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Victoria I Bunik - One of the best experts on this subject based on the ideXlab platform.
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positive correlation between rat brain glutamate concentrations and mitochondrial 2 Oxoglutarate Dehydrogenase activity
Analytical Biochemistry, 2018Co-Authors: Garik Mkrtchyan, A V Graf, L K Trofimova, A L Ksenofontov, L A Baratova, Victoria I BunikAbstract:Abstract Glutamate is a key metabolite and major excitatory neurotransmitter, degraded through transformation to 2-Oxoglutarate which is further catabolized by 2-Oxoglutarate Dehydrogenase complex (OGDHC). Both the glutamate excitotoxicity and impaired OGDHC activity are hallmarks of neurodegeneration. This work quantifies a relationship between the brain OGDHC activity and glutamate levels, assessing its diagnostic value to characterize (patho)physiology. A moderate to strong positive correlation of the two parameters determined under varied physiological settings (brain regions, seasons, gender, pregnancy, rat line), is revealed. Mitochondrial impairment (OGDHC inhibition or acute hypobaric hypoxia) decreases the interdependence, even when the parameter means do not change significantly. Compared to the cortex, the cerebellum exhibits a lower inter-individual glutamate variation and a weaker glutamate-OGDHC interdependence. Specific metabolism of the brain regions is also characterized by a positive correlation between glutamate and γ-aminobutyric acid (GABA) concentrations in the cortex but not in the cerebellum. In contrast, a strong positive correlation between glutamate and glutamine is present in both the cortex and cerebellum. The differences in metabolic correlations are in line with transcriptomics data which suggest that glutamate distribution between competitive pathways contributes to the brain-region-specific features of the interdependences of glutamate and OGDHC or GABA.
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cellular thiamine status is coupled to function of mitochondrial 2 Oxoglutarate Dehydrogenase
Neurochemistry International, 2016Co-Authors: Garik Mkrtchyan, A V Graf, Lucien Bettendorff, Victoria I BunikAbstract:Abstract Decreased thiamine and reduced activity of thiamine diphosphate (ThDP)-dependent 2-Oxoglutarate Dehydrogenase (OGDH) cause neurodegeneration. We hypothesized on concerted cell-specific regulation of the thiamine metabolism and ThDP-dependent reactions. We identified a smaller thiamine pool, a lower expression of the mitochondrial ThDP transporter, and a higher expression of OGDH in rat astrocytes versus neuroblastoma N2A. According to the data, the astrocytic OGDH may be up-regulated by an increase in intracellular ThDP, while the neuroblastomal OGDH functions at full ThDP saturation. Indeed, in rat astrocytes and brain cortex, OGDH inhibition by succinyl phosphonate (SP) enlarged the pool of thiamine compounds. Increased ThDP level in response to the OGDH inhibition presumably up-regulated the enzyme to compensate for a decrease in reducing power which occurred in SP-treated astrocytes. Under the same SP treatment of N2A cells, their thiamine pool and reducing power were unchanged, although SP action was evident from accumulation of glutamate. The presented data indicate that functional interplay between OGDH, other proteins of the tricarbocylic acid cycle and proteins of thiamine metabolism is an important determinant of physiology-specific networks and their homeostatic mechanisms.
