79626

TNFAIP8L2

Hypoxia-induced epithelial-to-mesenchymal transition (EMT) could facilitate tumor progression. TIPE2, the tumor necrosis factor-alpha (TNF-alpha)-induced protein 8-like 2 (also known as TNFAIP8L2), is a member of the TNF-alpha-induced protein 8 (TNFAIP8, TIPE) family and has been involved in the development and progression of several tumors. However, the effects of TIPE2 on the EMT process in glioma cells and the underlying mechanisms of these effects have not been previously reported. In our study, we assessed the roles of TIPE2 in the EMT process in glioma cells in response to hypoxia. Our results indicated that TIPE2 expression was significantly decreased in human glioma cell lines. TIPE2 overexpression significantly inhibited hypoxia-induced migration and invasion, as well as suppressed the EMT process in glioma cells. Furthermore, TIPE2 overexpression prevented hypoxia-induced expression of beta-catenin, cyclin D1, and c-myc in human glioma cells. In summary, these data suggest that TIPE2 overexpression inhibited hypoxia-induced Wnt/beta-catenin pathway activation and EMT in glioma cells.

tumor necrosis factor-alpha (TNF-alpha)-induced protein 8-like-2 (TNFAIP8L2 or TIPE2), a member of the tumor necrosis TNFAIP8 family, was found to be involved in the development and progression of several tumors. However, to date, the role of TIPE2 in breast cancer is still unclear. Thus, the aim of this study is to explore the role of TIPE2 in breast cancer. Our results indicated that TIPE2 expression was significantly decreased in human breast cancer tissue and cell lines. Overexpression of TIPE2 inhibited the proliferation in vitro and tumor xenograft growth in vivo. TIPE2 also inhibited the migration/invasion of breast cancer cells through preventing the epithelial-to-mesenchymal transition (EMT) phenotype. Mechanically, TIPE2 inhibited the expression of beta-catenin, cyclin D1, and c-Myc in breast cancer cells. In conclusion, our findings show that TIPE2 may play an important role in breast cancer cell proliferation, invasion, and tumorigenesis in vivo. Therefore, TIPE2 may be a potential molecular target for the treatment of breast cancer.

tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2; also termed TIPE2) has been shown to be involved in both the immune-negative modulation and cancer. We previously found that TIPE2 is lost in human gastric cancer, and TIPE2 restoration suppresses gastric cancer growth by induction of apoptosis and impairment of protein kinase B (PKB/AKT) and extracellular signal-regulated kinase-1/2 (ERK1/2) signaling. However, its correlation with epithelial-mesenchymal transition (EMT) in gastric cancer is largely elusive. In the present report, we carried out a gain-of-function study in AGS and HGC-27 human gastric cancer cells by adenovirus-mediated human TIPE2 gene transfer (AdVTIPE2). We then examined the effects of AdVTIPE2 on in vitro migration and invasion of AGS and HGC-27 tumor cells by wound-healing assay and Transwell invasion assay, respectively. We also investigated the effects of AdVTIPE2 on in vivo lung metastasis of AGS and HGC-27 tumor cells by intravenous (i.v.) injection in athymic BALB/c nude mice. We demonstrated that AdVTIPE2 remarkably suppressed the migratory, invasive and metastatic potential of AGS and HGC-27 tumor cells in vitro and in vivo in BALB/c nude mouse model. Mechanistically, AdVTIPE2 obviously upregulated E-cadherin epithelial marker in AGS and HGC-27 tumor cells, whereas it downregulated N-cadherin and Vimentin mesenchymal markers, Snail1, Snail2/Slug and Zeb1 EMT-inducing transcription factors (EMT-TFs), and tripartite motif-containing 29 (TRIM29) and phosphatase regenerating liver 3 (PRL-3) gastric cancer-specific metastasis markers. Importantly, glycogen synthase kinase-3beta (GSK-3beta) inhibitor VIII and 26S proteasome inhibitor MG132 assays revealed that TIPE2 downregulated Snail1 and Snail2/Slug in a GSK-3beta- and proteasome-dependent manner possibly by impairing AKT signaling. Our data provided the first evidence that TIPE2 inhibits gastric cancer cell migration, invasion and metastasis very probably via reversal of EMT, revealing that TIPE2 may be a novel therapeutic target for human gastric cancer EMT and metastasis.