Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated with malignancy in human colon cancer patients. The migratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of human GDNF. The expression of vascular endothelial growth factor (VEGF) was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-induced cancer cell migration was reduced by a VEGFR inhibitor. The GDNF-induced VEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 a (HIF1a) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1a by a pharmacological inhibitor or dominant-negative mutant reduced the GDNF-induced migratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF-VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1a signaling pathways.

SummaryNinety-one patients were randomly allocated to one of two groups. Group A was induced with a single vital capacity breath of 6% (end-tidal) sevoflurane in nitrous oxide±oxygen (2 : 1 l.min 21 ), whereas group B was induced with intravenous fentanyl 1 mg.kg 21 1 propofol 2 mg.kg 21 followed by nitrous oxide±oxygen (2 : 1 l.min 21 ) and sevoflurane. Induction was considered to have been achieved when the bispectral index value decreased to below 70. Mean induction time in group A (95.2 s, 95% CI 88.5±101.9 s) was longer than group B (70.3 s, 95% CI 66.3±74.3 s; p , 0.0001). Mild coughing was more common in group A, but relative hypotension was more common in group B. There was no difference in the emergence times. Thirty minutes after emergence, there was no difference in the incidence of adverse effects, with the exception of essentially mild abdominal pain which was more frequent in group A.

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