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SCD1 表达对于 AKT 和 Ras 癌基因在小鼠中诱导的肝癌发生是可有可无的。

SCD1 Expression is dispensable for hepatocarcinogenesis induced by AKT and Ras oncogenes in mice.

机构信息

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America ; School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

出版信息

PLoS One. 2013 Sep 19;8(9):e75104. doi: 10.1371/journal.pone.0075104. eCollection 2013.

Abstract

Increased de novo lipogenesis is one of the major metabolic events in cancer. In human hepatocellular carcinoma (HCC), de novo lipogenesis has been found to be increased and associated with the activation of AKT/mTOR signaling. In mice, overexpression of an activated form of AKT results in increased lipogenesis and hepatic steatosis, ultimately leading to liver tumor development. Hepatocarcinogenesis is dramatically accelerated when AKT is co-expressed with an oncogenic form of N-Ras. SCD1, the major isoform of stearoyl-CoA desaturases, catalyzing the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), is a key enzyme involved in de novo lipogenesis. While many studies demonstrated the requirement of SCD1 for tumor cell growth in vitro, whether SCD1 is necessary for tumor development in vivo has not been previously investigated. Here, we show that genetic ablation of SCD1 neither inhibits lipogenesis and hepatic steatosis in AKT-overexpressing mice nor affects liver tumor development in mice co-expressing AKT and Ras oncogenes. Molecular analysis showed that SCD2 was strongly upregulated in liver tumors from AKT/Ras injected SCD1(-/-) mice. Noticeably, concomitant silencing of SCD1 and SCD2 genes was highly detrimental for the growth of AKT/Ras cells in vitro. Altogether, our study provides the evidence, for the first time, that SCD1 expression is dispensable for AKT/mTOR-dependent hepatic steatosis and AKT/Ras-induced hepatocarcinogenesis in mice. Complete inhibition of stearoyl-CoA desaturase activity may be required to efficiently suppress liver tumor development.

摘要

从头合成脂肪是癌症的主要代谢事件之一。在人类肝细胞癌(HCC)中,已发现从头合成脂肪增加,并与 AKT/mTOR 信号的激活有关。在小鼠中,过表达激活形式的 AKT 会导致脂肪生成增加和肝脂肪变性,最终导致肝肿瘤的发展。当 AKT 与致癌形式的 N-Ras 共同表达时,肝癌发生会显著加速。SCD1 是硬脂酰辅酶 A 去饱和酶的主要同工酶,催化饱和脂肪酸(SFA)转化为单不饱和脂肪酸(MUFA),是参与从头合成脂肪的关键酶。虽然许多研究表明 SCD1 是肿瘤细胞在体外生长所必需的,但 SCD1 是否是体内肿瘤发展所必需的尚未被研究过。在这里,我们表明 SCD1 的基因缺失既不能抑制 AKT 过表达小鼠中的脂肪生成和肝脂肪变性,也不能影响共表达 AKT 和 Ras 癌基因的小鼠中的肝肿瘤发展。分子分析表明,SCD1(-/-)小鼠中 AKT/Ras 注射的肝肿瘤中 SCD2 强烈上调。值得注意的是,SCD1 和 SCD2 基因的同时沉默对 AKT/Ras 细胞在体外的生长具有高度危害性。总之,我们的研究首次提供了证据,表明 SCD1 表达对于 AKT/mTOR 依赖性肝脂肪变性和 AKT/Ras 诱导的肝癌发生在小鼠中是可有可无的。完全抑制硬脂酰辅酶 A 去饱和酶活性可能是有效抑制肝肿瘤发展所必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/323f/3777889/b04bbf396f5b/pone.0075104.g001.jpg

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