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Hypoxia Induces Hypoxia-Inducible Factor 1α and Potential HIF-Responsive Gene Expression in Uterine Leiomyoma

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Abstract

Uterine leiomyoma is characterized by abundant extracellular matrix and broad avascular areas, both constantly resulting in hypoxia, suggesting some hypoxia-induced response function. Here, we examined whether hypoxia-inducible factor 1α (HIF-1α)-mediated hypoxic response function in uterine leiomyoma. Immunoblotting detected higher basal HIF-1α protein expression in nuclear extracts from uterine leiomyoma tissues than in those from the adjacent myometrium (P =.0011). Immunohistochemical analysis revealed the presence of HIF-1α-positive cellular components in both leiomyoma and surrounding myometrial tissues. Hypoxia decreased HIF-1α messenger RNA (mRNA), but increased HIF-1α protein in primary culture leiomyoma smooth muscle cells, and caused translocation of HIF-1α from the cytoplasm to the nucleus. Hypoxia upregulated mRNAs of 6 potential HIF-responsive genes (ALDOA, ENO1, LDHA, VEGFA, PFKFB3, and SLC2A1). Chromatin immunoprecipitation quantitative polymerase chain reaction revealed that hypoxia significantly increased recruitment of HIF-1α binding to putative HIF-responsive elements in the HIF-responsive genes, suggesting that the HIF transcriptional complex initiates hypoxia-induced transcription of HIF-responsive genes. These results demonstrated a HIF-1α-mediated hypoxic response in uterine leiomyoma.

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Authors and Affiliations

  1. Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Hiroshi Ishikawa MD, PhD, Linlin Xu BS, Kunizui Sone MD, Tatsuya Kobayashi MS, Guiwen Wang MD, PhD & Makio Shozu MD, PhD

Authors
  1. Hiroshi Ishikawa MD, PhD
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  2. Linlin Xu BS
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  3. Kunizui Sone MD
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  4. Tatsuya Kobayashi MS
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  5. Guiwen Wang MD, PhD
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  6. Makio Shozu MD, PhD
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Corresponding author

Correspondence to Hiroshi Ishikawa MD, PhD.

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Authors’ Note

This study was conducted in the Department of Reproductive Medicine, Graduate School of Medicine, Chiba University.

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Ishikawa, H., Xu, L., Sone, K. et al. Hypoxia Induces Hypoxia-Inducible Factor 1α and Potential HIF-Responsive Gene Expression in Uterine Leiomyoma. Reprod. Sci. 26, 428–435 (2019). https://doi.org/10.1177/1933719118776793

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