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Breast cancer is the females' most common cancer. Targeting the immune microenvironment is a new and promising treatment method for breast cancer. Nevertheless, only a small section of patients can profit by immunotherapy, and improving the ability to accurately predict the potential for immunotherapy response is still awaiting further exploration. In this study, we found that the key factors of glutamine metabolism, glutaminase 1 (GLS) and mitochondrial aspartate transaminase (GOT2), showed opposite expression patterns in breast cancer samples. Based on the expression level of GLS and GOT2, we divided the breast cancer samples into two clusters: Cluster 2 showed GLS expressed higher and GOT2 expressed lower, whereas Cluster 1 showed GOT2 expressed higher and GLS expressed lower. GSEA showed that the clusters were related to pathways of immunity. Further analysis showed that Cluster 2 was positively associated with immunity infiltration. Through WGCNA, we identified a module strongly correlated with glutamine metabolism and immunity and identified 11 dendritic cell-associated genes involved in dendritic cell development, maturation, activation and other functions. In addition, Cluster 2 also showed higher immune checkpoint gene expression, which suggest the Cluster 2 had even better response to immunotherapy. The validation dataset could also be clustered into two groups. Cluster 2 (GLS expressed higher and GOT2 expressed lower) of the validation dataset was also positively associated with dendritic cells and a better immunotherapy response. Thus, these data indicate that GLS and GOT2 are prognostic biomarkers which closely related to dendritic cells and better reacted to immunotherapy in breast cancer.

Hepatocellular carcinoma (HCC) remains a global challenge as it is the sixth most common neoplasm worldwide and the third leading cause of cancer-related death. A key feature of HCC is abnormal metabolism, which promotes cancer cell proliferation, survival, invasion, and metastasis. However, the significance of metabolism-related genes (MRGs) in HCC remains to be elucidated. Here, we aim to establish a novel metabolism-related prognostic signature for the prediction of patient outcomes and to investigate the value of MRG expression in the prognostic prediction of HCC. In our research, a Metabolism-Related Risk Score (MRRS) model was constructed using 14 MRGs (DLAT, SEPHS1, ACADS, UCK2, GOT2, ADH4, LDHA, ME1, TXNRD1, B4GALT2, AK2, PTDSS2, CSAD, and AMD1). The Kaplan-Meier curve confirmed that the MRRS has a high accuracy in predicting the prognosis of HCC patients (p<0:001). According to theMRRSmodel, the area under the curve (AUC) values for predicting the prognosis of patients with hepatocellular carcinoma at 1, 3, and 5 years reached 0.829, 0.760, and 0.739, respectively. Functional analyses revealed that signaling pathways associated with the cell cycle were largely enriched by differential genes between high and low-risk groups. In addition, dendritic cells (DCs) (p < 0:001), CD4+ T cells (p < 0:01), CD8+ T cells (p < 0:001), B cells (p < 0:001), neutrophils (p < 0:001), macrophages (p<0:001) had a higher proportion of infiltrates in high-risk populations. Low GOT2 expression is associated with poor prognosis in patients with hepatocellular carcinoma. Knockdown of GOT2 significantly increased the migration capacity of the Huh7 and MHCC97H hepatocellular carcinoma lines. Our research reveals that GOT2 is negatively related to the survival of patients with hepatocellular carcinoma and GOT2 may contribute to tumor progression by inhibiting the ability of tumor cells to migrate. [ABSTRACT FROM AUTHOR]

Background: Reprogramming in glutamine metabolism is a hallmark of cancers, while its role in cutaneous melanoma has not been studied at great length. Methods: Here, we constructed a glutamine metabolism-related prognostic signature in cutaneous melanoma with a variety of bioinformatics methods according to the glutamine metabolism regulatory molecules. Moreover, experimental verification was carried out for the key gene. Results: We have identified two subgroups of cutaneous melanoma patients, each with different prognoses, immune characteristics, and genetic mutations. GOT2 was the most concerned key gene among the model genes. We verified its role in promoting tumor cell proliferation by CCK-8 and clone formation assays. Conclusion: Our study cast new light on the prognosis of cutaneous melanoma, and the internal mechanism regulating glutamine metabolism of GOT2 may provide a new avenue for treating the cutaneous melanoma disease precisely. [ABSTRACT FROM AUTHOR]

Abstract Introduction and objectives hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood. Methods By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan–Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method. Results HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells. Conclusions Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes.

