Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9

Oncotarget. 2014 Nov 15;5(21):10584-95. doi: 10.18632/oncotarget.2513.

Abstract

Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in gastric cancer (GC) are poorly characterized. Here, we investigated the role of AR in GC cell migration, invasion and metastatic potential. Our data showed that AR expression was positively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by activation of AKT and upregulation of matrix metalloproteinase 9 (MMP9). AR overexpression induced increases in GC cell migration, invasion and proliferation in vitro and in vivo. These effects were attenuated by inhibition of AKT, AR and MMP9. AR overexpression upregulated MMP9 protein levels, whereas this effect was counteracted by AR siRNA. Inhibition of AKT by siRNA or an inhibitor (MK-2206 2HC) decreased AR protein expression in both stably transfected and parental SGC-7901 cells. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that AR bound to the AR-binding sites of the MMP9 promoter. In summary, AR overexpression induced by AKT phosphorylation upregulated MMP9 by binding to its promoter region to promote gastric carcinogenesis. The AKT/AR/MMP9 pathway plays an important role in GC metastasis and may be a novel therapeutic target for GC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Base Sequence
  • Blotting, Western
  • Cell Adhesion
  • Cell Movement*
  • Cell Proliferation*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoenzyme Techniques
  • Lymphatic Metastasis
  • Male
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Nude
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Phosphorylation
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • RNA, Small Interfering
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-akt
  • MMP9 protein, human
  • Matrix Metalloproteinase 9