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.
Highlights
Gastric cancer (GC), hepatocellular carcinoma (HCC), and pancreatic cancer are all male-predominant cancers [1,2,3]
androgen receptor (AR) expression in GC and its correlation with clinicopathological parameters To explore the role of AR in GC, we performed IHC to analyze the protein expression of 40 GC tissue samples
Compared with the control group, we found that the protein expression level of matrix metalloproteinase 9 (MMP9), but not MMP2, was markedly increased in the AR+ group
Summary
Gastric cancer (GC), hepatocellular carcinoma (HCC), and pancreatic cancer are all male-predominant cancers [1,2,3]. In view of this remarkable gender disparity, some studies have explored the importance of the androgen receptor (AR) axis in these cancers [3, 4]. The results have demonstrated that aberrant expression or functions of AR are major contributors to the sex-related disparity in these cancers, which indicated the strong oncogenic properties of AR. Elucidation of the factors causing the sexrelated disparity of GC may be important to reveal critical pathways in gastric carcinogenesis. We hypothesized that AR may be responsible for such disparity
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