Clear cell renal cell carcinoma (KIRC) is the most common and highly malignant pathological type of kidney cancer, characterized by a profound metabolism dysregulation. As part of aspartate biosynthesis, mitochondrial GOT2 (glutamic-oxaloacetic transaminase 2) is essential for regulating cellular energy production and biosynthesis, linking multiple pathways. Nevertheless, the expression profile and prognostic significance of GOT2 in KIRC remain unclear. This study comprehensively analyzed the transcriptional levels, epigenetic regulation, correlation with immune infiltration, and prognosis of GOT2 in KIRC using rigorous bioinformatics analysis. We discovered that the expression levels of both mRNA and protein of GOT2 were remarkably decreased in KIRC tissues in comparison with normal tissues and were also significantly related to the clinical features and prognosis of KIRC. Remarkably, low GOT2 expression was positively associated with poorer overall survival (OS) and disease-free survival (DFS). Further analysis revealed that GOT2 downregulation is driven by DNA methylation in the promoter-related CpG islands. Finally, we also shed light on the influence of GOT2 expression in immune cell infiltration, suggesting that GOT2 may be a potential prognostic marker and therapeutic target for KIRC patients.

Background: Acute allograft rejection (AR) following renal transplantation contributes to chronic rejection and allograft dysfunction. The current diagnosis of AR remains dependent on renal allograft biopsy which cannot immediately detect renal allograft injury in the presence of AR. In this study, sensitive biomarkers for AR diagnosis were investigated and developed to protect renal function. Methods: We analyzed pre- and postoperative data from five databases combined with our own data to identify the key differently expressed genes (DEGs). Furthermore, we performed a bioinformatics analysis to determine the immune characteristics of DEGs. The expression of key DEGs was further confirmed using the real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemical (IHC) staining in patients with AR. ROC curves analysis was used to estimate the performance of key DEGs in the early diagnosis of AR. Results: We identified glutamic-oxaloacetic transaminase 2 (GOT2) and syntaxin binding protein 3 (STXBP3) as key DEGs. The higher expression of STXBP3 and GOT2 in patients with AR was confirmed using RT-qPCR, ELISA, and IHC staining. ROC curve analysis also showed favorable values of STXBP3 and GOT2 for the diagnosis of early stage AR. Conclusions: STXBP3 and GOT2 could reflect the immunological status of patients with AR and have strong potential for the diagnosis of early-stage AR. [ABSTRACT FROM AUTHOR]

Introduction and objectives: hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood. Methods: By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan–Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method. Results: HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells. Conclusions: Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes. [ABSTRACT FROM AUTHOR]

To provide a novel perspective on the pathogenesis of acute myocardial infarction (AMI) patients with respect to glutamic oxaloacetic transaminase (GOT). The plasma proteome of 20 patients with AMI were matched for age and sex and compared with 10 healthy individuals. We analyzed the mass spectrum data and compared the signal intensity of the corresponding peptides which related to their corresponding proteins. A sample-specific protein database was constructed and a quality control analysis was conducted to screen out the key regulatory proteins under specific experimental conditions. The data from 37 new AMI patients and 13 healthy adults were subjected to parallel reaction monitoring (PRM) to verify the target proteins found. Finally, the survival status of the key genes (> 1.5-fold) in the PPI were analyzed. 2589 and 2162 proteins were identified and quantified, respectively, and 143 differentially expressed proteins (DEPs) (≥1.5-fold) were found between the AMI and control groups. Of these 90 and 53 were significantly up-regulated and down-regulated, respectively. Gene ontology, KEGG enrichment, protein domain and cluster analysis as well as PPI networks of the DEPs revealed a central role of acute inflammatory response processes in patients with AMI. A cluster of proteins were found to be related to cysteine, methionine, arginine, proline, phenylalanine and propanoate metabolism as well as the cAMP signaling pathway. PPI network analysis showed CHI3L1, COPB2, GOT2, MB, CYCS, GOT1, CKM, SAA1 and PRKCD and RPS3 were in key positions, but only MB, CKM, GOT1, PRKCD, CYCS and GOT2 were found in a cluster. PRM verified the high levels of MB, CKM, GOT1 and GOT2 in 37 AMI patients but there was no statistical difference in the survival status for patients with either high or low expression levels of these proteins. Our findings showed that acute inflammatory response processes play a central role in patients with AMI. Cysteine and methionine metabolism was also activated, in which GOT1 and GOT2 were key proteins. These pathways might be potential targets for diagnosis and novel therapies to improve the poor outcomes observed in patients with heart failure. [Display omitted] • The plasma proteome of AMI patients and controls expressed different proteins. • PPI network analysis showed GOT1, GOT2, CKM, MB, PRKCD and CYCS in a cluster. • Parallel reaction monitoring verified GOT1, GOT2, CKM and MB as target proteins. • The related pathways provide potential targets for diagnosis and therapies for AMI. [ABSTRACT FROM AUTHOR]

The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate-aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD(+) redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate-aspartate NADH shuttle activity and oxidative protection.

Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD+/NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox‐dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3‐phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation. [ABSTRACT FROM AUTHOR]

Breast cancer susceptibility gene 1 (BRCA1) has been implicated in modulating metabolism via transcriptional regulation. However, direct metabolic targets of BRCA1 and the underlying regulatory mechanisms are still unknown. Here, we identified several metabolic genes, including the gene which encodes glutamate‐oxaloacetate transaminase 2 (GOT2), a key enzyme for aspartate biosynthesis, which are repressed by BRCA1. We report that BRCA1 forms a co‐repressor complex with ZBRK1 that coordinately represses GOT2 expression via a ZBRK1 recognition element in the promoter of GOT2. Impairment of this complex results in upregulation of GOT2, which in turn increases aspartate and alpha ketoglutarate production, leading to rapid cell proliferation of breast cancer cells. Importantly, we found that GOT2 can serve as an independent prognostic factor for overall survival and disease‐free survival of patients with breast cancer, especially triple‐negative breast cancer. Interestingly, we also demonstrated that GOT2 overexpression sensitized breast cancer cells to methotrexate, suggesting a promising precision therapeutic strategy for breast cancer treatment. In summary, our findings reveal that BRCA1 modulates aspartate biosynthesis through transcriptional repression of GOT2, and provides a biological basis for treatment choices in breast cancer.

Breast cancer is the females' most common cancer. Targeting the immune microenvironment is a new and promising treatment method for breast cancer. Nevertheless, only a small section of patients can profit by immunotherapy, and improving the ability to accurately predict the potential for immunotherapy response is still awaiting further exploration. In this study, we found that the key factors of glutamine metabolism, glutaminase 1 (GLS) and mitochondrial aspartate transaminase (GOT2), showed opposite expression patterns in breast cancer samples. Based on the expression level of GLS and GOT2, we divided the breast cancer samples into two clusters: Cluster 2 showed GLS expressed higher and GOT2 expressed lower, whereas Cluster 1 showed GOT2 expressed higher and GLS expressed lower. GSEA showed that the clusters were related to pathways of immunity. Further analysis showed that Cluster 2 was positively associated with immunity infiltration. Through WGCNA, we identified a module strongly correlated with glutamine metabolism and immunity and identified 11 dendritic cell-associated genes involved in dendritic cell development, maturation, activation and other functions. In addition, Cluster 2 also showed higher immune checkpoint gene expression, which suggest the Cluster 2 had even better response to immunotherapy. The validation dataset could also be clustered into two groups. Cluster 2 (GLS expressed higher and GOT2 expressed lower) of the validation dataset was also positively associated with dendritic cells and a better immunotherapy response. Thus, these data indicate that GLS and GOT2 are prognostic biomarkers which closely related to dendritic cells and better reacted to immunotherapy in breast cancer., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jing Feng reports financial support was provided by 10.13039/501100001809National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Mammary epithelial cells (MECs) in culture are a useful model for elucidating mammary gland metabolism and changes that occur under different nutrient disponibility. MECs were exposed to different treatments: 100% EAA for 8 h and 24 h restriction (R); 2% EAA for 8 h and 24 h R; 2% EAA for 8 h and 24 h + 100% EAA for 8 h and 24 h restriction + re-feeding (R + RF). Western blotting and protein quantification was performed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) software identified the amino acids (AAs) and signaling pathways. The chi-squared test, multiple classification analysis, and analysis of variance were used for the purification and identification of data. Intracellular casein levels were not affected. The KEGG analysis revealed that the important pathways of metabolism of AAs, which were involved in processes related to metabolism and biosynthesis of phenylalanine, tyrosine, and tryptophan (fumarate, acetyl-CoA, and tricarboxylic acid (TCA) cycle), were affected by both R and R + RF treatments, mainly through the glutamic-oxaloacetic transaminase-2 enzyme. Additionally, metabolic processes mediated by the mitochondrial malate dehydrogenase, S-adenosylmethionine synthetase, and asparagine synthase proteins positively regulated the carbohydrate pathway, pyruvate, and TCA cycles, as well as the metabolism of alanine, aspartate, and glutamate metabolism (carbohydrate and TCA cycle). We hypothesized that MECs have the capacity to utilize alternative pathways that ensure the availability of substrates for composing milk proteins.

