Abstract
Survivin, a member of the inhibitors of apoptosis protein family, is expressed during development and in various human cancers. However, the clinical relevance of survivin in cancer is still a matter of debate. Genes induced by hepatocyte growth factor (HGF) were screened using cDNA microarray technology in the stomach cancer cell lines, NUGC3 and MKN28. The levels of JunB, survivin, and uro-plasminogen activator (uPA) were up-regulated in cells treated with HGF in a dose-dependent manner. HGF-induced up regulation of JunB, survivin, and uPA was inhibited by pre-treatment with a MEK inhibitor (PD 98059). HGF-induced up-regulation of uPA was repressed by survivin knockdown. HGF enhanced the binding activity of JunB to the survivin promoter in control cells, but not in the JunB-shRNA cells. Transfection with survivin- shRNA resulted in a decrement of cell proliferation, as determined with MTT assays. In an in vitro invasion assay, significantly fewer cells transfected with survivin shRNA than control cells were able to invade across a Matrigel membrane barrier. In conclusion, survivin appeared to play an important role in the up-regulation of uPA induced by HGF via JunB and might contribute to HGF-mediated tumor invasion and metastasis, which may serve as a promising target for gastric cancer therapy.
Highlights
Gastric cancer is one of the leading causes of cancer death in Korea
We found that the levels of survivin, JunB and uro-plasminogen activator (uPA) were increased in hepatocyte growth factor (HGF)-treated gastric cancer cells and investigated the role of HGF-induced survivin activation in the expression of uPA
RT-polymerase chain reaction (PCR) showed that the level of expression of survivin was increased after HGF-treatment (Figure 2A)
Summary
Gastric cancer is one of the leading causes of cancer death in Korea. In spite of some progress in treatment, the diagnosis of gastric cancer still carries a poor prognosis. Considerable interest has focused on the regulation of apoptosis, which may potentially contribute to the development of cancer. Survivin is a novel member of the inhibitors of apoptosis family. Survivin is expressed during human embryonic development in most tumor tissues, but not expressed in terminally differentiated normal tissues (Altieri, 2003a; Chiou et al, 2003). A series of studies have indicated that survivin has a dual role in blocking cell apoptosis and regulating cell proliferation; over-expression of survivin correlates with the occurrence and development of gastric cancer (Altieri, 2003b; Miyachi et al, 2003). The over-expression of survivin has been shown to be correlated with aggressive and histologically-unfavorable neuroblastoma (Adida et al, 1998)
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