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The diacylglycerol kinase α (DGKα)/Akt/NF-κB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner

Oncogene volume 38, pages 2533–2550 (2019)Cite this article

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Abstract

Many reports have described DGKα as an oncogene, hence, we investigated its function and the underlying mechanisms in esophageal squamous cell carcinoma (ESCC) progression. This study demonstrated that DGKα was upregulated by inflammatory stimulants and formed feedforward loop with Akt/NF-κB signaling in ESCC cells. Mechanistically, DGKα-activated Akt/NF-κB 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 DGKα promoted cancer malignant progression both in vitro and in vivo, whereas depletion of DGKα suppressed these effects. Importantly, DGKα expression was tightly correlated with the malignancy of various inflammation-related squamous carcinomas and the oncogenic Akt/NF-κB activity. Therefore, DGKα is critically involved in inflammation-mediated ESCC progression, supporting DGKα as a potential target for ESCC therapy.

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Acknowledgements

This work is supported by the National 973 Program (2015CB553904) and National Natural Fund of China (81830086, 81490753, 81502110, and 81772504). Beijing Municipal Administration of Hospitals’s Youth Program, code: QML20171105.

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Authors and Affiliations

  1. Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China

    Jie Chen, Weimin Zhang, Yan Wang, Di Zhao, Mengjiao Wu, Jiawen Fan, Jinting Li, Ying Gong, Nana Dan, Di Yang, Rui Liu & Qimin Zhan

  2. State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Qimin Zhan

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Chen, J., Zhang, W., Wang, Y. et al. The diacylglycerol kinase α (DGKα)/Akt/NF-κB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner. Oncogene 38, 2533–2550 (2019). https://doi.org/10.1038/s41388-018-0604-6

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