Downregulation of TNFAIP2 suppresses proliferation and metastasis in esophageal squamous cell carcinoma through activation of the Wnt/β-catenin signaling pathway

Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in malignant tumor formation in the tumor microenvironment. To investigate the role of TNF-alpha in esophageal squamous cell carcinoma (ESCC), we assessed expression profiles of the downstream gene TNF-alpha-induced protein 2 (TNFAIP2), which e previously unknown in ESCC. TNFAIP2 mRNA and protein expression levels were examined by qRT-PCR and immunohistochemical analysis in 24 fresh and 55 paraffin-embedded specimens, respectively. The results demonstrated that TNFAIP2 mRNA and protein levels were overexpressed in tumor cells, and TNFAIP2 overexpression was significantly associated with T stage (p=0.049), N stage (p=0.019) and the International Union Against Cancer (UICC) stage (p=0.028). In vitro, TNFAIP2 was highly expressed in TNF alpha-stimulated Eca109, Kyse150, Kyse510 and TE-10 cells. Lentivirus-mediated RNA interference of TNFAIP2 inhibited cell proliferation, colony formation, migration, invasion and the cell cycle. Moreover, LV-RNAi-mediated TNFAIP2 was found to regulate the Wnt/beta-catenin by decreasing expression of some genes downstream from beta-catenin (i.e., C-myc, cyclin D1, MMP-7 and Snail), and upregulating expression of E-cadherin and p-GSK-3 beta. Taken together, these results show that TNFAIP2 may be a potential tumorigenesis gene in ESCC. Our data indicate that TNFAIP2 overexpression may facilitate proliferation and metastasis via activation of the Wnt/beta-catenin signaling pathway in ESCC.