近日，一项最新研究证实当变成癌细胞时肝癌细胞停止制造葡萄糖随着肝癌的发展，肿瘤细胞失去产生并释放葡萄糖到血液中的能力，一个健康的肝细胞的主要功能就是维持机体所需的血糖水平。该研究由俄亥俄州立大学综合癌症中心科学家、Arthur G. James肿瘤医院和Richard J. Solove研究所完成。
肝癌细胞缺失葡萄糖生成也即糖异生的过程，肝癌细胞由于过度表达microRNA-23A分子，造成了这种糖异生能力的缺失。保持高水平的线粒体呼吸减少导致的糖酵解可能有助于癌症细胞的生长和增殖。调查结果表明，抑制miR-23A可能扭转这一进程，并提供新的治疗肝细胞癌（HCC）。这项研究发表在Hepatology杂志。Samson Jacob表示：这项研究确定严重阻断葡萄糖的生成以及肝脏中肝细胞转化为癌细胞后释放的机制，抗肿瘤部位的miR23a可以扭转这种。
在这项研究中，Jacob和他的同事们用动物模型以及肝癌患者和肝癌细胞株研究发现：
1）糖异生途径中相关酶的水平急剧下降，伴随的是参与编码该酶的基因表达的转录因子也降低。
2）在动物模型和人原位肝癌组织中MiR-23a的表达显著上调。
3）miR-23a抑制酶葡萄糖-6-磷酸酶和转录因子PGC-1a，这两个是两种糖异生途径的重要组成部分。
4）白细胞介素6和STAT-3信号导致miR-23a的上调。
Jacob等人得出这样的结论：在肝癌组织中IL-6-STAT3介导的miR-23a激活，直接靶向针对和抑制葡萄糖-6-磷酸酶和PGC-1a能降低肝癌组织中的葡萄糖的生成。这项研究资金支持来自美国国立卫生研究院/国立癌症研究所（CA086978和DK088076）。（生物谷：Bioon.com）
编译自：Liver Cancer Cells Stop Making Glucose as They Become Cancerous
doi:10.1002/hep.25632
PMC:
PMID:
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
Bo Wang1,2, Shu-Hao Hsu1,2, Wendy Frankel3, Kalpana Ghoshal3,4,*, Samson T. Jacob1,4*
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)
