Signal transduction and activator of transcription 3(STAT3) signaling is constitutively activated in various tumors, and is involved in cell survival and proliferation during oncogenesis. There are few reports, however, on the role of STAT3 signaling in gastric cancer. The aim of the present study was to clarify the role of STAT3 signaling in apoptosis and cellular proliferation in gastric cancer. Here we reported that STAT3 was constitutively activated in various human gastric cancer cells and its inhibition by ectopic dominant-negative STAT3 or Janus kinase inhibitor, tyrphostin AG490, induced apoptosis. Furthermore, STAT3 inhibition markedly decreased survivin expression, and forced expression of survivin rescued AGS cells from apoptosis induced by STAT3 inhibition. Although some reports demonstrated that the PI3K/Akt pathway regulates survivin expression, inhibition of the PI3K/Akt pathway did not affect survivin expression in AGS and MKN1 cells. Finally, activated form of STAT3, Tyr-705 phospho-stat3, was found in the nucleus of cancer cells in 11 of 40 (27.5%) human gastric cancer specimens. These findings suggest that constitutively activated STAT3 signaling supports gastric cancer cell survival in association with survivin expression.

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The regenerating gene (REG) IV gene was isolated from a cDNA library of ulcerative colitis (UC) tissues. However, its role in the pathophysiology of UC and subsequent development of colitic cancer is still unclear. We investigated the expression of the REG IV gene in UC and colitic cancer tissues and examined whether cytokines or growth factors are responsible for REG IV gene expression and whether REG IV gene induction affects cell growth and apoptosis in colon cancer cells. The expressions of REG IV and growth factor genes in UC tissues were analyzed by real time reverse transcription-polymerase chain reaction. The effects of cytokines and growth factors on REG IV gene expression were examined in SW403 cells by Northern blot analysis. The effects of REG IV gene induction on cell growth and H 2 O 2 -induced apoptosis were examined in DLD-1 cells by MTT and TUNEL assays, respectively. REG IV mRNA was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG IV mRNA expression was correlated with that of basic fibroblast growth factor (bFGF) as well as hepatocyte growth factor (HGF) mRNA expression in UC tissues. The REG IV gene expression in SW403 colon cancer cells was enhanced by stimulation with transforming growth factor-a, epidermal growth factor, bFGF, and HGF. REG IV gene induction promoted cell growth and conferred resistance to H 2 O 2 -induced apoptosis in DLD-1 cells. The REG IV gene is inducible by growth factors and may function as a growth promoting and/or an antiapoptotic factor in the pathophysiology of UC. The pathogenesis of ulcerative colitis (UC) is still unclear, but dysregulated immune function appears to be involved in its chronic inflammatory process, resulting in continuous damage of the colonic mucosa. [1][2][3][4][5] To regenerate the injured colonic tissues, growth factors are thought to play very important roles, and indeed, several growth factors are reported to be upregulated in the colonic tissues in UC. 3,6,7 However, few comprehensive studies have examined the expression patterns of various growth factors in UC tissues simultaneously, and the network of and the relationships among growth factors in UC tissues are not fully understood.Regenerating gene (REG) IV, the most recently discovered member of the REG gene family, was isolated from a cDNA library of UC tissues by Hartupee et al. 8 Although the biological function of REG IV protein is still unclear, REG IV protein may play a role in cell growth because other REG family proteins have been shown to act as growth factors in gastrointestinal organs. 9-14 However, it still remains unknown whether the REG IV gene is indeed involved in the pathophysiology of UC and whether REG IV protein really functions as a growth factor. Moreover, it has not been examined how REG IV gene expression is regulated. In the present study, therefore, in order to elucidate roles for REG IV in the pathophysiology of UC, we investigated the relationship between REG IV gene expression and clinicopat...

Differentiation-inducing factor-1 (DIF-1) is a chlorinated hexaphenone isolated from Dictyostelium. DIF-1 exhibits antitumor activity in several types of mammalian tumor cells, although the underlying mechanisms remain unknown. On the other hand, recent studies indicate that constitutively activated STAT3 acts as an oncogene and could be a target for antitumor drug. In the present study, we examined the effects of DIF-1 on proliferation of gastric cancer cell lines as well as on its signal transduction pathways, focusing mainly on STAT proteins. DIF-1 inhibited proliferation of gastric cancer cells. Western blot analysis and electrophoretic mobility shift assay showed that DIF-1 inhibited STAT3 activity in an MEK-ERK-dependent manner in gastric cancer cell lines, AGS and MKN28. Moreover, blockade of STAT3 activity by ectopic expression of dominant-negative STAT3 or the Janus kinase inhibitor, tyrphostin AG490, inhibited cell growth of AGS cells. These results suggest that STAT3 activity plays an important role for cell growth in AGS cells, and raises the possibility that inhibition of STAT3 activity is one of the mechanisms responsible for the antitumor effect of DIF-1 in these cells.

Background/Aims: Although regeneratinggene(Reg) Iα protein has a trophic effect on gastric epithelial cells, it is unclear whether Reg Iα protein and its receptor are involved in gastric carcinogenesis. Therefore, we investigated the Reg Iα protein expression in human gastric cancers and assessed its relationship to clinicopathological factors. Methods: Sixty-one gastric cancer specimens were examined, using immunohistochemistry, for Reg Iα protein, p53, and proliferating cell nuclear antigen. The expression of both Reg Iα and Reg receptor mRNA was examined in seven human gastric cancer cell lines (MKN1, MKN28, MKN45, MKN74, KATOIII, GCIY, and AGS) by reverse transcription-polymerase chain reaction and Northern blot analysis. Results: Twenty-three (37.7%) of the 61 gastric cancer tissues samples were positive for Reg Iα protein. The Reg Iα expression was significantly related to the presence of lymphatic invasion but not to tumor size, tumor stage, Lauren’s classification, presence of venous invasion, lymph node metastases, or p53 overexpression. Gastric cancers positive for Reg Iα protein showed a significantly higher proliferating cell nuclear antigen labeling index than negative ones. The expression of both Reg Iα and Reg receptor mRNA was detected in all seven gastric cancer cell lines. Conclusion: Reg Iα protein may play a role in the development of gastric cancers.