OGDH通过调节线粒体生物能量学和Wnt/β-catenin信号通路促进胃癌的进展。,OncoTargets and Therapy

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OGDH通过调节线粒体生物能量学和Wnt/β-catenin信号通路促进胃癌的进展。
OncoTargets and Therapy ( IF 2.7 ) Pub Date : 2019-09-12 , DOI: 10.2147/ott.s208848
Xin Lu ₁ , Nan Wu ₂ , Wanli Yang ₂ , Jia Sun ₃ , Kemin Yan ₃ , Jing Wu ₁

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背景/目的 2-氧代戊二酸脱氢酶 (OGDH) 是 OGDH 复合物 (OGDHC) 的第一个限速 E1 亚基，在 TCA 循环和谷氨酰胺代谢的交叉路口起调节作用。到目前为止，OGDH 在致癌过程中的作用还不清楚。方法在本研究中，我们分别通过RT-qPCR、Western印迹和免疫组织化学染色测定人胃癌（GC）组织和细胞系中OGDH的表达。通过调节 GC 细胞中的 OGDH 表达来探索 OGDH 对细胞生长和迁移的生物学影响。此外，还分析了线粒体功能和 Wnt/β-catenin 信号，以阐明 OGDH 参与 GC 进展的机制。结果 GC组织中OGDH mRNA和蛋白水平显着升高，与GC患者的临床病理参数呈正相关。OGDH 抑制剂 SP 显着抑制 GC 细胞活力。OGDH 的调节对 GC 细胞系 AGS 和 BGC823 中的细胞增殖、细胞周期和细胞迁移具有明显的影响。OGDH的过表达导致EMT分子标志物E-cadherin和ZO-1的下调，N-cadherin和claudin-1的上调。OGDH 缺乏在 GC 细胞中具有相反的结果。同时，OGDH敲低细胞显示线粒体膜电位、耗氧率、细胞内ATP产物降低，ROS水平和NADP+/NADPH比值升高。一致地，OGDH的过表达增强了GC细胞中的线粒体功能。此外，OGDH 敲低降低了 β-catenin、slug 和 TCF8/ZEB1 的表达，下游靶向 GC 细胞中的 cyclin D1 和 MMP9。OGDH过表达促进了Wnt/β-catenin信号通路的激活。此外，OGDH 的过表达促进了裸鼠 GC 细胞的肿瘤发生。结论综上所述，这些结果表明 OGDH 通过增强线粒体功能和激活 Wnt/β-catenin 信号传导作为 GC 进展的正调节剂。

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OGDH promotes the progression of gastric cancer by regulating mitochondrial bioenergetics and Wnt/β-catenin signal pathway.

BACKGROUND/AIMS 2-oxoglutarate dehydrogenase (OGDH) is the first rate-limiting E1 subunit of OGDH complex (OGDHC), which plays as a regulatory point in the cross-road of TCA cycle and glutamine metabolism. Until now, the role of OGDH in carcinogenesis has been unclear. METHODS In the present study, we determined the expression of OGDH in human gastric cancer (GC) tissues and cell lines by RT-qPCR, Western blotting and immunohistochemical staining respectively. The biological impacts of OGDH on cell growth and migration were explored through modulation OGDH expression in GC cells. Furthermore, mitochondrial functions and Wnt/β-catenin signal were analyzed to elucidate the mechanism by which OGDH was involved in GC progression. RESULTS The results showed that the levels of OGDH mRNA and protein were significantly higher in GC tissues, which was positively correlated with clinicalpathological parameters of GC patients. OGDH inhibitor SP significantly suppressed GC cell viability. Modulation of OGDH had distinct effects on cell proliferation, cell cycle and cell migration in the GC cell lines AGS and BGC823. Overexpression of OGDH resulted in the downregulation of the EMT molecular markers E-cadherin and ZO-1, the upregulation of N-cadherin and claudin-1. OGDH deficiency had the opposite outcomes in GC cells. Meantime, OGDH knockdown cells showed decreased mitochondrial membrane potential, oxygen consumption rate, intracellular ATP product, and increased ROS level and NADP+/NADPH ratio. Consistently, overexpression of OGDH enhanced the mitochondrial function in GC cells. Furthermore, OGDH knockdown reduced the expressions of β-catenin, slug and TCF8/ZEB1, and the downstream targets cyclin D1 and MMP9 in GC cells. OGDH overexpression facilitated the activation of Wnt/β-catenin signal pathway. Additionally, overexpression of OGDH promoted tumorigenesis of GC cells in nude mice. CONCLUSION Taken together, these results indicate that OGDH serves as a positive regulator of GC progression through enhancement of mitochondrial function and activation of Wnt/β-catenin signaling.

更新日期：2019-11-01

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