Cystathionine‑γ‑lyase promotes the metastasis of breast cancer via the VEGF signaling pathway

Int J Oncol. 2019 Aug;55(2):473-487. doi: 10.3892/ijo.2019.4823. Epub 2019 Jun 6.


The present study aimed to provide data to support the association between cystathionine‑γ‑lyase (CSE) and breast cancer metastasis. Reverse transcription‑quantitative polymerase chain reaction, immunohistochemistry and western blot analysis were used to detect the mRNA and protein expression levels of CSE in human breast cancer tissues and cells. MTS and 5‑ethynyl‑2'‑deoxyuridine assays were used to assess cell viability and proliferation. Scratch wound and Transwell assays were conducted to determine cell migration and invasion. In addition, hydrogen sulfide determination was performed using the methylene blue method. The expression of CSE was upregulated in samples from patients with breast cancer that also exhibit lymph node metastasis, and in grade III and readily metastatic breast cancer cell lines. The proliferation, migration and invasion of breast cancer cells were examined in the present study, and tumor metastasis was observed in nude mice. The function of CSE in breast cancer metastasis depends on the vascular endothelial growth factor (VEGF) signaling pathway, a key mediator of angiogenesis that is crucial for the development and metastasis of tumors. CSE positively regulated the expression of VEGF and increased the levels of certain key proteins in the VEGF pathway, including the phosphoinositide (PI3K)/protein kinase B (AKT) pathway [PI3K, Akt and phosphorylated (p)Akt], focal adhesion kinase (FAK)‑paxillin pathway (FAK and paxillin) and rat sarcoma (Ras)‑mitogen‑activated protein kinase pathway [Ras, rapidly accelerated fibrosarcoma, extracellular signal‑regulated kinase (ERK)1/2 and pERK1/2]. Furthermore, the novel CSE inhibitor I157172 possessed antiproliferative and anti‑metastatic activities in early MDA‑MB‑231 metastatic breast cancer cells via inhibition of the VEGF signaling pathway, which further confirmed the role of CSE in breast cancer metastasis. Overall, these data demonstrate for the first time, to the best of our knowledge, that the functions of CSE in breast cancer metastasis are associated with the VEGF signaling pathway.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / surgery
  • Cell Movement*
  • Cell Proliferation
  • Cystathionine gamma-Lyase / metabolism*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Lung Neoplasms / surgery
  • Lymphatic Metastasis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic
  • Phosphorylation
  • Prognosis
  • Signal Transduction
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / metabolism*
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Cystathionine gamma-Lyase