Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans.
Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans.
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DOI：
10.1016/j.jhep.2015.10.004
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发表时间：
2016-02
影响因子：
25.7
通讯作者：
Calvisi DF
中科院分区：
文献类型：
--
作者：
Li L;Pilo GM;Li X;Cigliano A;Latte G;Che L;Joseph C;Mela M;Wang C;Jiang L;Ribback S;Simile MM;Pascale RM;Dombrowski F;Evert M;Semenkovich CF;Chen X;Calvisi DF
越来越多的证据凸显了异常脂肪生成在人类肝细胞癌（HCC）中的关键作用。在此，我们研究了脂肪酸合酶（FASN）——从头脂肪生成的主要调节因子——在小鼠肝脏中的致癌潜力。
通过水动力注射，FASN在小鼠肝脏中单独或与激活的N - Ras、c - Met或SCD1联合过表达。在条件性FASN或Rictor基因敲除小鼠的肝脏中，通过水动力注射使激活的AKT过表达。在人类肝癌细胞系中，通过特异性小干扰RNA抑制FASN。
FASN单独或与其他与肝癌发生相关的基因联合过表达，均未诱导肝脏组织学改变。相反，FASN的基因敲除完全抑制了AKT过表达小鼠的肝癌发生。在人类HCC细胞系中，FASN失活导致细胞增殖下降和细胞凋亡增加，同时伴随着磷酸化/激活的AKT水平降低，这一事件受哺乳动物雷帕霉素靶蛋白复合物2（mTORC2）调控。FASN失活后AKT磷酸化/激活的下调与mTORC2的主要成分——雷帕霉素不敏感的mTOR伴侣蛋白（Rictor）在转录后水平的强烈抑制有关。最后，Rictor的基因敲除削弱了小鼠中AKT驱动的肝癌发生。
FASN本身在小鼠肝脏中并不致癌，但对于AKT驱动的肝癌发生是必需的。FASN的药物阻断可能对以AKT通路激活为特征的人类HCC的治疗非常有用。
Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver. FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA. Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice. FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.