Institut für Pathologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
Gastroenterology. 2011 Mar;140(3):1071-83. doi: 10.1053/j.gastro.2010.12.006. Epub 2010 Dec 11.
BACKGROUND & AIMS: De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC).
We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo.
In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development.
De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.
从头合成脂肪生成被认为与肿瘤发生有关。我们研究了异常脂质生物合成在人类肝细胞癌（HCC）发病机制中的作用。
我们使用实时逆转录聚合酶链反应、免疫印迹、免疫组织化学和生化测定评估了调节脂肪生成的酶在人正常肝组织和 HCC 及周围非肿瘤性肝组织中的表达。使用抑制剂和过表达实验评估了脂肪生成酶对人 HCC 细胞系的影响。体外和体内评估了原癌基因 AKT 的脂肪生成作用。
在人类肝组织样本中，从头脂肪生成从非肿瘤性肝组织逐渐诱导到 HCC。异常脂肪生成的程度与临床侵袭性、AKT-雷帕霉素靶蛋白信号通路的激活以及腺苷单磷酸激活蛋白激酶的抑制有关。在 HCC 细胞系中，AKT-雷帕霉素靶蛋白复合物 1-核糖体蛋白 S6 途径通过转录和转录后机制促进脂肪生成，包括 USP2a 去泛素酶抑制脂肪酸合酶泛素化和破坏 SREBP1 和 SREBP2 降解复合物。抑制参与脂肪生成的基因三磷酸腺苷柠檬酸裂解酶、乙酰辅酶 A 羧化酶、脂肪酸合酶、硬脂酰辅酶 A 去饱和酶 1 或固醇调节元件结合蛋白 1 可降低 HCC 细胞系和 AKT 依赖性细胞增殖的增殖和存活。在小鼠肝脏中过表达激活形式的 AKT 可诱导脂肪生成和肿瘤发展。
从头脂肪生成对 HCC 具有发病和预后意义。抑制脂肪生成信号的抑制剂，包括抑制 AKT 途径的抑制剂，可能可作为肝癌患者的治疗药物。
