Downregulation of Methionine Cycle Genes MAT1A and GNMT Enriches Protein-Associated Translation Process and Worsens Hepatocellular Carcinoma Prognosis

Chen, Po‐Ming; Tsai, Cheng-Hsueh; Huang, Chieh-Chen; Hwang, Hau-Hsuan; Lǐ, Jiànróng; Liu, Chun-Chi; Ko, Hsin-An; Chiang, En‐Pei Isabel

doi:10.3390/ijms23010481

Cited by 10 publications

(11 citation statements)

References 55 publications

(74 reference statements)

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“…MAT in the liver and extrahepatic tissues is the product of two genes, MAT1A and MAT2A, respectively [ 46 ]. MAT1A is a strong prognostic indicator for HCC, and data from HCC patients with reduced MAT1A suggest that the RETOME pathway may be involved in HCC tumorigenesis [ 47 ]. However, the remaining genes are equally poorly studied in HCC, which reminds us of the gaps in the field of HB-related hub gene research.…”

Section: Discussionmentioning

confidence: 99%

Exploration of Potential Biomarkers and Immune Landscape for Hepatoblastoma: Evidence from Machine Learning Algorithm

Zhou

Gao

2022

Evidence-Based Complementary and Alternative Medicine

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This study aimed to investigate the immune landscape in hepatoblastoma (HB) based on deconvolution methods and identify a biomarkers panel for diagnosis based on a machine learning algorithm. Firstly, we identified 277 differentially expressed genes (DEGs) and differentiated and functionally identified the modules in DEGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and GO (gene ontology) were used to annotate these DEGs, and the results suggested that the occurrence of HB was related to DNA adducts, bile secretion, and metabolism of xenobiotics by cytochrome P450. We selected the top 10 genes for our final diagnostic panel based on the random forest tree method. Interestingly, TNFRSF19 and TOP2A were significantly down-regulated in normal samples, while other genes (TRIB1, MAT1A, SAA2-SAA4, NAT2, HABP2, CYP2CB, APOF, and CFHR3) were significantly down-regulated in HB samples. Finally, we constructed a neural network model based on the above hub genes for diagnosis. After cross-validation, the area under the ROC curve was close to 1 (AUC = 0.972), and the AUC of the validation set was 0.870. In addition, the results of single-sample gene-set enrichment analysis (ssGSEA) and deconvolution methods revealed a more active immune responses in the HB tissue. In conclusion, we have developed a robust biomarkers panel for HB patients.

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Section: Discussionmentioning

confidence: 99%

Exploration of Potential Biomarkers and Immune Landscape for Hepatoblastoma: Evidence from Machine Learning Algorithm

Zhou

Gao

2022

Evidence-Based Complementary and Alternative Medicine

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“…20Q1), shRNA screening data (Achilles + DRIVE + Marcotte, DEMETER2), were obtained from the DepMap portal (https://depmap.org/portal/) [17] . Venn diagrams were drawn [13] from DNM1 correlated genes in TCGA, and shDNM1 database, and sgRNA database of HCC cell lines via LinkedOmics.…”

Section: Cell Line Datamentioning

confidence: 99%

“…The common genes obtained from the Venn diagrams were then examined with their potential prognostic role in LIHC using GEPIA2 (http://gepia2.cancer-pku.cn/#index, accessed on 1 June 2022) [13] . GEPIA2 performs survival analyses based on expression levels [34].…”

Section: Survival Analysismentioning

confidence: 99%

“…Utilizing RNA-seq data from the Cancer Genome Atlas (TCGA), we previously identi ed novel biomarkers for human HCC and proposed a potential novel mechanism that may confer poor prognosis for HCC [13 https://www.google.com/url?q = https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F35008908%2F&sa = D&sntz = 1&usg = AOvVaw1uw34DFz_NEh64MAlZb5Ut ] . We have also proposed an approach for successfully identifying novel potential therapeutic targets in human HCC with mutated p53 [14] .…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic role of a long-term high-fat diet-induced DNM1 in hepatocellular carcinoma