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up regulation of 2 Oxoglutarate Dehydrogenase as a stress response
The International Journal of Biochemistry & Cell Biology, 2013Co-Authors: A V Graf, Slawomir Strumilo, Garik Mkrtchyan, Lucien Bettendorff, L K Trofimova, Alexandra Loshinskaja, Anastasiia Strokina, M L Lovat, Adam Tylicky, Victoria I BunikAbstract:Abstract 2-Oxoglutarate Dehydrogenase multienzyme complex (OGDHC) operates at a metabolic cross-road, mediating Ca2+- and ADP-dependent signals in mitochondria. Here, we test our hypothesis that OGDHC plays a major role in the neurotransmitter metabolism and associated stress response. This possibility was assessed using succinyl phosphonate (SP), a highly specific and efficient in vivo inhibitor of OGDHC. Animals exposed to toxicants (SP, ethanol or MnCl2), trauma or acute hypoxia showed intrinsic up-regulation of OGDHC in brain and heart. The known mechanism of the SP action as OGDHC inhibitor pointed to the up-regulation triggered by the enzyme impairment. The animal behavior and skeletal muscle or heart performance were tested to correlate physiology with the OGDHC regulation and associated changes in the glutamate and cellular energy status. The SP-treated animals exhibited interdependent changes in the brain OGDHC activity, glutamate level and cardiac autonomic balance, suggesting the neurotransmitter role of glutamate to be involved in the changed heart performance. Energy insufficiency after OGDHC inhibition was detectable neither in animals up to 25 mg/kg SP, nor in cell culture during 24 h incubation with 0.1 mM SP. However, in animals subjected to acute ethanol intoxication SP did evoke energy deficit, decreasing muscular strength and locomotion and increasing the narcotic sleep duration. This correlated with the SP-induced decrease in NAD(P)H levels of the ethanol-exposed neurons. Thus, we show the existence of natural mechanisms to up-regulate mammalian OGDHC in response to stress, with both the glutamate neurotransmission and energy production potentially involved in the OGDHC impact on physiological performance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
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2 Oxoglutarate Dehydrogenase complex and its multipoint control
Postepy biochemii, 2011Co-Authors: A Tylicki, Victoria I Bunik, Slawomir StrumiloAbstract:Abstract Enzymes control the course of biochemical reactions. The enzymes involved in bioenergetic processes play most important role in cell metabolism. One of them is 2-Oxoglutarate Dehydrogenase complex (OGDHC), the key regulatory enzyme of Krebs cycle. Krebs cycle integrates basic metabolic pathways of carbohydrates, fatty acids and amino acids during catabolic as well as anabolic reactions. Due to the key position of OGDHC in mitochondrial metabolism, its activity is controlled by many factors. Allosteric regulation by positive effectors (ADP, Pi, Ca2+, Mn2+) of the complex is very important. These effectors strongly enhances affinity of the first component of OGDHC to 2-Oxoglutarate. Moreover there are negative effectors (ATP, NADH, succinyl-CoA) which affect all three enzymes of the complex. Regulation of biosynthesis of individual components of the complex by activation or inactivation of genes expression is very important for proper OGDHC activity too. Activity of OGDHC also depends on posttranslational modifications of its components. All of this control processes maintain OGDHC activity on adequate level and prevent the complex against its excessive action.
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inhibition of 2 Oxoglutarate Dehydrogenase in potato tuber suggests the enzyme is limiting for respiration and confirms its importance in nitrogen assimilation
Plant Physiology, 2008Co-Authors: Wagner L Araujo, Adriano Nunesnesi, Sandra Trenkamp, Victoria I Bunik, Alisdair R FernieAbstract:The 2-Oxoglutarate Dehydrogenase complex constitutes a mitochondrially localized tricarboxylic acid cycle multienzyme system responsible for the conversion of 2-Oxoglutarate to succinyl-coenzyme A concomitant with NAD+ reduction. Although regulatory mechanisms of plant enzyme complexes have been characterized in vitro, little is known concerning their role in plant metabolism in situ. This issue has recently been addressed at the cellular level in nonplant systems via the use of specific phosphonate inhibitors of the enzyme. Here, we describe the application of these inhibitors for the functional analysis of the potato (Solanum tuberosum) tuber 2-Oxoglutarate Dehydrogenase complex. In vitro experiments revealed that succinyl phosphonate (SP) and a carboxy ethyl ester of SP are slow-binding inhibitors of the 2-Oxoglutarate Dehydrogenase complex, displaying greater inhibitory effects than a diethyl ester of SP, a phosphono ethyl ester of SP, or a triethyl ester of SP. Incubation of potato tuber slices with the inhibitors revealed that they were adequately taken up by the tissue and produced the anticipated effects on the in situ enzyme activity. In order to assess the metabolic consequences of the 2-Oxoglutarate Dehydrogenase complex inhibition, we evaluated the levels of a broad range of primary metabolites using an established gas chromatography-mass spectrometry method. We additionally analyzed the rate of respiration in both tuber discs and isolated mitochondria. Finally, we evaluated the metabolic fate of radiolabeled acetate, 2-Oxoglutarate or glucose, and 13C-labeled pyruvate and glutamate following incubation of tuber discs in the presence or absence of either SP or the carboxy ethyl ester of SP. The data obtained are discussed in the context of the roles of the 2-Oxoglutarate Dehydrogenase complex in respiration and carbon-nitrogen interactions.
