Obesity promotes gastric cancer metastasis via diacylglycerol acyltransferase 2-dependent lipid droplets accumulation and redox homeostasis

Redox Biology

Teng Wu¹  Mei-Zhu Yang²  Shuai Li²  Tian Tian²  Yun-Xin Lu²  Feng-Hai Yu²  Yi-Jia Huang³  Zhi-Jing Li³  Sen-Lan Wang³  Jin-Xiang Wang⁴  Lei Lu⁵  Ling Huang⁵ 

[1] Corresponding author. Guangzhou Medical University, Guangzhou, 511436, PR China.;Department of Biochemistry and Molecular Biology, GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China;Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, PR China;Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China;The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510510, PR China;

关键词: DGAT2;    Gastric cancer;    Lipid droplets;    Anoikis resistance;    NADPH;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 adipocyte-rich 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/EBPα-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.

【 授权许可】

Unknown