Transcription factor RUNX2 up-regulates chemokine receptor CXCR4 to promote invasive and metastatic potentials of human gastric cancer
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Zheng-Jun Guo1, Lang Yang1, Feng Qian2, Yan-Xia Wang1, Xi Yu1, Cheng-Dong Ji1, Wei Cui1, Dong-Fang Xiang1, Xia Zhang1, Peng Zhang1, Ji Ming Wang3, You-Hong Cui1, Xiu-Wu Bian1,4
1Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Third Military Medical University, Chongqing, China
2Department of General Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
3Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
4Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
Xiu-Wu Bian, e-mail: [email protected]
You-Hong Cui, e-mail: [email protected]
Keywords: RUNX2, gastric cancer, invasion, metastasis, CXCR4
Received: August 12, 2015 Accepted: February 06, 2016 Published: March 21, 2016
Runt-related transcription factor 2 (RUNX2) is a regulator of embryogenesis and development, but has also been implicated in the progression of certain human cancer. This study aimed to elucidate the role of RUNX2 in the invasive and metastatic potentials of human gastric cancer (GC) and the underlying mechanisms. We found that the levels of RUNX2 expression in gastric cancer tissues were correlated with the differentiation degrees, invasion depth and lymph node metastasis. COX regression analysis indicated that RUNX2 was an independent prognostic indicator for GC patients. RUNX2 significantly increased the migration and invasion ability of GC cells in vitro and enhanced the invasion and metastatic potential of GC cells in an orthotopic GC model of nude mice. Mechanistically, RUNX2 directly bound to the promoter region of the gene coding for the chemokine receptor CXCR4 to enhance its transcription. CXCR4 knockdown or treatment with AMD3100, a CXCR4 inhibitor, attenuated RUNX2-promoted invasion and metastasis. These results demonstrate that RUNX2 promotes the invasion and metastasis of human GC by transcriptionally up-regulating the chemokine receptor CXCR4. Therefore, the RUNX2-CXCR4 axis is a potential therapeutic target for GC.
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