Yan Wang - One of the best experts on this subject based on the ideXlab platform.
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a novel Oxoglutarate Dehydrogenase like mediated mir 214 twist1 negative feedback loop inhibits pancreatic cancer growth and metastasis
Clinical Cancer Research, 2019Co-Authors: Fanzheng Meng, Jiabei Wang, Guangchao Yang, Ruipeng Song, Tongsen Zheng, Yingjian Liang, Shugeng Zhang, Jizhou Wang, Haiyan Yang, Yan WangAbstract:Purpose: As a main rate-limiting subunit of the 2-Oxoglutarate Dehydrogenase multienzyme complex, Oxoglutarate Dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental Design: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. Results: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF-1α and regulating AKT pathways. A combination of OGDHL down-regulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. Conclusions: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
Fanzheng Meng - One of the best experts on this subject based on the ideXlab platform.
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A Novel Oxoglutarate Dehydrogenase-Like Mediated miR-214/TWIST1 Negative Feedback Loop Inhibits Pancreatic Cancer Growth and Metastasis
Clinical Cancer Research, 2019Co-Authors: Fanzheng Meng, Jiabei Wang, Guangchao Yang, Ruipeng Song, Tongsen Zheng, Yingjian Liang, Shugeng ZhangAbstract:Purpose: As a main rate-limiting subunit of the 2-Oxoglutarate Dehydrogenase multienzyme complex, Oxoglutarate Dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental Design: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. Results: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF-1α and regulating AKT pathways. A combination of OGDHL down-regulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. Conclusions: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
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a novel Oxoglutarate Dehydrogenase like mediated mir 214 twist1 negative feedback loop inhibits pancreatic cancer growth and metastasis
Clinical Cancer Research, 2019Co-Authors: Fanzheng Meng, Jiabei Wang, Guangchao Yang, Ruipeng Song, Tongsen Zheng, Yingjian Liang, Shugeng Zhang, Jizhou Wang, Haiyan Yang, Yan WangAbstract:Purpose: As a main rate-limiting subunit of the 2-Oxoglutarate Dehydrogenase multienzyme complex, Oxoglutarate Dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental Design: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. Results: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF-1α and regulating AKT pathways. A combination of OGDHL down-regulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. Conclusions: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
Kichiko Koike - One of the best experts on this subject based on the ideXlab platform.
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human pyruvate and 2 Oxoglutarate Dehydrogenase complexes tissue specific expression
Journal of Clinical Biochemistry and Nutrition, 2001Co-Authors: Kichiko KoikeAbstract:Highly sensitive and rapid assay procedures for human mitochondrial the pyruvate Dehydrogenase (PDH) complex, the 2-Oxoglutarate Dehydrogenase (OGDH) complex and their 5 component enzymes were established for use with crude tissue extracts, and their enzymatic activities were determined. Overall reaction activities of the PDH and OGDH complexes were very high, in order of heart>abdominal skeletal muscle>kidney. Full-length cDNA encoding the precursor of theporcine dihydrolipoamide acetyltransferase (E2p) subunit was isolated and characterized. It contained an open reading frame encoding a leader peptide (86 residues) and a mature enzyme protein (561 residues, Mr=59, 699). The reduced enzyme protein showed 91% identity with the human enzyme. All genes encoding the component enzymes of the 2 human complexes were expressed in a variety of organs, but most strongly in heart and skeletal muscle (abdominal muscle) in a similar order as found for their enzymatic activities.
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cloning structure chromosomal localization and promoter analysis of human 2 Oxoglutarate Dehydrogenase gene
Biochimica et Biophysica Acta, 1998Co-Authors: Kichiko KoikeAbstract:Abstract Human 2-Oxoglutarate Dehydrogenase (OGDH) is an E1-component of the OGDH multi-enzyme complex and catalyzes both the ThDP-dependent decarboxylation of 2-Oxoglutarate and the subsequent reductive succinylation of the lipoyl moiety which is covalently bound to the E2 component, dihydrolipoamide succinyltransferase. The cDNA and genomic DNA encoding human OGDH has been cloned and sequenced. The cDNA contains a 3006-bp open reading frame encoding a 40-amino acid leader peptide and a 962-amino acid mature OGDH protein ( M r =108 878). The gene contains 22 exons spanning approximately 85 kb. The putative ThDP-binding sequence motif is identified in both DNAs. The gene is localized to chromosome 7 at p13–p14 by fluorescence in situ hybridization. With the TATA- and CAAT-less 5′-flanking region (wild type, −3276/+212) of the OGDH gene-luciferase reporter vector construct and its nested deletion or linker-scanning mutant constructs the transient reporter expression assays in BHK-21 cells reveal the existence of two 10-bp cis -acting elements (−53/−44 and −33/−24) and two trans -acting elements (−536/−496 and −93/−84). A nuclear factor that binds to the region from −63 to −24 including two cis -acting elements.
