PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner

Cell Physiol Biochem. 2018;50(6):2108-2123. doi: 10.1159/000495055. Epub 2018 Nov 9.


Background/aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells.

Methods: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively.

Results: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling.

Conclusion: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer.

Keywords: Breast cancer; Hyaluronan; Metastasis; PFKFB4; p38.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Humans
  • Hyaluronan Synthases / antagonists & inhibitors
  • Hyaluronan Synthases / genetics
  • Hyaluronan Synthases / metabolism
  • Hyaluronic Acid / metabolism*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phosphofructokinase-2 / antagonists & inhibitors
  • Phosphofructokinase-2 / genetics
  • Phosphofructokinase-2 / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • PFKFB4 protein, human
  • RNA, Small Interfering
  • Hyaluronic Acid
  • HAS2 protein, human
  • Hyaluronan Synthases
  • Phosphofructokinase-2
  • p38 Mitogen-Activated Protein Kinases