title: GDNF increases cell motility in human colon cancer through VEGF-VEGFR1 interaction.
abstract: 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 α (HIF1α) 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 HIF1α 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 HIF1α signaling pathways.
authors.affiliation: Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan Preventive Medicine Center, Department of Community Medicine, Taichung Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan Division of Colon and Rectal Surgery, Department of Surgery, Taichung Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan School of Medicine, Tzu Chi University, Hualien, Taiwan Departments of Pathology Internal Medicine, Taichung Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan Graduate Institute of Integrated Medicine, Department of Chinese Medicine, China Medical University, Taichung, Taiwan Department of Medical Research, Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan Graduate Institute of Neural and Cognitive Sciences, China Medical University, No.91 Hsueh-Shih Road, Taichung, Taiwan.
authors.forename: Ssu-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Tzu-Sheng
authors.initials: TS
authors.lastname: Chen
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Chiu
authors.forename: Leang-Kai
authors.initials: LK
authors.lastname: Chang
authors.forename: Kuan-Fu
authors.initials: KF
authors.lastname: Liao
authors.forename: Hsiao-Ming
authors.initials: HM
authors.lastname: Tan
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.forename: Gary Ro-Lin
authors.initials: GR
authors.lastname: Chang
authors.forename: Min-Ying
authors.initials: MY
authors.lastname: Wang
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D040281:Vascular Endothelial Growth Factor Receptor-1; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
keywords: GDNF; HIF1; VEGF; cell motility; colon cancer