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Platelet-activating factor receptor-mediated PI3K/AKT activation contributes to the malignant development of esophageal squamous cell carcinoma

Oncogene volume 34, pages 5114–5127 (2015)Cite this article

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Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide and occurs at a relatively high frequency in China, yet the mechanisms underlying its devastating outcome remain unclear. Here we report that platelet-activating factor receptor (PAFR), a type of G-protein-coupled receptor, was upregulated in ESCC tumors and cell lines, compared with controls; PAFR levels were positively correlated with ESCC clinical stages and survival time. Overexpression of PAFR promoted the malignant development of ESCC in vitro and in vivo, whereas depletion of PAFR suppressed these effects. Interestingly, PAFR was observed to activate PI3K/AKT (phosphatidylinositol 3-kinase/AKT) through the upregulation of FAK kinase activity. AKT-triggered nuclear factor-κB transcriptionally activated PAFR expression. This mutual positive regulation between PAFR and AKT was required for the aggressiveness of ESCC cells both in vitro and in vivo. Furthermore, treating mice bearing ESCC tumors with cholesterol-conjugated PAFR small interfering RNA effectively inhibited tumor progression and the expression of AKT-mediated oncogenic proteins. Taken together, we made the first demonstration that dysregulation of PAFR and the positive regulatory loop between PAFR and pAKT contribute to malignant progression of ESCC.

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Acknowledgements

The ESCC cell lines (KYSE180, KYSE140, KYSE150, KYSE30, KYSE410, KYSE450 and KYSE510) were generously provided by Dr Shemada of Kyoto University. This work is supported by the National 973 Program (2015CB553904), National Natural Fund of China (81021061 and 81230047) and China Postdoctoral Science Foundation (2013M530555).

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  1. J Chen and T Lan: These authors contributed equally to this work.

Authors and Affiliations

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

    J Chen, T Lan, W Zhang, L Dong, N Kang, S Zhang, M Fu & Q Zhan

  2. Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China,

    T Lan

  3. Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China

    B Liu

  4. National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Tsinghua University and Chinese Academy of Medical Sciences, Beijing, China

    K Liu

  5. Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China

    C Zhang & J Hou

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Chen, J., Lan, T., Zhang, W. et al. Platelet-activating factor receptor-mediated PI3K/AKT activation contributes to the malignant development of esophageal squamous cell carcinoma. Oncogene 34, 5114–5127 (2015). https://doi.org/10.1038/onc.2014.434

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