Abstract
BackgroundDeregulated purine metabolism is critical for fast-growing tumor cells by providing nucleotide building blocks and cofactors. Importantly, purine antimetabolites belong to the earliest developed anticancer drugs and are still prescribed in clinics today. However, these antimetabolites can inhibit non-tumor cells and cause undesired side effects. As liver has the highest concentration of purines, it makes liver cancer a good model to study important nodes of dysregulated purine metabolism for better patient selection and precisive cancer treatment.MethodsBy using a training dataset from TCGA, we investigated the differentially expressed genes (DEG) of purine metabolism pathway (hsa00230) in hepatocellular carcinoma (HCC) and determined their clinical correlations to patient survival. A prognosis model was established by Lasso‐penalized Cox regression analysis, and then validated through multiple examinations including Cox regression analysis, stratified analysis, and nomogram using another ICGC test dataset. We next treated HCC cells using chemical drugs of the key enzymes in vitro to determine targetable candidates in HCC.ResultsThe DEG analysis found 43 up-regulated and 2 down-regulated genes in the purine metabolism pathway. Among them, 10 were markedly associated with HCC patient survival. A prognostic correlation model including five genes (PPAT, DCK, ATIC, IMPDH1, RRM2) was established and then validated using the ICGC test dataset. Multivariate Cox regression analysis found that both prognostic risk model (HR = 4.703 or 3.977) and TNM stage (HR = 2.303 or 2.957) independently predicted HCC patient survival in the two datasets respectively. The up-regulations of the five genes were further validated by comparing between 10 pairs of HCC tissues and neighboring non-tumor tissues. In vitro cellular experiments further confirmed that inhibition of IMPDH1 significantly repressed HCC cell proliferation.ConclusionIn summary, this study suggests that purine metabolism is deregulated in HCC. The prognostic gene correlation model based on the five purine metabolic genes may be useful in predicting HCC prognosis and patient selection. Moreover, the deregulated genes are targetable by specific inhibitors.
Highlights
It is central for all living organisms to uptake nutrients and execute metabolism
To identify the differentially expressed genes of purine metabolism pathway (KEGG hsa00230) in HCC, we compared the mRNA expressions of 374 cases of HCC with those of 50 normal liver tissues in the TCGA-LIHC dataset
The results demonstrate that these five purine metabolic genes are all up-regulated in HCC (Figure 8A), which are consistent with the results by the bioinformatics analyses (Figure 1C)
Summary
It is central for all living organisms to uptake nutrients and execute metabolism. As one of the most abundant metabolic products, purines are essential for life because they provide building blocks (adenine and guanine) of DNA and RNA [1, 2]. Purines are significant components of several important biomolecules including ATP, GTP, cAMP, NADH, and coenzyme A These biomolecules actively participate in energy production, cellular signaling pathways, redox metabolism, and fatty acid synthesis. Rapid proliferating cells and tumor cells have higher demands of purines which are mainly fulfilled through up-regulation of purine de novo biosynthesis pathway. Several enzymes in this pathway further form purinosome, a dynamic multienzyme complex, to facilitate purine metabolic flux [4]. Purine antimetabolites belong to the earliest developed anticancer drugs and are still prescribed in clinics today These antimetabolites can inhibit non-tumor cells and cause undesired side effects. As liver has the highest concentration of purines, it makes liver cancer a good model to study important nodes of dysregulated purine metabolism for better patient selection and precisive cancer treatment
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