Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9
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Bao-gui Zhang1,*,Tao Du1,2,*, Ming-de Zang1,Qing Chang1, Zhi-yuan Fan1, Jian-fang Li1, Bei-qin Yu1, Li-ping Su1, Chen Li1, Chao Yan1, Qin-long Gu1, Zheng-gang Zhu1, Min Yan1 and Bingya Liu1
1 Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Department of Surgery, Shanghai East Hospital, Tongji University School of Medicine, No 150 Jimo Road, Shanghai, China
* These authors contributed equally to this work
Bingya Liu, email:
Min Yan, email:
Keywords: Androgen receptor, AKT, MMP9, Gastric cancer
Received: August 14, 2014 Accepted: September 24, 2014 Published: September 25, 2014
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.
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