Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer

Cancer Biol Ther. 2015;16(6):866-75. doi: 10.1080/15384047.2015.1040958.

Abstract

Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.

Keywords: BCSCs, breast cancer stem cells; EGFR, epidermal growth factor receptor; HIF-1α, hypoxia inducible factor-1α; MDR, multidrug resistance; PARP, poly ADP ribose polymerase; PI3K, phosphatidylinositol 3-kinase; TNBC, triple negative breast cancer; VEGF, va; HIF-1α; apoptosis; gene therapy; recombinant lentivirus; siRNA therapy; stably transfected cell lines; triple negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Genetic Therapy
  • Genetic Vectors / genetics*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Lentivirus / genetics*
  • Male
  • Mice
  • RNA Interference
  • RNA, Small Interfering / genetics*
  • Transduction, Genetic*
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy
  • Xenograft Model Antitumor Assays

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering

Grants and funding

This work was sponsored by a grant from the National Natural Science Foundation of China (No. 81101749).