Development of lymphoproliferative diseases by hypoxia inducible factor-1alpha is associated with prolonged lymphocyte survival

PLoS One. 2013 Apr 12;8(4):e57833. doi: 10.1371/journal.pone.0057833. Print 2013.

Abstract

Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Hematopoietic System / metabolism
  • Hematopoietic System / pathology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lymphocytes / metabolism
  • Lymphocytes / pathology*
  • Lymphoid Tissue / metabolism
  • Lymphoid Tissue / pathology
  • Lymphoproliferative Disorders / metabolism*
  • Lymphoproliferative Disorders / pathology*
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Survival Analysis
  • Transgenes / genetics

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Antigen, T-Cell

Grants and funding

This work was supported by the following Grants-in Aid for Cancer Research: Special Cancer Research, from the Ministry of Education, Science, Sports and Culture, Japan (Grant No. 23591393). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.