Abstract 116: ATF3 suppresses the invasion and metastasis of esophageal squamous cell carcinoma cells by inducing the MDM2-mediated degradation of MMP-2

Abstract

Abstract Objective: Activating transcription factor 3 (ATF3) was a transcription factor involved in cell cycle progression, invasion and metastasis of cancer cells. This study explored the clinical significance and biological function of ATF3 in esophageal squamous cell carcinomas (ESCC). Methods: Tissue microarray analysis, immunohistochemistry and Western blotting were utilized to examine the expression status of ATF3 in 150 ESCC samples and 21 paired adjacent normal epithelial tissues. Impact of ATF3 altered expression on cell growth, invasion, metastasis and the underlying mechanisms were also assessed by using in vitro and animal models of ESCC. Results: ATF3 expression was significantly lower in ESCC tissue than in the adjacent normal squamous mucosa (P=0.001). ATF3 expression was associated with both overall survival (OS, P=0.006) and disease-free survival (DFS, P=0.001) of ESCC patients. Multivariate analysis showed that ATF3 was an independent prognostic factor in ESCC. Experimentally, forced expression of ATF3 led to decreased cell growth and invasion properties in vitro, whereas knockdown of ATF3 did the opposite. ATF3 expression inhibited the tumourigenesis and lung metastasis of ESCC cells in nude mice. Further analysis revealed that the expression and activity of MMP-2 was decreased upon ATF3 expression. ATF3 upregulated MDM2 and formed an ATF3/MDM2/MMP-2 complex that facilitated MDM2-mediated MMP-2 degradation and subsequently inhibited the invasion and metastasis of ESCC cells. Finally, we showed that Cisplatin could suppress the invasion of ESCC cells by targeting the ATF3/MDM2/MMP-2 signaling. Conclusions: Decreased ATF3 expression in ESCC resulted in increased invasion and metastasis and contributed to ESCC poor prognosis. ATF3 expression is an ESCC candidate clinical prognostic marker and a potential treatment target. Citation Format: Jianjun Xie, Liyan Xu, Enmin Li. ATF3 suppresses the invasion and metastasis of esophageal squamous cell carcinoma cells by inducing the MDM2-mediated degradation of MMP-2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 116. doi:10.1158/1538-7445.AM2014-116