Mxi1-0 regulates the growth of human umbilical vein endothelial cells through extracellular signal-regulated kinase 1/2 (ERK1/2) and interleukin-8 (IL-8)-dependent pathways

PLoS One. 2017 Jun 2;12(6):e0178831. doi: 10.1371/journal.pone.0178831. eCollection 2017.


Mxi1 plays an important role in the regulation of cell proliferation. Mxi1-0, a Mxi1 isoform, has a different N-terminal amino acid sequence, intracellular location and expression profile from Mxi1. However, the precise role of Mxi1-0 in cell proliferation and the molecular mechanism underlying its function remain poorly understood. Here, we showed that Mxi1-0 suppression decreased the proliferation of human umbilical vein endothelial cells (HUVECs) along with cell accumulation in the G2/M phase. Mxi1-0 suppression also significantly decreased the expression and secretion of interleukin (IL-8). Neutralizing IL-8 in conditioned medium (CM) from Mxi1-0-overexpressed HUVECs significantly eliminated CM-induced proliferation of HUVECs. In addition, Mxi1-0 suppression significantly decreased the activity of MAP kinase ERK1/2. Treatment of HUVECs with U0126, an ERK1/2 signaling inhibitor, attenuated autocrine production of IL-8 induced by Mxi1-0 overexpression. On the other hand, Mxi1-0 overexpression-induced IL-8 increased the level of phosphorylated ERK1/2 in HUVECs, and such increasing was diminished in cells incubated with CM, which neutralized with anti-IL-8 antibody. Taken together, our results suggest that Mxi1-0 regulates the growth of HUVECs via the IL-8 and ERK1/2 pathways, which apparently reciprocally activate each other.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / enzymology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Interleukin-8 / metabolism*
  • MAP Kinase Signaling System*
  • Phosphorylation
  • Tumor Suppressor Proteins / physiology*
  • Umbilical Veins / cytology
  • Umbilical Veins / enzymology


  • Basic Helix-Loop-Helix Transcription Factors
  • Interleukin-8
  • MXI1 protein, human
  • Tumor Suppressor Proteins

Grants and funding

This work was supported by research grants from State Key Laboratory of Reproductive Medicine, Nanjing Medical University (SKLRM-KF-1202) to Weiling Wu, the National Natural Science Foundation of China (81301822) and the Research Program funded by Nanjing Medical University (2012NJMU088) to Zhenzhen Hu, Key Project supported by Medical Science and technology development Foundation, Nanjing Department of Health (YKK13177) to Datong Zheng. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.