Vasohibin‑2 promotes proliferation in human breast cancer cells via upregulation of fibroblast growth factor‑2 and growth/differentiation factor‑15 expression

Mol Med Rep. 2014 Aug;10(2):663-9. doi: 10.3892/mmr.2014.2317. Epub 2014 Jun 10.


Vasohibin‑2 (VASH2) is an angiogenic factor, and has been previously reported to be a cancer‑related gene, with cytoplasmic and karyotypic forms. In the current study VASH2 expression in human breast cancer tissue and adjacent non‑cancerous tissue was investigated with immunohistochemistry. MCF‑7 and BT474 human breast cancer cells were transfected with lentiviral constructs to generate in vitro VASH2 overexpression and knockdown models. In addition, BALB/cA nude mice were inoculated subcutaneously with transfected cells to generate in vivo models of VASH2 overexpression and knockdown. The effect of VASH2 on cell proliferation was investigated using a bromodeoxyuridine assay in vitro and immunohistochemistry of Ki67 in xenograft tumors. Growth factors were investigated using a human growth factor array, and certain factors were further confirmed by an immunoblot. The results indicated that the expression level of cytoplasmic VASH2 was higher in breast cancer tissues with a Ki67 (a proliferation marker) level of ≥14%, compared with tissues with a Ki67 level of <14%. VASH2 induced proliferation in vitro and in vivo. Four growth factors activated by VASH2 were identified as follows: Fibroblast growth factor 2 (FGF2), growth/differentiation factor‑15 (GDF15), insulin‑like growth factor‑binding protein (IGFBP)3 and IGFBP6. FGF2 and GDF15 may contribute to VASH2‑induced proliferation. The current study identified a novel role for VASH2 in human breast cancer, and this knowledge suggests that VASH2 may be a novel target in breast cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiogenic Proteins / antagonists & inhibitors
  • Angiogenic Proteins / genetics
  • Angiogenic Proteins / metabolism*
  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Proliferation
  • Female
  • Fibroblast Growth Factor 2 / metabolism*
  • Growth Differentiation Factor 15 / metabolism*
  • Humans
  • Immunohistochemistry
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Insulin-Like Growth Factor Binding Protein 6 / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Protein Array Analysis
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Transplantation, Heterologous
  • Up-Regulation


  • Angiogenic Proteins
  • Growth Differentiation Factor 15
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Protein 6
  • Intercellular Signaling Peptides and Proteins
  • Ki-67 Antigen
  • RNA, Small Interfering
  • VASH2 protein, human
  • Fibroblast Growth Factor 2