Objective: To investigate the effects of the interactions between the CYP2E1 and GOT2 gene polymorphisms and N,N-dimethylformamide (DMF) on liver injury. Methods: A total of 672 DMF-exposed workers were randomly selected from two synthetic leather enterprises in Suzhou, China, for follow-up in a cohort study. Information on exposure to DMF in the air was collected through a fixed-point air sampler in the worker's breathing zone. The subjects were assessed every year during the period of 2010–2015, they underwent occupational health examinations. Alanine aminotransferase and aspartate aminotransferase levels were measured. Peripheral blood was collected and DNA was extracted. The genotypes rs2031920, rs3813867 and rs6413432 of the CYP2E1 gene and rs7204324 of the GOT2 gene were detected by PCR, and analyzed using the Chi-square test and logistic regression analysis. Results: Workers exposed to a high cumulative dose of DMF were significantly more likely than low-exposed workers to develop liver injury. No association was observed between rs2031920, rs3813867 and rs6413432 of the CYP2E1 gene and DMF-induced liver damage. However, the A allele of rs7204324 on the GOT2 gene may be a risk factor for susceptibility to DMF-induced liver injury. Conclusion: Polymorphisms of rs7204324 on GOT2 may play an important role in susceptibility to liver injury following exposure to DMF. [ABSTRACT FROM AUTHOR]

Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects. [ABSTRACT FROM AUTHOR]

Breast cancer susceptibility gene 1 (BRCA1) has been implicated in modulating metabolism via transcriptional regulation. However, direct metabolic targets of BRCA1 and the underlying regulatory mechanisms are still unknown. Here, we identified several metabolic genes, including the gene which encodes glutamate‐oxaloacetate transaminase 2 (GOT2), a key enzyme for aspartate biosynthesis, which are repressed by BRCA1. We report that BRCA1 forms a co‐repressor complex with ZBRK1 that coordinately represses GOT2 expression via a ZBRK1 recognition element in the promoter of GOT2. Impairment of this complex results in upregulation of GOT2, which in turn increases aspartate and alpha ketoglutarate production, leading to rapid cell proliferation of breast cancer cells. Importantly, we found that GOT2 can serve as an independent prognostic factor for overall survival and disease‐free survival of patients with breast cancer, especially triple‐negative breast cancer. Interestingly, we also demonstrated that GOT2 overexpression sensitized breast cancer cells to methotrexate, suggesting a promising precision therapeutic strategy for breast cancer treatment. In summary, our findings reveal that BRCA1 modulates aspartate biosynthesis through transcriptional repression of GOT2, and provides a biological basis for treatment choices in breast cancer. Breast cancer susceptibility gene 1 (BRCA1) has been implicated in cell metabolism in previous studies, however, the underlying mechanisms are still unclear. Here, we demonstrated that BRCA1 forms a co‐repressor complex with ZBRK1 on the promoter of GOT2 via the ZBRK1 recognition element, and that BRCA1 deficiency promotes aspartate and α‐KG production and accelerates tumor cell growth together with GOT2 upregulation. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) remains a global challenge as it is the sixth most common neoplasm worldwide and the third leading cause of cancer-related death. A key feature of HCC is abnormal metabolism, which promotes cancer cell proliferation, survival, invasion, and metastasis. However, the significance of metabolism-related genes (MRGs) in HCC remains to be elucidated. Here, we aim to establish a novel metabolism-related prognostic signature for the prediction of patient outcomes and to investigate the value of MRG expression in the prognostic prediction of HCC. In our research, a Metabolism-Related Risk Score (MRRS) model was constructed using 14 MRGs (DLAT, SEPHS1, ACADS, UCK2, GOT2, ADH4, LDHA, ME1, TXNRD1, B4GALT2, AK2, PTDSS2, CSAD, and AMD1). The Kaplan-Meier curve confirmed that the MRRS has a high accuracy in predicting the prognosis of HCC patients ( p  < 0.001). According to the MRRS model, the area under the curve (AUC) values for predicting the prognosis of patients with hepatocellular carcinoma at 1, 3, and 5 years reached 0.829, 0.760, and 0.739, respectively. Functional analyses revealed that signaling pathways associated with the cell cycle were largely enriched by differential genes between high and low-risk groups. In addition, dendritic cells (DCs) ( p  < 0.001), CD4+ T cells ( p  < 0.01), CD8+ T cells ( p  < 0.001), B cells ( p  < 0.001), neutrophils ( p  < 0.001), macrophages ( p  < 0.001) had a higher proportion of infiltrates in high-risk populations. Low GOT2 expression is associated with poor prognosis in patients with hepatocellular carcinoma. Knockdown of GOT2 significantly increased the migration capacity of the Huh7 and MHCC97H hepatocellular carcinoma lines. Our research reveals that GOT2 is negatively related to the survival of patients with hepatocellular carcinoma and GOT2 may contribute to tumor progression by inhibiting the ability of tumor cells to migrate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©2023 Ru et al.)

