Yeh Hsi-Wen, Lee Szu-Shuo, Chang Chieh-Yu, Hu Chun-Mei, Jou Yuh-Shan
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Oncotarget. 2017 Sep 8;8(44):77734-77751. doi: 10.18632/oncotarget.20774. eCollection 2017 Sep 29.
Cellular metabolism of cancer cell is generally recognized to provide energy for facilitating tumor growth, but little is known about the aberrant metabolism in tumor progression and its prognostic value. Here, we applied integrated genomic approach to uncover the aberrant expression of metabolic enzymes in poorly-differentiated human hepatocellular carcinoma (HCC) for revealing targets against HCC malignancy. A total of 135 upregulated (22 are rate-limiting enzymes (RLEs)) and 362 down-regulated (77 are RLEs) metabolic genes were identified and associated with poor patient survival in large-cohorts of HCC patients in TCGA-LIHC and two other independent transcriptomic studies. Ten out of 22 upregulated RLEs in poorly-differentiated HCC are critical enzymes in pyrimidine metabolism pathways in association with stemness features by gene enrichment analysis and upregulated in ALDH1 stem-like HCC subpopulations. By focusing on three RLEs including TK1, TYMS and DTYMK of dTTP biosynthesis pathway, expression of 3 RLEs in well-differentiated HCC cells increased ALDH1 and spheroid stemness population but reversed by knockdown in poorly-differentiated HCC cells. Up-regulated 3 RLEs in HCC were associated with poor patient survival in multiple cohorts. Together, we identified aberrant pyrimidine pathway in poorly-differentiated HCC promotes cancer stemness served as potential theranostic target for battling HCC tumor progression.
癌细胞的细胞代谢通常被认为可为促进肿瘤生长提供能量，但对于肿瘤进展中的异常代谢及其预后价值知之甚少。在此，我们应用综合基因组方法来揭示低分化人肝细胞癌（HCC）中代谢酶的异常表达，以发现针对HCC恶性肿瘤的靶点。在TCGA-LIHC的大量HCC患者队列以及另外两项独立的转录组学研究中，共鉴定出135个上调的代谢基因（22个是限速酶（RLEs））和362个下调的代谢基因（77个是RLEs），这些基因与患者的不良生存相关。通过基因富集分析，低分化HCC中22个上调的RLEs中有10个是嘧啶代谢途径中的关键酶，与干性特征相关，并且在ALDH1干细胞样HCC亚群中上调。通过聚焦于dTTP生物合成途径的三个RLEs，即TK1、TYMS和DTYMK，在高分化HCC细胞中这3个RLEs的表达增加了ALDH1和球状体干性群体，但在低分化HCC细胞中敲低则使其逆转。HCC中上调的3个RLEs与多个队列中的患者不良生存相关。总之，我们发现低分化HCC中的异常嘧啶途径促进癌症干性，可作为对抗HCC肿瘤进展的潜在治疗诊断靶点。
