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Regulatory circuit of PKM2/NF-κB/miR-148a/152-modulated tumor angiogenesis and cancer progression

Oncogene volume 34, pages 5482–5493 (2015)Cite this article

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Abstract

Upregulation of the embryonic M2 isoform of pyruvate kinase (PKM2) emerges as a critical player in the cancer development and metabolism, yet the underlying mechanism of PKM2 overexpression remains to be elucidated. Here we demonstrate that IGF-1/IGF-IR regulates PKM2 expression by enhancing HIF-1α-p65 complex binding to PKM2 promoter. PKM2 expression is regulated by miR-148a/152 suppression. PKM2 directly interacts with NF-κB p65 subunit to promote EGR1 expression for regulating miR-148a/152 feedback circuit in normal cells, but not in cancer cells because of the DNA hypermethylation of miR-148a and miR-152 gene promoters. The silencing of miR-148a/152 contributes to the overexpression of PKM2, NF-κB or/and IGF-IR in some cancer cells. We show that disruption of PKM2/NF-κB/miR-148a/152 feedback loop can regulate cancer cell growth and angiogenesis, and is also associated with triple-negative breast cancer (TNBC) phenotype, which may have clinical implication for providing novel biomarker(s) of TNBC and potential therapeutic target(s) in the future.

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Acknowledgements

This work was supported in part by National Natural Science Foundation of China (81320108019, 81270736, 81071642), by Jiangsu Province Clinical Science and Technology Project (BL2012008), the Priority Academic Program Development of Jiangsu Higher Education Institutions (JX10231801), Jiangsu Province’s Key Discipline of Medicine (XK201117), and by National Institutes of Health grants R01ES020868 and R21CA175975.

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Author notes

  1. Q Xu and L-Z Liu: These authors contributed equally to this work.

  2. Y Shu and B-H Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, State Key lab of Reproductive Medicine, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China

    Q Xu, Y Yin, Q Li, X Qian & B-H Jiang

  2. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

    L-Z Liu, J He, S C Peiper & B-H Jiang

  3. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China

    Y Shu

  4. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

    Y You

  5. Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Lu

  6. Department of Pathology, Anhui Medical University, Hefei, China

    Y Yin

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  1. Q Xu
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Correspondence to Y Shu or B-H Jiang.

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Xu, Q., Liu, LZ., Yin, Y. et al. Regulatory circuit of PKM2/NF-κB/miR-148a/152-modulated tumor angiogenesis and cancer progression. Oncogene 34, 5482–5493 (2015). https://doi.org/10.1038/onc.2015.6

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  • DOI: https://doi.org/10.1038/onc.2015.6

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