Tumor Necrosis Factor‐α‐Induced Protein‐8 Like‐2 (TIPE2) Upregulates p27 to Decrease Gastic Cancer Cell Proliferation

Abstract

The pathogenesis of gastric cancer is not completely understood. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has recently been identified as a novel negative regulator gene of the immune system, and studies in mice and humans have suggested its inhibitory action in both inflammation and cancer. In this study, we examined the expression levels of TIPE2 in human gastric cancer tissues and also samples of paraneoplastic control tissue, and found that TIPE2 expression was reduced in gastric cancer. To investigate the role of TIPE2 in gastric cell carcinogenesis, a TIPE2 plasmid was introduced into gastric cell lines and TIPE2 function was examined. Colony-forming assays showed that restoration of TIPE2 expression in gastric cells significantly suppressed cell proliferation. Analysis by flow cytometry showed that the number of cells in the S phase of the cell cycle was reduced concomitant with TIPE2 expression, and cell apoptosis was maintained at a low level. Microarray and western blot analyses revealed that TIPE2 selectively up-regulated N-ras and p27 expression. The role of p27 in mediating TIPE2-associated cell growth inhibition was verified by a p27 siRNA interference assay. In this study, we proved that TIPE2 is an inhibitor of gastric cancer cell growth, and suggest that TIPE2 might promote a p27-associated signaling cascade that leads to restored control of the cell cycle and cell division. Our results provide a new molecular mechanism by which TIPE2 may regulate proliferation of gastric cells.

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

“…52 In neoplastic studies, TIPE2 expression has been found to be decreased or completely lost in human hepatic cancer, 23 and reduced TIPE2 expression is associated with metastasis. It is also downregulated in gastric cancer tissues, 53 NSCLC tumors 54 and small cell lung cancer tumors, 55 and the levels of TIPE2 inversely correlate with NSCLC TNM staging. 54 Moreover, reduced TIPE2 expression is associated with metastasis of hepatic cancer.…”

“…68 In contrast, TIPE2 overexpression induced cell death and inhibited Ras-mediated tumorigenesis in mice. 23 In gastric cell lines, increased TIPE2 expression decreased cell proliferation by upregulating N-ras and p27 expression, 53 the latter of which is mediated by interferon regulatory factor 4 via NF-κB; 69 TIPE2 has also been found to regulate AKT and ERK1/2 signaling in these cells 70 as well as GSK3β and downstream β-catenin translocation. 71 Finally, TIPE appears to regulate angiogenesis in retinal pigment epithelium by inhibiting VEGF.…”

TIPE2 acts as a biomarker for tumor aggressiveness and suppresses cell invasiveness in papillary thyroid cancer (PTC)

“…Decreased TIPE2 expression were previously reported in a number of tumors such as hepatocellular carcinoma (HCC), gastric cancer, glioma and prostate cancer [14, 15, 17, 32]. However, increased TIPE2 expression was also observed in some specific tumors including colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and skin squamous cancer [16, 33, 34].…”

“…It has been demonstrated that TIPE2 may function as a tumor suppressor by inhibiting several classic oncogenic signaling pathways [15, 17]. Our previous research demonstrated that TIPE2 suppressed the migration and invasion of HCC and NSCLC cells by inhibiting Rac1 [14, 16].…”

“…Interestingly, it has been demonstrated that TIPE2 also plays a pivotal role in tumorigenesis and tumor development in the recent years. TIPE2 has been found to be a tumor suppressor in a number of tumors [14–17]. However, detailed mechanisms were still required in most of these studies.…”