Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, China.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Gut. 2020 Jan;69(1):177-186. doi: 10.1136/gutjnl-2018-317581. Epub 2019 Apr 6.
Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).
We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and knockout mice. Human HCC cell lines were used for in vitro studies.
Ablation of significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 () completely prevented sgPten/c-Met-driven hepatocarcinogenesis in knockout mice. Similarly, silencing of resulted in increased activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase ( expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.
Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.
脂肪酸（FA）从头合成和胆固醇生物合成的增加已在许多肿瘤类型中得到独立描述，包括肝细胞癌（HCC）。
我们使用肝特异性敲除小鼠研究了脂肪酸合酶（Fasn）介导的从头 FA 合成在由 Pten 缺失和 c-Met 过表达诱导的小鼠 HCC 模型中的功能贡献。进行表达谱和脂质组学分析分别以特征化 sgPten/c-Met HCC 的全基因表达和脂质谱来自野生型和 敲除小鼠。使用人 HCC 细胞系进行体外研究。
敲除显着延迟了 sgPten/c-Met 驱动的肝癌发生在小鼠中。然而，最终 HCC 出现在 敲除小鼠中。比较基因组学和脂质组学分析揭示了胆固醇生物合成相关基因的上调，以及甘油三酯水平降低和胆固醇酯增加，在这些小鼠的 HCC 中。在机制上， 缺失促进了固醇调节元件结合蛋白 2（Srebp2）的核定位和激活，从而触发了胆固醇生成。通过 Srebp2 的显性负形式（）阻断胆固醇合成完全阻止了 sgPten/c-Met 驱动的肝癌发生在 敲除小鼠中。同样， 沉默导致增加 激活和羟甲基戊二酰辅酶 A（HMG-CoA）还原酶（在人 HCC 细胞系中表达。同时抑制 Fasn 介导的 FA 合成和 HMGCR 驱动的胆固醇生成对 HCC 细胞在培养中的生长极为有害。
我们的研究揭示了肝癌发生中异常脂发生和胆固醇生物合成途径之间的新的功能串扰，其同时抑制可能代表 HCC 的治疗选择。
