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Cancer cell-associated cytoplasmic B7-H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation.

Abstract
Aberrant B7-H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7-H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7-H4 transcription in primary CD138(+) multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7-H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7-H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7-H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7-H4 expression. Furthermore, knockdown of cytoplasmic B7-H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7-H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7-H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment.
AuthorsYou-Kyoung Jeon, Sae-Gwang Park, Il-Whan Choi, Soo-Woong Lee, Sang Min Lee, Inhak Choi
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 459 Issue 2 Pg. 277-283 (Apr 03 2015) ISSN: 1090-2104 [Electronic] United States
PMID25725157 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Recombinant Proteins
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • VTCN1 protein, human
Topics
  • Cell Hypoxia (physiology)
  • Cell Line, Tumor
  • Cell Proliferation (physiology)
  • Chromatin Immunoprecipitation
  • Cytoplasm (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
  • MCF-7 Cells
  • Multiple Myeloma (genetics, metabolism, pathology)
  • Promoter Regions, Genetic
  • Recombinant Proteins (genetics, metabolism)
  • Tumor Microenvironment (genetics, physiology)
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 (antagonists & inhibitors, biosynthesis, genetics)

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