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PRL-3 promotes gastric cancer migration and invasion through a NF-κB-HIF-1α-miR-210 axis

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Abstract

Phosphatase of regenerating liver-3 (PRL-3) has been implicated in controlling cancer cell invasiveness. Deregulated expression of PRL-3 is involved in cancer progression and predicts poor overall survival. Recent studies have revealed critical roles for microRNAs in various cellular processes, including tumorigenic development. In this study, we aimed to explore the linkage between PRL-3 and microRNAs in gastric cancer. We found that PRL-3 transcript levels were positively correlated with miR-210 levels in gastric cancer tissues. In gastric cancer cells, PRL-3 upregulated miR-210 expression in a HIF-1α-dependent fashion under normoxia and hypoxia. In addition, PRL-3 activated NF-κB signaling and promoted HIF-1α expression through modulating phosphorylation of p65. NF-κB signaling, HIF-1α, and miR-210 partially contributed to PRL-3-induced migration and invasion. Furthermore, the levels of PRL-3, HIF-1α, and miR-210 transcripts inversely affected the overall survival of gastric cancer patients. Our work identified the existence of a PRL-3-NF-κB-HIF-1α-miR-210 axis, thus providing new insight into the role of PRL-3 in promoting gastric cancer invasiveness.

Key Message

  • PRL-3 regulates microRNA in gastric cancer.

  • PRL-3 elevates hsa-miR-210 by upregulating HIF-1α.

  • PRL-3 activates a NF-κB-HIF-1α-miR-210 axis by enhancing the phosphorylation of p65.

  • PRL-3 promotes cell migration and invasion via the NF-κB-HIF-1α-miR-210 axis.

  • High levels of PRL-3 and miR-210 are related with poor OS in gastric cancer.

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Acknowledgments

We deeply appreciate Jingyan Han, Chunshui Pan (Peking University Health Science Center), Caiyun Liu and Lixin Wang (Peking University Cancer Hospital & Institute) for the helpful suggestions on study design and experimental procedures and Dr. Lorenzo Finci (Tsinghua University) for the meticulous editing of this manuscript. This study was supported by National Basic Research Program of China (2015CB553906, 2013CB910504) and National Natural Science Foundation of China (81230046).

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    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China

      Cheng Zhang, Wei Tian, Lin Meng, Like Qu & Chengchao Shou

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    1. Cheng Zhang
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    2. Wei Tian
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    Correspondence to Chengchao Shou.

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    None. The experiments described in the manuscript comply with the current laws of the countries in which they were performed.

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    Cheng Zhang and Wei Tian contributed equally to this work.

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    Zhang, C., Tian, W., Meng, L. et al. PRL-3 promotes gastric cancer migration and invasion through a NF-κB-HIF-1α-miR-210 axis. J Mol Med 94, 401–415 (2016). https://doi.org/10.1007/s00109-015-1350-7

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