Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis
Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis
复制标题
脂肪酸通过O-GlcNAcylation诱导CD36表达驱动胃癌转移
DOI：
10.7150/thno.34024
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Jiang, Mingzuo;Wu, Nan;Fan, Daiming
转移是晚期癌症患者死亡的主要原因。最近，研究表明高脂肪饮食可以以CD 36依赖性方式特异性促进特定癌细胞的转移潜力。方法：采用RT-qPCR、流式细胞仪分析、免疫印迹和免疫组化等方法，结合TCGA数据库，对胃癌组织和胃癌细胞系中CD36的表达进行定量分析。用Transwell法和异种移植物法检测细胞在体外和体内的转移能力。采用荧光素酶报告基因分析法检测GC细胞中O-GlcNAc化水平升高时信号通路的变化，并采用体外O-GlcNAc化分析法检测野生型和突变型CD36蛋白的O-GlcNAc化位点。高CD36表达是生存不良的预测因子，并促进GC细胞的转移，使用中和抗体阻断CD36抑制了GC细胞的转移。小鼠中的GC转移。FA或HFD通过增加O-GlcNAc酰化水平上调CD36来促进GC细胞的转移潜能。结论：FA诱导的O-GlcNAc高修饰通过激活NF-κ B通路促进CD36的转录和功能，并直接修饰S468和T470位点，从而促进胃癌转移。
Metastasis is the primary cause of death in patients with advanced cancer. Recently, a high-fat diet was shown to specifically promote the metastatic potential of specific cancer cells in a CD36-dependent manner. However, the molecular basis of the fatty acid (FA)-induced upregulation of CD36 has remained unclear.Methods: RT-qPCR, FACS analysis, immunoblotting and immunohistochemistry, as well as retrieving TCGA database, were carried out to quantitate CD36 expression in gastric cancer (GC) tissues and cell lines. Transwell assay and xenografts were used to assess cell metastasis abilities in vitro and in vivo after indicated treatment. Luciferase reporter assay was carried out to evaluate the changes in signaling pathways when O-GlcNAcylation level was increased in GC cells and in vitro O-GlcNAcylation assay was utilized for wild and mutant types of CD36 protein to explore the potential O-GlcNAcylation sites.Results: High CD36 expression is a predictor of poor survival and promotes metastasis of GC cells and the use of neutralizing antibodies to block CD36 inhibits GC metastasis in mice. FA or a HFD promotes the metastatic potential of GC cells by upregulating CD36 via increasing the O-GlcNAcylation level. Increased O-GlcNAcylation levels promote the transcription of CD36 by activating the NF-kappa B pathway and also increase its FA uptake activity by directly modifying CD36 at S468 and T470.Conclusion: FA-induced hyper-O-GlcNAcylation promotes the transcription and function of CD36 by activating the NF-kappa B pathway and directly modifying CD36 at S468 and T470, which drives GC metastasis.