Identification of Key Genes in Purine Metabolism as Prognostic Biomarker for Hepatocellular Carcinoma.
Identification of Key Genes in Purine Metabolism as Prognostic Biomarker for Hepatocellular Carcinoma.
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DOI：
10.3389/fonc.2020.583053
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发表时间：
2020
影响因子：
4.7
通讯作者：
Lu GD
中科院分区：
文献类型：
--
作者：
Su WJ;Lu PZ;Wu Y;Kalpana K;Yang CK;Lu GD
嘌呤代谢失调通过提供核苷酸构件和辅因子对快速生长的肿瘤细胞至关重要。重要的是，嘌呤抗代谢物属于最早开发的抗癌药物，并且今天仍在临床上使用。然而，这些抗代谢物可以抑制非肿瘤细胞并引起不期望的副作用。由于肝脏中嘌呤浓度最高，因此肝癌是研究嘌呤代谢失调的重要节点的良好模型，以更好地选择患者和精确的癌症治疗。通过使用TCGA的训练数据集，我们研究了肝细胞癌（HCC）中嘌呤代谢途径（hsa00230）的差异表达基因（DEG），并确定其与患者生存的临床相关性。通过Lasso惩罚考克斯回归分析建立预后模型，然后使用另一个ICGC测试数据集通过考克斯回归分析、分层分析和列线图等多重检查进行验证。我们接下来在体外使用关键酶的化学药物处理HCC细胞以确定HCC中的靶向候选物。DEG分析发现嘌呤代谢途径中有43个上调基因和2个下调基因。其中，10个与HCC患者生存率显著相关。建立了包括PPAT、DCK、ATIC、IMPDH1、RRM2五个基因的预后相关模型，并使用ICGC检验数据集进行了验证。多因素考克斯回归分析发现，预后风险模型（HR = 4.703或3.977）和TNM分期（HR = 2.303或2.957）分别独立预测两组数据中HCC患者的生存率。通过比较10对肝癌组织和邻近的非肿瘤组织，进一步验证了这5个基因的上调。体外细胞实验进一步证实，IMPDH 1的抑制显著抑制HCC细胞增殖。总之，这项研究表明，嘌呤代谢失调，在肝癌。基于这5个嘌呤代谢基因的预后基因相关模型对肝癌预后的预测和患者的选择有一定的参考价值。此外，去调控的基因可被特异性抑制剂靶向。
Deregulated 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. By 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. The 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. In 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.
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影响因子：
--
作者：
Barfeld SJ;Fazli L;Persson M;Marjavaara L;Urbanucci A;Kaukoniemi KM;Rennie PS;Ceder Y;Chabes A;Visakorpi T;Mills IG
通讯作者：
Mills IG
细胞外嘌呤，嘌呤能受体和肿瘤生长。
影响因子：
8
作者：
Di Virgilio F;Adinolfi E
通讯作者：
Adinolfi E
对嘌呤代谢调节的新观点：嘌呤体。
影响因子：
13.8
作者：
Pedley AM;Benkovic SJ
通讯作者：
Benkovic SJ
影响因子：
2.8
作者：
Hu, Shu Fang;Lin, Xia;Jin, Li
通讯作者：
Jin, Li
双功能酶ATIC通过调节AMPK-mTOR-S6 K1信号促进肝细胞癌的增殖
DOI：
10.1186/s12964-017-0208-8
发表时间：
2017-12-16
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Li M;Jin C;Xu M;Zhou L;Li D;Yin Y
通讯作者：
Yin Y