Hepatology：肝癌细胞Warburg效应有望逆转

研究人员发现随着肝癌的发展，肿瘤细胞丧失了生产葡萄糖并将其释放到血液中的能力，这是由microRNA-23a分子的过表达造成的。而抑制miR-23a可能逆转这一过程，这为治疗肝细胞癌 (HCC)带来了新希望。文章发表在Hepatology杂志上。

　　

生物通报道：俄亥俄州州立大学综合癌症中心OSUCCC的科学家发现，随着肝癌的发展，肿瘤细胞丧失了生产葡萄糖并将其释放到血液中的能力，这是健康肝细胞维持机体所需血糖水平的关键性功能。

癌细胞中有氧糖酵解的水平非常高，这一现象也被称为Warburg效应，人们在这一领域的研究已经取得了相当大的进展。OSUCCC的研究人员的这项研究是为了检测肝癌发生中的糖异质通路是否被调整，从而引起体内葡糖糖平衡的改变。

研究人员发现，microRNA-23a分子的过表达造成肝癌细胞产生葡萄糖的能力丧失，这种产生葡萄糖的过程也被称为糖异生作用gluconeogenesis。这种改变能在线粒体呼吸显著降低的条件下，帮助维持高水平的糖酵解来促进癌细胞生长和繁殖。

研究显示抑制miR-23a可能逆转这一过程，这为治疗最普遍的肝癌类型肝细胞癌 (HCC)带来了新希望。文章发表在Hepatology杂志上。

“我们的研究发现了一个重要的机制，当肝细胞转化为癌细胞时，其葡萄糖的生成和释放严重受阻，”研究的主要研究者，分子和细胞生化教授Samson Jacob博士说。“可以想见，将anti-miR23a的药物运送到肿瘤位点可能可以逆转这一过程。”

Jacob及其同事在HCC动物模型、患者原发肿瘤样本和HCC细胞系中进行了研究。这种小鼠模型能够模拟人类肝癌发生的不同阶段。

研究发现葡萄糖异生通路中酶的水平显著降低，涉及这些酶编码基因表达的转录因子也一同减少。基因G6pc、Pepck和Fbp1分别编码糖异生作用中的关键酶葡萄糖-6-磷酸酶、磷酸烯醇式丙酮酸羧激酶和果糖-1,6-磷酸酶，研究显示这些基因的表达显著降低。在HCC小鼠模型中发现转录因子Pgc-1α的表达也一同降低。与相应的癌周组织相比，这些基因的mRNA水平降低了80%。

研究显示，动物模型和人原发HCC中miR-23a的表达显著上调。miR-23a抑制了糖异生通路中的两个重要分子，葡萄糖-6-磷酸酶和转录因子PGC-1a。而白介素-6和Stat-3的信号传导引起miR-23a上调。

基于上述数据，研究人员总结道，在HCC中IL6-Stat3介导的miR-23a激活严重抑制了糖异生作用，miR-23a直接靶标并抑制葡萄糖-6-磷酸酶和PGC-1a，导致葡萄糖产量减少。

研究人员强调，由于葡萄糖-6-磷酸酶是干细胞将糖原glycogen（葡萄糖的储存形式）转化为葡萄糖所必须的酶，这种酶的抑制可能阻断了肝脏产生葡萄糖的所有通路。

生物通编辑：叶予

生物通推荐原文摘要：

Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating Glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha

Considerable effort has been made in elucidating the mechanism and functional significance of high levels of aerobic glycolysis in cancer cells, commonly referred to as the Warburg effect. Here we investigated whether the gluconeogenic pathway is significantly modulated in hepatocarcinogenesis, resulting in altered levels of glucose homeostasis. To test this possibility, we used a mouse model (mice fed a choline-deficient diet) that develops nonalcoholic steatohepatitis (NASH), preneoplastic nodules, and hepatocellular carcinoma (HCC), along with human primary HCCs and HCC cells. This study demonstrated marked reduction in the expressions of G6pc, Pepck, and Fbp1 encoding the key gluconeogenic enzymes glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, fructose-1,6-phosphatase, respectively, and the transcription factor Pgc-1α in HCCs developed in the mouse model that correlated with reduction in serum glucose in tumor-bearing mice. The messenger RNA (mRNA) levels of these genes were also reduced by ≈80% in the majority of primary human HCCs compared with matching peritumoral livers. The expression of microRNA (miR)-23a, a candidate miR targeting PGC-1α and G6PC, was up-regulated in the mouse liver tumors as well as in primary human HCC. We confirmed PGC-1α and G6PC as direct targets of miR-23a and their expressions negatively correlated with miR-23a expression in human HCCs. G6PC expression also correlated with tumor grade in human primary HCCs. Finally, this study showed that the activation of interleukin (IL)-6-Stat3 signaling caused the up-regulation of miR-23a expression in HCC. Conclusion: Based on these data, we conclude that gluconeogenesis is severely compromised in HCC by IL6-Stat3-mediated activation of miR-23a, which directly targets PGC-1α and G6PC, leading to decreased glucose production. (HEPATOLOGY 2012;56:186–197)