Institut National de la Sante et de la Recherche Medicale, U674, Génomique fonctionnelle des tumeurs solides, Paris, France.
Hepatology. 2010 Feb;51(2):557-66. doi: 10.1002/hep.23362.
Hepatocellular adenomas (HCAs) are benign liver tumors that usually develop in women who are taking oral contraceptives. Among these tumors, biallelic inactivating mutations of the hepatocyte nuclear factor 1alpha (HNF1A) transcription factor have been frequently identified and in rare cases of hepatocellular carcinomas developed in noncirrhotic liver. Because HNF1A meets the genetic criteria of a tumor suppressor gene, we aimed to elucidate the tumorigenic mechanisms related to HNF1alpha inactivation in hepatocytes. We searched for signaling pathways aberrantly activated in human HNF1A-mutated HCA (H-HCA) using a genome-wide transcriptome analysis comparing five H-HCA with four normal livers. We validated the main pathways by quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting in a large series of samples. Then, we assessed the role of HNF1alpha in the observed deregulations in hepatocellular cell models (HepG2 and Hep3B) by silencing its endogenous expression using small interfering RNA. Along with the previously described induction of glycolysis and lipogenesis, H-HCA also displayed overexpression of several genes encoding growth factor receptors, components of the translation machinery, cell cycle, and angiogenesis regulators, with, in particular, activation of the mammalian target of rapamycin (mTOR) pathway. Moreover, estradiol detoxification activities were shut down, suggesting a hypersensitivity of H-HCA to estrogenic stimulation. In the cell model, inhibition of HNF1alpha recapitulated most of these identified transcriptional deregulations, demonstrating that they were related to HNF1alpha inhibition.
H-HCA showed a combination of alterations related to HNF1alpha inactivation that may cooperate to promote tumor development. Interestingly, mTOR appears as a potential new attractive therapeutic target for treatment of this group of HCAs.
肝细胞腺瘤 (HCA) 是良性肝肿瘤，通常发生在正在服用口服避孕药的女性中。在这些肿瘤中，肝细胞核因子 1alpha (HNF1A) 转录因子的双等位基因失活突变经常被发现，并且在极少数非肝硬化肝脏中发生的肝细胞癌病例中也发现了这种突变。由于 HNF1A 符合肿瘤抑制基因的遗传标准，我们旨在阐明与肝细胞中 HNF1alpha 失活相关的肿瘤发生机制。我们使用全基因组转录组分析比较了五例 H-HCA 与四例正常肝脏，寻找在人类 HNF1A 突变 HCA (H-HCA) 中异常激活的信号通路。我们通过定量逆转录聚合酶链反应 (RT-PCR) 和 Western blot 在大量样本中验证了主要途径。然后，我们通过使用小干扰 RNA 沉默其内源性表达，在肝细胞细胞模型 (HepG2 和 Hep3B) 中评估 HNF1alpha 在观察到的失调中的作用。除了先前描述的糖酵解和脂肪生成诱导外，H-HCA 还显示出多个编码生长因子受体、翻译机制成分、细胞周期和血管生成调节剂的基因的过表达，特别是哺乳动物雷帕霉素靶蛋白 (mTOR) 途径的激活。此外，雌激素解毒活性被关闭，表明 H-HCA 对雌激素刺激的敏感性增加。在细胞模型中，抑制 HNF1alpha 重现了大多数这些鉴定的转录失调，表明它们与 HNF1alpha 抑制有关。
H-HCA 显示出与 HNF1alpha 失活相关的改变组合，这些改变可能共同促进肿瘤的发展。有趣的是，mTOR 似乎是治疗这组 HCA 的一个有吸引力的新治疗靶点。