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the gene encoding human 2 Oxoglutarate Dehydrogenase structural organization and mapping to chromosome 7p13 p14
Gene, 1995Co-Authors: Kichiko KoikeAbstract:Abstract Genomic clones covering the entire sequence of the gene encoding human 2-Oxoglutarate Dehydrogenase (OGDH) were isolated by screening leukocyte and placenta genomic libraries with radio- and digoxigenin (DIG)-labeled human OGDH cDNAs. The human OGDH gene contains 22 exons spanning approx. 85 kb. All exon/intron splice junctions follow the GT/AG rule. The results of primer extension analysis imply that the OGDH transcription start point is a thymine residue 55 bp upstream from the ATG start codon. The 5′-flanking region of OGDH lacked canonical TATA or CAAT boxes. Using DNAs from human × rodent somatic cell hybrids that segregate human chromosomes in conjunction with fluorescence in situ hybridization, human OGDH was assigned to chromosome arm 7p, an area that corresponds to the boundary between bands 7p13 and 7p14.
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cloning and nucleotide sequence of the cdna encoding human 2 Oxoglutarate Dehydrogenase lipoamide
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Kichiko Koike, Yoshishige Urata, Shinji GotoAbstract:Abstract 2-Oxoglutarate Dehydrogenase (lipoamide) (( OGDH: 2-Oxoglutarate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-succinylating), EC 1.2.4.2 )) is a component enzyme of the 2-Oxoglutarate Dehydrogenase complex. We have cloned a human cDNA encoding OGDH from a fetal liver cDNA library by plaque hybridization with a mixture of oligonucleotide probes designed from the amino acid sequences of porcine OGDH. This cDNA spans 4156 bases and contains an open reading frame of 3009 nucleotides encoding a presequence of 40 amino acid residues and a mature protein of 963 amino acid residues (Mr = 108,642). The size of the mRNA is approximately 4.2 kilobases. Comparison of the deduced amino acid sequence of the human OGDH with experimentally determined segments of porcine OGDH comprising 308 amino acid residues shows 93% sequence identity. The human OGDH has 37% sequence identity with 933 amino acid residues of the Escherichia coli OGDH and 40% sequence identity with 1014 residues of the yeast OGDH.
Shugeng Zhang - One of the best experts on this subject based on the ideXlab platform.
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A Novel Oxoglutarate Dehydrogenase-Like Mediated miR-214/TWIST1 Negative Feedback Loop Inhibits Pancreatic Cancer Growth and Metastasis
Clinical Cancer Research, 2019Co-Authors: Fanzheng Meng, Jiabei Wang, Guangchao Yang, Ruipeng Song, Tongsen Zheng, Yingjian Liang, Shugeng ZhangAbstract:Purpose: As a main rate-limiting subunit of the 2-Oxoglutarate Dehydrogenase multienzyme complex, Oxoglutarate Dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental Design: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. Results: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF-1α and regulating AKT pathways. A combination of OGDHL down-regulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. Conclusions: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
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a novel Oxoglutarate Dehydrogenase like mediated mir 214 twist1 negative feedback loop inhibits pancreatic cancer growth and metastasis
Clinical Cancer Research, 2019Co-Authors: Fanzheng Meng, Jiabei Wang, Guangchao Yang, Ruipeng Song, Tongsen Zheng, Yingjian Liang, Shugeng Zhang, Jizhou Wang, Haiyan Yang, Yan WangAbstract:Purpose: As a main rate-limiting subunit of the 2-Oxoglutarate Dehydrogenase multienzyme complex, Oxoglutarate Dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental Design: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. Results: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF-1α and regulating AKT pathways. A combination of OGDHL down-regulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. Conclusions: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