Background: To explore the biological function and the underlying mechanisms of GOT2 in hepatocellular carcinoma (HCC). Materials & methods: The expression level and prognostic value of GOT2 were examined using International Cancer Genome Consortium and International Cancer Proteogenome Consortium databases. The cell counting kit-8 method, clone formation, Transwell ® assays and western blotting were used to evaluate the effects of GOT2 on the biological function and autophagy of HCC cells. Results: The expression of GOT2 was downregulated in HCC tissues and correlated with poor prognosis of HCC patients. Knockdown of GOT2 promoted proliferation, migration and invasion of HCC cells and promoted cells' proliferation by inducing autophagy. Conclusion: GOT2 plays a tumor-inhibitory role in HCC and may be a potential therapeutic target for HCC.

Background: Reprogramming in glutamine metabolism is a hallmark of cancers, while its role in cutaneous melanoma has not been studied at great length. Methods: Here, we constructed a glutamine metabolism-related prognostic signature in cutaneous melanoma with a variety of bioinformatics methods according to the glutamine metabolism regulatory molecules. Moreover, experimental verification was carried out for the key gene. Results: We have identified two subgroups of cutaneous melanoma patients, each with different prognoses, immune characteristics, and genetic mutations. GOT2 was the most concerned key gene among the model genes. We verified its role in promoting tumor cell proliferation by CCK-8 and clone formation assays. Conclusion: Our study cast new light on the prognosis of cutaneous melanoma, and the internal mechanism regulating glutamine metabolism of GOT2 may provide a new avenue for treating the cutaneous melanoma disease precisely., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Song, Wei, Zhang and Lu.)

Purpose: Dysregulated circular RNAs (circRNAs) have shown crucial modulatory functions in tumorigenesis, containing non-small cell lung cancer (NSCLC). The purpose of this study was to explore the biological functions and regulatory theory of circ&#95;0006220 in NSCLC., Methods: Reverse transcription-quantitative polymerase chain reaction and Western blot assay were conducted to measure RNA and protein expression, respectively. A total of 73 cases of NSCLC tumor samples were collected for expression analysis, and A-549 and NCI-H1299 cell lines were used for functional experiments. Cell proliferation was assessed by cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine assay, and flow cytometry. Cell apoptosis, motility, and angiogenesis ability were analyzed by flow cytometry, transwell assays, and capillary-like network formation assay. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to verify the target relationships., Results: Circ&#95;0006220 was highly expressed in NSCLC tissues and cell lines. Circ&#95;0006220 silencing inhibited the proliferation, migration, invasion, and angiogenesis but induced the apoptosis of NSCLC cells. Circ&#95;0006220 acted as a microRNA-342-3p (miR-342-3p) sponge, and circ&#95;0006220 knockdown-induced changes on the phenotypes of NSCLC cells were largely overturned by the knockdown of miR-342-3p. miR-342-3p interacted with the 3' untranslated region of glutamic-oxaloacetic transaminase 2 (GOT2), and GOT2 overexpression largely diminished miR-342-3p overexpression-mediated influences in NSCLC cells. Circ&#95;0006220 could up-regulate GOT2 expression by sponging miR-342-3p., Conclusion: Circ&#95;0006220 promoted the malignant behaviors of NSCLC cells through mediating the miR-342-3p/GOT2 regulation cascade.

