The diacylglycerol kinase α (DGKα)/Akt/NF-κB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner
The diacylglycerol kinase α (DGKα)/Akt/NF-κB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner
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二酰甘油激酶 α (DGKα)/Akt/NF-κB 前馈环通过 FAK 依赖性和 FAK 独立方式促进食管鳞状细胞癌 (ESCC) 进展
DOI：
10.1038/s41388-018-0604-6
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发表时间：
2019-04-04
期刊：
影响因子：
8
通讯作者：
Zhan, Qimin
中科院分区：
文献类型：
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作者：
Chen, Jie;Zhang, Weimin;Zhan, Qimin
许多报道将DGKα描述为癌基因，因此，我们研究了DGKα的功能及其在食管鳞癌进展中的潜在机制。本研究表明，在ESCC细胞中，DGKα被炎性刺激物上调，并与Akt/NF-kappa B信号形成前馈环路。在机制上，DGKα通过刺激PA的产生来激活Akt/NF-kappa B信号，从而降低cAMP水平和PTEN活性，特别是通过与FAK的FERM结构域直接相互作用来解除FERM结构域对FAK的自身抑制作用，而不依赖于其激酶功能。在体外和体内，DGKα的过表达都促进了癌症的恶性进展，而DGKα的缺失则抑制了这些作用。重要的是，DGKα的表达与各种炎症相关鳞癌的恶性程度和致癌的Akt/NF-kappa B活性密切相关。因此，DGKα在炎症介导的ESCC进展中起关键作用，支持DGKα作为ESCC治疗的潜在靶点。
Many reports have described DGK alpha as an oncogene, hence, we investigated its function and the underlying mechanisms in esophageal squamous cell carcinoma (ESCC) progression. This study demonstrated that DGK alpha was upregulated by inflammatory stimulants and formed feedforward loop with Akt/NF-kappa B signaling in ESCC cells. Mechanistically, DGK alpha-activated Akt/NF-kappa B signaling via stimulating PA production to reduce cAMP level and PTEN activity, and specifically, independently of its kinase function, through direct interaction with the FERM domain of FAK to relieve the auto-inhibitory effect of FERM domain on FAK. Overexpression of DGK alpha promoted cancer malignant progression both in vitro and in vivo, whereas depletion of DGK alpha suppressed these effects. Importantly, DGK alpha expression was tightly correlated with the malignancy of various inflammation-related squamous carcinomas and the oncogenic Akt/NF-kappa B activity. Therefore, DGK alpha is critically involved in inflammation-mediated ESCC progression, supporting DGK alpha as a potential target for ESCC therapy.