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A Novel Purine and Uric Metabolism Signature Predicting the Prognosis of Hepatocellular Carcinoma

ABSTRACT: Background: Hepatocellular carcinoma (HCC) is regarded as one of the most common cancers in the world with a poor prognosis. Patients with HCC often have abnormal purine and uric acid metabolism, but their relationship with prognosis is unclear. Methods: Here, we collected the data of peripheral blood uric acid and clinical data in 50 patients with HCC and analyzed the relationship with prognosis. At the same time, the transcriptome sequencing data of TCGA and GEO databases were collected to analyze the changes in purine metabolic pathway activity and construct a prognosis prediction model. Based on the prognosis prediction model related to purine metabolism, we further looked for the differences in the immune microenvironment and molecular level and provided possible drug targets. Results: We found that the level of serum uric acid was positively correlated with the prognosis of HCC. At the same time, purine metabolism and purine biosynthesis pathway activities were significantly activated in patients with a poor prognosis of HCC. The prognosis prediction model of HCC based on purine metabolism and purine biosynthesis pathway can accurately evaluate the prognosis of patients with HCC. Meanwhile, we found that there were significant changes in tumor immune infiltration microenvironment and biological function at the molecular level in patients with over-activation of purine metabolism and purine biosynthesis pathway. In addition, we found that uric acid level was positively correlated with peripheral blood leukocytes in HCC patients. Conclusion: In this study, we found that the level of peripheral blood uric acid in patients with HCC is correlated with their prognosis. The prognosis of patients with HCC can be accurately predicted through the metabolic process of uric acid and purine.

SUBMITTER: Yang S

PROVIDER: S-EPMC9315342 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Globally, hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors. Studies have shown that alterations in the tumor immune microenvironment (TIME) play a significant role in the pathogenesis and progression of HCC, and notably, lipid metabolism has been shown to regulate TIME. Therefore, in predicting the prognosis and efficacy of immunotherapy in patients with HCC, lipid metabolism-related prognostic factors are highly relevant. mRNA expression data of HCC were obtained from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and gene expression omnibus (GEO) databases. and lipid metabolism-related genes were also obtained from the GSEA databases. Least absolute shrinkage and selection operator regression analysis, univariate and multivariate Cox proportional hazards analysis were used to explore lipid metabolism-related prognostic genes and further construct a prognostic signature in the training set, ICGC and GSE54236 were used to validate the accuracy of the signature. qRT-PCR was used to detect the mRNA levels of lipid metabolism-related prognostic genes in HCC tissues and their paired adjacent tissues. Nile red staining was used to demonstrate lipid content in HCC tissues. Immunofluores-cence and ELISA were used to detect immune cells and immune responses in HCC tissues and serum. Six lipid metabolism-related genes (ADH1C, APEX1, ME1, S100A10, ACACA and CYP2C9) were identified as independent prognostic factors, which were used for risk model construction for HCC patients. The areas under the 1-, 2-, and 3-year ROC curves for the TCGA cohort were 0.758, 0.701 and 0.671, respectively. Compared with paired paracancerous tissues, qRT-PCR revealed that APEX1, ME1, S100A10 and ACACA were up-regulated in HCC tissues, whereas ADH1C and CYP2C9 were down-regulated in HCC tissues. Nile red staining indicated that this study showed that both the HCC tissue and serum of patients in the high-risk group exhibited lipid accumulation. Our identified prognostic model comprising six lipid metabolism-related genes could provide survival prediction. Moreover, HCC drug therapy target selection and molecular marker research can be guided by our predictive model.

Project description:BackgroundHepatocellular carcinoma (HCC) is a highly lethal disease. Effective prognostic tools to guide clinical decision-making for HCC patients are lacking.ObjectiveWe aimed to establish a robust prognostic model based on differentially expressed genes (DEGs) in HCC.MethodsUsing datasets from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the International Genome Consortium (ICGC), DEGs between HCC tissues and adjacent normal tissues were identified. Using TCGA dataset as the training cohort, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analyses to identify a multi-gene expression signature. Proportional hazard assumptions and multicollinearity among covariates were evaluated while building the model. The ICGC cohort was used for validation. The Pearson test was used to evaluate the correlation between tumor mutational burden and risk score. Through single-sample gene set enrichment analysis, we investigated the role of signature genes in the HCC microenvironment.ResultsA total of 274 DEGs were identified, and a six-DEG prognostic model was developed. Patients were stratified into low- or high-risk groups based on risk scoring by the model. Kaplan-Meier analysis revealed significant differences in overall survival and progression-free interval. Through univariate and multivariate Cox analyses, the model proved to be an independent prognostic factor compared to other clinic-pathological parameters. Time-dependent receiver operating characteristic curve analysis revealed satisfactory prediction of overall survival, but not progression-free interval. Functional enrichment analysis showed that cancer-related pathways were enriched, while immune infiltration analyses differed between the two risk groups. The risk score did not correlate with levels of PD-1, PD-L1, CTLA4, or tumor mutational burden.ConclusionsWe propose a six-gene expression signature that could help to determine HCC patient prognosis. These genes may serve as biomarkers in HCC and support personalized disease management.

