoma cell line (hPheo1), we knocked down SDHB gene expression using CRISPR-cas9 technology. Results: Microarray gene expression analysis showed that >500 differentially expressed gene targets, about 54%, were upregulated in response to SDHB knock down. Notably, genes involved in glycolysis, hypoxia, cell proliferation, and cell differentiation were up regulated, whereas genes involved in oxidative phosphorylation (OXPHOS) were downregulated. In vitro studies show that hPheo1 proliferation is not affected negatively and the cells that survive by shifting their metabolism to the use of glutamine as an alternative energy source and promote OXPHOS activity. Knock down of SDHB expression results in a significant increase in GLUD1 expression in hPheo1 cells cultured as monolayer or as 3D culture. Analysis of TCGA data confirms the enhancement of GLUD1 in SDHB mutated/low expressed PCCs/PGLs. Conclusions: Our data suggest that the downregulation of SDHB in PCCs/PGLs results in increased GLUD1 expression and may represent a potential biomarker and therapeutic target in SDHB mutated tumors and SDHB loss of activity-dependent diseases.

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High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma

Cited by 9 publications

References 48 publications

Proteomics analysis of carotid body tumor revealed potential mechanisms and molecular differences among Shamblin classifications

Proteomics analysis of carotid body tumor revealed potential mechanisms and molecular differences among Shamblin classifications

Identification of an immune-related metabolic gene signature to predict possible prognosis in endometrial cancer and reveals immune landscape feature

Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS

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