The Functional Interplay Between Pro-oncogenic RUNX2 and Hypoxia-Inducible Factor-1α (HIF-1α) During Hypoxia-Mediated Tumor Progression

  • Toshinori Ozaki
  • Mizuyo Nakamura
  • Takehiko Ogata
  • Meijie Sang
  • Osamu Shimozato
Chapter
Part of the Current Human Cell Research and Applications book series (CHCRA)

Abstract

Solid tumor tissues often have functional and phenotypical heterogeneities, arising at least in part from the local hypoxic tumor microenvironment (generally O2 concentration is less than 2%). The elevated level of hypoxia is tightly associated with genetic instability, tumor progression, drug resistance, and/or poor clinical outcome after treatment, indicating that hypoxia exerts a strong selection pressure for the survival of cancer stem cells (CSCs) within tumors and also permits their maintenance. Thus, it has become urgent to precisely clarify the molecular basis of how hypoxia could contribute to the acquisition and/or maintenance of the aggressive phenotypes of this deadly disease. Meanwhile, cells keep genomic integrity to avoid genetic instability-mediated tumorigenesis through the proper stress response under normoxia. Upon hypoxia, hypoxia-inducible factor-1α (HIF-1α) which has an O2-sensing ability accumulates and then facilitates tumor development through an induction of vascular endothelial growth factor (VEGF)-dependent angiogenesis. Therefore, the hypoxic HIF-1α/VEGF regulatory axis plays a vital role during the malignant tumor progression. Intriguingly, pro-oncogenic runt-related transcription factor 2 (RUNX2) has an ability to stimulate HIF-1α-mediated induction of VEGF. Recently, we have found for the first time that RUNX2 contributes to the acquisition of drug-resistant phenotype of malignant tumor cells. In this review, we focus on the functional interplay between HIF-1α/VEGF and RUNX2 within the hypoxic tumor microenvironment. Finally, we would like to discuss the potential therapeutic strategy targeting this tumor hypoxia.

Keywords

Cancer stem cells Drug resistance HIF-1α Hypoxia RUNX2 VEGF 

Notes

Acknowledgments

The authors are grateful to Dr. Hiroki Nagase for his helpful discussions.

Conflicts of Interest

The authors have no conflict of interest.

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Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Toshinori Ozaki
    • 1
  • Mizuyo Nakamura
    • 1
  • Takehiko Ogata
    • 1
  • Meijie Sang
    • 1
    • 2
  • Osamu Shimozato
    • 1
  1. 1.Laboratory of DNA Damage SignalingChiba Cancer Center Research InstituteChibaJapan
  2. 2.Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical ScienceUniversity of ToyamaToyamaJapan

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