Project description:Background: Pyroptosis, a newly discovered type of programmed cell death, has both anti-tumor and tumor-promoting effects on carcinogenesis. In hepatocellular carcinoma (HCC), however, the associations between pyroptosis-regulated genes and prognosis, immune microenvironment, and immunotherapy response remain unclear. Samples and methods: Sequencing data were collected from The Cancer Genome Atlas database, The International Cancer Genome Consortium (ICGC), and The Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). First, we investigated the expression levels and copy number variations (CNVs) of 56 pyroptosis genes in HCC and pan-cancer. Next, we identified 614 genes related to 56 pyroptosis-associated genes at the expression, mutation, and CNVs levels. Pathway enrichment analysis of 614 genes in the Hallmark, KEGG, and Reactome databases yielded a total of 253 significant signaling pathways. The pyroptosis-regulated genes (PRGs) comprised 108 genes that were derived from the top 20 signaling pathways, of which 57 genes had prognostic value in HCC. The least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for PRGs with prognostic values. Ultimately, we constructed a risk score model with seven PRGs to predict HCC prognosis and validated its predictive value in three independent HCC cohorts. Risk scores were used to illustrate receiver operating characteristic (ROC) curves predicting 1, 3, and 5-years overall survival (OS). Single-sample gene set enrichment analysis (ssGSEA), was performed to study 28 types of immune cells infiltrated in HCC. The relationship between the risk signature and six immune checkpoint genes and immunotherapy was analyzed. Results: A total of seven PRGs were obtained following multiple screening steps. The risk score model containing seven PRGs was found to correlate significantly with the HCC prognosis of the training group. In addition, we validated the risk score model in two additional HCC cohorts. The risk score significantly correlated with infiltrating immune cells (i. e. CD4+ T cells, etc.), ICB key molecules (i. e. HAVCR2, etc.), and ICB response. Conclusions: This study demonstrated a vital role of PRGs in predicting the prognosis and immunotherapy response of HCC patients. The risk model could pave the way for drugs targeting pyroptosis and immune checkpoints in HCC.

Project description:Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its prognosis remains unsatisfactory. The identification of new and effective markers is helpful for better predicting the prognosis of patients with HCC and for conducting individualized management. The oncogene Aurora kinase A (AURKA) is involved in a variety of tumors; however, its role in liver cancer is poorly understood. The aim of this study was to establish AURKA-related gene signatures for predicting the prognosis of patients with HCC. Methods: We first analyzed the expression of AURKA in liver cancer and its prognostic significance in different data sets. Subsequently, we selected genes with prognostic value related to AURKA and constructed a gene signature based on them. The predictive ability of the gene signature was tested using the HCC cohort development and verification data sets. A nomogram was constructed by integrating the risk score and clinicopathological characteristics. Finally, the influence of the gene signature on the immune microenvironment in HCC was comprehensively analyzed. Results: We found that AURKA was highly expressed in HCC, and it exhibited prognostic value. We selected eight AURKA-related genes with prognostic value through the protein-protein interaction network and successfully constructed a gene signature. The nine-gene signature could effectively stratify the risk of patients with HCC and demonstrated a good ability in predicting survival. The nomogram showed good discrimination and consistency of risk scores. In addition, the high-risk group showed a higher percentage of immune cell infiltration (i.e., macrophages, myeloid dendritic cells, neutrophils, and CD4+T cells). Moreover, the immune checkpoints SIGLEC15, TIGIT, CD274, HAVCR2, and PDCD1LG2 were also higher in the high-risk group versus the low-risk group. Conclusions: This gene signature may be useful prognostic markers and therapeutic targets in patients with HCC.

Project description:Hepatocellular carcinoma (HCC), the most frequently occurring type of cancer, is strongly associated with metabolic disorders. In this study, we aimed to characterize the metabolic features of HCC and normal tissue adjacent to the tumor (NAT). By using samples from The Cancer Genome Atlas (TCGA) liver cancer cohort and comparing 85 well-defined metabolic pathways obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG), 70 and 7 pathways were found to be significantly downregulated and upregulated, respectively, in HCC, revealing that tumor tissue lacks the ability to maintain normal metabolic levels. Through unsupervised hierarchical clustering of metabolic pathways, we found that metabolic heterogeneity correlated with prognosis in HCC samples. Thus, using the least absolute shrinkage and selection operator (LASSO) and filtering independent prognostic genes by the Cox proportional hazards model, a six-gene-based metabolic score model was constructed to enable HCC classification. This model showed that high expression of LDHA and CHAC2 was associated with an unfavorable prognosis but that high ADPGK, GOT2, MTHFS, and FTCD expression was associated with a favorable prognosis. Patients with higher metabolic scores had poor prognoses (p value = 2.19e-11, hazard ratio = 3.767, 95% CI = 2.555-5.555). By associating the score level with clinical features and genomic alterations, it was found that NAT had the lowest metabolic score and HCC with tumor stage III/IV the highest. qRT‒PCR results for HCC patients also revealed that tumor samples had higher score levels than NAT. Regarding genetic alterations, patients with higher metabolic scores had more TP53 gene mutations than those with lower metabolic scores (p value = 8.383e-05). Validation of this metabolic score model was performed using another two independent HCC cohorts from the Gene Expression Omnibus (GEO) repository and other TCGA datasets and achieved good performance, suggesting that this model may be used as a reliable tool for predicting the prognosis of HCC patients.

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A Novel Purine and Uric Metabolism Signature Predicting the Prognosis of Hepatocellular Carcinoma

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