Chou

Chen

et al. 2022

Preprint

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Background:Dietary patterns play important roles in the occurrence and development of numerous human cancers including hepatocellular carcinoma (HCC). In this study, we explored and investigated the potential tumor-promoting genes in mice received high-fat diet (HFD).Methods:We initiated the process by analyzing liver gene expression profile of mice received HFD downloaded from Gene Expression Omnibus (GEO No. GSE108169). Differentially overexpressed genes were assembled and analyzed for the clinical prognosis and biological functions in human cancer databases. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) were screened by The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), Human Protein Atlas (HPA), LinkedOmics analysis, TIMER2.0, and Q-omics analysis. Survival analyses were performed to examine the significance for the newly identified biomarkers for HCC.Results: Among the top 10 overexpressing genes in HFD-fed mice liver, a neuron-specific protein, dynamin 1 (DNM1) was identified as a significant prognostic predictor for poor HCC survival examined by UALCAN. Using HPA, we discovered that normal liver tissue does not express DNM1 protein whereas it was found in 30% HCC, and abundant DNM1 protein was detected in HCC cell cytoplasm and membrane. DNM1 gene expression is positively correlated some genes enhanced epithelial-mesenchymal transition (EMT), proliferation, and neural transduction signaling, and its negatively correlated genes enhanced certain metabolism and host-defense ability. Furthermore, positive correlations between DNM1 and CD8 T cells, regulatory T cells (Treg), B cells, macrophages, and natural killer (NK) cells were observed, indicating possible associations between DNM1 and infiltrating immune cells. We then identified a common gene, TAR (HIV-1) RNA Binding Protein 1 (TARBP1) by overlapping the differentially downregulated genes of HCC cells with single-guide DNM1 (sgDNM1), short-hairpin DNM1 (shDNM1), and the TCGA DNM1 correlated genes that also correlated significantly with poor overall survival and disease-free survival of HCC. ConclusionsThis is the first study proposing a role of the HFD-induced hepatic DNM1 over-expression might affect tumor development and immune microenvironment in human HCC. The discovery of this novel marker can add insights into the link of high fat diet and HCC, and provide potential therapeutic target pathways for treating HCC. We suggest DNM1 be a potential prognostic biomarker and therapeutic target for HCV-positive human HCC.

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“…Folate-mediated 1C metabolism is a major target of many therapies in human diseases [ 16 , 17 , 18 , 19 ]. Although several lines of evidence implied that ketogenesis may impact 1C metabolism, the impacts of ketogenesis and ketone bodies on 1C metabolic kinetics have not been fully illustrated.…”

Section: Introductionmentioning

confidence: 99%

Ketogenic Diet Consumption Inhibited Mitochondrial One-Carbon Metabolism

Hsu

Liou

Tang

et al. 2022

IJMS

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Given the popularity of ketogenic diets, their potential long-term consequences deserve to be more carefully monitored. Mitochondrially derived formate has a critical role in mammalian one-carbon (1C) metabolism and development. The glycine cleavage system (GCS) accounts for another substantial source for mitochondrially derived 1C units. Objective: We investigated how the ketogenic state modulates mitochondrial formate generation and partitioning of 1C metabolic fluxes. Design: HepG2 cells treated with physiological doses (1 mM and 10 mM) of β-hydroxybutyrate (βHB) were utilized as the in vitro ketogenic model. Eight-week male C57BL/6JNarl mice received either a medium-chain fatty-acid-enriched ketogenic diet (MCT-KD) or a control diet AIN 93M for 8 weeks. Stable isotopic labeling experiments were conducted. Results and Conclusions: MCT-KD is effective in weight and fat loss. Deoxythymidine (dTMP) synthesis from the mitochondrial GCS-derived formate was significantly suppressed by βHB and consumption of MCT-KD. Consistently, plasma formate concentrations, as well as the metabolic fluxes from serine and glycine, were suppressed by MCT-KD. MCT-KD also decreased the fractional contribution of mitochondrially derived formate in methionine synthesis from serine. With the worldwide application, people and medical professionals should be more aware of the potential metabolic perturbations when practicing a long-term ketogenic diet.

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Downregulation of Methionine Cycle Genes MAT1A and GNMT Enriches Protein-Associated Translation Process and Worsens Hepatocellular Carcinoma Prognosis

Cited by 10 publications

References 55 publications

Exploration of Potential Biomarkers and Immune Landscape for Hepatoblastoma: Evidence from Machine Learning Algorithm

Exploration of Potential Biomarkers and Immune Landscape for Hepatoblastoma: Evidence from Machine Learning Algorithm

Oncogenic role of a long-term high-fat diet-induced DNM1 in hepatocellular carcinoma

Ketogenic Diet Consumption Inhibited Mitochondrial One-Carbon Metabolism

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