Obesity promotes gastric cancer metastasis via diacylglycerol acyltransferase 2-dependent lipid droplets accumulation and redox homeostasis
Obesity promotes gastric cancer metastasis via diacylglycerol acyltransferase 2-dependent lipid droplets accumulation and redox homeostasis
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肥胖通过二酰基甘油酰基转移酶2依赖的脂滴积累和氧化还原稳态促进胃癌转移
DOI：
10.1016/j.redox.2020.101596
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Tian, Tian
中科院分区：
文献类型：
--
作者：
Li, Shuai;Wu, Teng;Tian, Tian
实验和分子流行病学研究表明，脂肪组织或高脂饮食(HFD)在肿瘤生长和转移中起重要作用。胃癌(GC)有腹膜脂肪转移倾向。然而，HFD在胃癌腹膜转移中的确切分子相关性仍不清楚。在这里，我们发现HFD在体内引起明显的脂肪积聚，并促进GC的腹膜扩散。腹膜来源的脂肪细胞通过转录上调DGAT2，以C/EBPα依赖的方式诱导GC细胞中脂滴(LD)的积累和脂肪酸的氧化，并防止腹膜扩散过程中的失巢凋亡。用FAs处理GC细胞或与脂肪细胞共培养，在体外诱导细胞内LDS的形成和NADPH的产生，以克服氧化应激。重要的是，DGAT2的过度表达被认为是促进GC肺和腹膜转移的一个独立的生存不良预测因子，而DGAT2的基因或药物抑制通过破坏富脂环境中脂滴的形成，在体外增强了GC对Nacikis的敏感性，并抑制了体内的腹膜转移。总体而言，我们的发现强调了DGAT2可能是胃癌腹膜植入治疗的一个有前景的治疗靶点，并为揭示肥胖与肿瘤转移之间的联系提供了一些证据。
Experimental and molecular epidemiological studies indicate important roles for adipose tissue or high-fat diet (HFD) in tumor growth and metastasis. Gastric cancer (GC) possesses a metastatic predilection for the adipocyterich peritoneum. However, the precise molecular relevance of HFD in the peritoneal metastasis of GC remains unclear. Here, we showed that HFD causes obvious fat accumulation and promotes peritoneal dissemination of GC in vivo. Peritoneum-derived adipocytes induces robust lipid droplet (LD) accumulation and fatty acid oxidation in GC cells through transcriptional upregulation of DGAT2 in a C/EBP alpha-dependent manner and prevents anoikis during peritoneal dissemination. Treatment of GC cells with FAs or coculture with adipocytes induces intracellular formation of LDs and production of NADPH to overcome oxidative stress in vitro. Importantly, overexpression of DGAT2 was identified as an independent predictor of poor survival that promotes lung and peritoneal metastasis of GC, and genetic or pharmacological inhibition of DGAT2, via disruption of lipid droplet formation in a lipid-rich environment, enhances the sensitivity of GC to anoikis in vitro and inhibits peritoneal metastasis in vivo. Overall, our findings highlight the notion that DGAT2 may be a promising therapeutic target in GC with peritoneal implantation and provide some evidence for uncovering the link between obesity and tumor metastasis.