Background: Acute allograft rejection (AR) following renal transplantation contributes to chronic rejection and allograft dysfunction. The current diagnosis of AR remains dependent on renal allograft biopsy which cannot immediately detect renal allograft injury in the presence of AR. In this study, sensitive biomarkers for AR diagnosis were investigated and developed to protect renal function., Methods: We analyzed pre- and postoperative data from five databases combined with our own data to identify the key differently expressed genes (DEGs). Furthermore, we performed a bioinformatics analysis to determine the immune characteristics of DEGs. The expression of key DEGs was further confirmed using the real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemical (IHC) staining in patients with AR. ROC curves analysis was used to estimate the performance of key DEGs in the early diagnosis of AR., Results: We identified glutamic-oxaloacetic transaminase 2 (GOT2) and syntaxin binding protein 3 (STXBP3) as key DEGs. The higher expression of STXBP3 and GOT2 in patients with AR was confirmed using RT-qPCR, ELISA, and IHC staining. ROC curve analysis also showed favorable values of STXBP3 and GOT2 for the diagnosis of early stage AR., Conclusions: STXBP3 and GOT2 could reflect the immunological status of patients with AR and have strong potential for the diagnosis of early-stage AR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yao, Wang, Wang, Xiang, Chen, Zhou, Chen, Jiang and Chen.)

Clear cell renal cell carcinoma (KIRC) is the most common and highly malignant pathological type of kidney cancer, characterized by a profound metabolism dysregulation. As part of aspartate biosynthesis, mitochondrial GOT2 (glutamic-oxaloacetic transaminase 2) is essential for regulating cellular energy production and biosynthesis, linking multiple pathways. Nevertheless, the expression profile and prognostic significance of GOT2 in KIRC remain unclear. This study comprehensively analyzed the transcriptional levels, epigenetic regulation, correlation with immune infiltration, and prognosis of GOT2 in KIRC using rigorous bioinformatics analysis. We discovered that the expression levels of both mRNA and protein of GOT2 were remarkably decreased in KIRC tissues in comparison with normal tissues and were also significantly related to the clinical features and prognosis of KIRC. Remarkably, low GOT2 expression was positively associated with poorer overall survival (OS) and disease-free survival (DFS). Further analysis revealed that GOT2 downregulation is driven by DNA methylation in the promoter-related CpG islands. Finally, we also shed light on the influence of GOT2 expression in immune cell infiltration, suggesting that GOT2 may be a potential prognostic marker and therapeutic target for KIRC patients.

Non-small cell lung cancer (NSCLC) is a common malignant tumor, with high morbidity and mortality. Circular RNA (circRNA) circ&#95;0003028 was reported to be upregulated in NSCLC. This study is designed to explore the role and mechanism of circ&#95;0003028 on NSCLC progression. In this work, circ&#95;0003028, microRNA-1298-5p (miR-1298-5p), and glutamic oxaloacetic transaminase 2 (GOT2) level were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The localization of circ&#95;0003028 was analyzed by subcellular fractionation assay. Cell proliferation, colony number, cell cycle progression, apoptosis, migration, invasion, and angiogenesis were measured by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, transwell, and tube formation assays. Protein levels of Beclin1, light chain 3 (LC3)-II/LC3-I, GOT2, proliferating cell nuclear antigen (PCNA) were examined by western blot assay. The binding relationship between miR-1298-5p and circ&#95;0003028 or GOT2 was predicted by circular RNA Interactome or starbase and then verified by dual-luciferase reporter, RNA Immunoprecipitation (RIP), and RNA pull-down assays. The biological role of circ&#95;0003028 on NSCLC tumor growth was examined by the xenograft tumor model in vivo . We reported that circ&#95;0003028 and GOT2 were upregulated, and miR-1298-5p was decreased in NSCLC tissues and cells. Moreover, circ&#95;0003028 knockdown curbed cell proliferative ability, migration, invasion, angiogenesis, and facilitate apoptosis and autophagy in NSCLC cells in vitro . Mechanical analysis discovered that circ&#95;0003028 regulated GOT2 expression by sponging miR-1298-5p. Circ&#95;0003028 silencing hindered the cell growth of NSCLC in vivo . Taken together, circ&#95;0003028 knockdown could suppress NSCLC progression partly by regulating the miR-1298-5p/GOT2 axis, providing an underlying therapeutic target for NSCLC.