Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
Sci Rep. 2018 Jun 14;8(1):9105. doi: 10.1038/s41598-018-27358-5.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Thus, a better understanding of molecular aberrations involved in HCC pathogenesis is necessary for developing effective therapy. It is well established that cancer cells metabolize energy sources differently to rapidly generate biomass. Glucose-6-phosphate-dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate Pathway (PPP), is often activated in human malignancies to generate precursors for nucleotide and lipid synthesis. Here, we determined the clinical significance of G6PD in primary human HCC by analyzing RNA-seq and clinical data in The Cancer Genome Atlas. We found that the upregulation of G6PD correlates with higher tumor grade, increased tumor recurrence, and poor patient survival. Notably, liver-specific miR-122, which is essential for metabolic homeostasis, suppresses G6PD expression by directly interacting with its 3'UTR. Luciferase reporter assay confirmed two conserved functional miR-122 binding sites located in the 3'-UTR of G6PD. Furthermore, we show that ectopic expression of miR-122 and miR-1, a known regulator of G6PD expression coordinately repress G6PD expression in HCC cells. These miRNAs also reduced G6PD activity in HepG2 cells that express relatively high activity of this enzyme. Collectively, this study provides evidence that anti-HCC efficacy of miR122 and miR-1 could be mediated, at least in part, through inhibition of PPP by suppressing the expression of G6PD.
肝细胞癌（HCC）是全球癌症相关死亡的第二大主要原因。因此，为了开发有效的治疗方法，有必要更好地了解参与 HCC 发病机制的分子异常。已经证实癌细胞以不同的方式代谢能量来源，以快速产生生物量。葡萄糖-6-磷酸脱氢酶（G6PD）是戊糖磷酸途径（PPP）的限速酶，在人类恶性肿瘤中经常被激活，以生成核苷酸和脂质合成的前体。在这里，我们通过分析癌症基因组图谱中的 RNA-seq 和临床数据来确定 G6PD 在原发性人 HCC 中的临床意义。我们发现 G6PD 的上调与更高的肿瘤分级、肿瘤复发增加和患者生存不良相关。值得注意的是，miR-122 是代谢平衡所必需的，通过直接与其 3'UTR 相互作用来抑制 G6PD 的表达。荧光素酶报告基因测定证实了位于 G6PD 3'-UTR 中的两个保守的功能性 miR-122 结合位点。此外，我们表明 miR-122 和 miR-1 的异位表达，miR-1 是 G6PD 表达的已知调节剂，可协同抑制 HCC 细胞中的 G6PD 表达。这些 miRNA 还降低了 HepG2 细胞中 G6PD 活性，该细胞表达相对较高的这种酶活性。总之，这项研究提供了证据表明，miR122 和 miR-1 的抗 HCC 功效至少部分可以通过抑制 PPP 来介导，通过抑制 G6PD 的表达。
