5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway

Oncotarget. 2015 Sep 22;6(28):25975-87. doi: 10.18632/oncotarget.4543.

Abstract

Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT(1D) receptor (5-HT(1D)R) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT(1D)R-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT(1D)R antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT(1D)R played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT(1D)R in pulmonary metastasis of colorectal cancer.

Keywords: 5-hydroxytryptamine (5-HT) receptor; Wnt signaling pathway; colorectal cancer; intestinal epithelium cells; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / genetics
  • Axin Protein / metabolism*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Immunohistochemistry
  • Male
  • Matrix Metalloproteinase 7 / genetics
  • Matrix Metalloproteinase 7 / metabolism*
  • Mice, Nude
  • Middle Aged
  • Neoplasm Metastasis
  • Oxadiazoles / pharmacology
  • Piperazines / pharmacology
  • Receptor, Serotonin, 5-HT1D / genetics
  • Receptor, Serotonin, 5-HT1D / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serotonin Antagonists / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • AXIN1 protein, human
  • Axin Protein
  • Oxadiazoles
  • Piperazines
  • Receptor, Serotonin, 5-HT1D
  • Serotonin Antagonists
  • beta Catenin
  • GR 127935
  • MMP7 protein, human
  • Matrix Metalloproteinase 7