Downregulation of ZIP kinase is associated with tumor invasion, metastasis and poor prognosis in gastric cancer

Deletion of 19p13 is one of the most frequent genetic changes in gastric carcinoma (GC), implying the existence of a tumor suppressor gene (TSG) that plays an important role in GC development. To identify the candidate TSG at 19p, array-comparative genomic hybridization (CGH) was applied to study DNA copy-number changes on chromosomes 3, 5p, 13, 16q and 19. The result showed that gains of 16q21, 19q13.1, 5p15.1 and 3q26.31, and losses of 3p21.32, 3p22.2, 19q13.33 and 19p13.3, were frequently detected by array-CGH. One candidate TSG, ZIP kinase (ZIPK), at 19p13.3 was further characterized by immunohistochemistry using a tissue microarray containing 172 primary GCs. Downregulation of ZIPK was detected in 111/162 informative GCs, which was significantly associated with invasion, metastasis and poorer prognosis of GC. To investigate the association of the downregulation of ZIPK with apoptosis, apoptosis assay (TUNEL) was used to compare the apoptotic index between GCs with normal expression and downregulation of ZIPK. TUNEL assay showed that the apoptotic index in GCs with normal ZIPK expression was significantly higher than that in GCs with downregulation of ZIPK (P < 0.001), indicating that ZIPK plays an important pro-apoptotic role in GC. Taken together, we demonstrated here that ZIPK is a tumor suppresser gene and plays an important role in GC development through its pro-apoptotic function. Downregulation of ZIPK can be used to evaluate tumor invasiveness, metastasis and to predict survival of GC. (C) 2008 Wiley-Liss, Inc.