Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Ssu-Ming Huang; Chingju Lin; Hsiao-Yun Lin; Chien-Ming Chiu; Chia-Wei Fang; Kuan-Fu Liao; Dar-Ren Chen; Wei-Lan Yeh

doi:10.1530/ERC-15-0007

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Endocr Relat Cancer. 2015 Jun;22(3):455-64. doi: 10.1530/ERC-15-0007. Epub 2015 Apr 15.

Authors

Ssu-Ming Huang¹, Chingju Lin², Hsiao-Yun Lin², Chien-Ming Chiu², Chia-Wei Fang², Kuan-Fu Liao¹, Dar-Ren Chen², Wei-Lan Yeh³

Affiliations

¹ Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Ch
² Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan.
³ Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan ibizayeh0816@hotmail.com.

PMID: 25876647
DOI: 10.1530/ERC-15-0007

Abstract

Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominant-negative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

Keywords: BDNF; HO-1; VEGF; colon cancer; migration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain-Derived Neurotrophic Factor / blood*
Brain-Derived Neurotrophic Factor / genetics
Cell Line, Tumor
Cell Movement / physiology*
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism*
Colonic Neoplasms / pathology*
Enzyme Induction
HCT116 Cells
Heme Oxygenase-1 / biosynthesis
Heme Oxygenase-1 / genetics
Humans
Signal Transduction
Transfection
Up-Regulation
Vascular Endothelial Growth Factor A / biosynthesis
Vascular Endothelial Growth Factor A / genetics

Substances

Brain-Derived Neurotrophic Factor
VEGFA protein, human
Vascular Endothelial Growth Factor A
BDNF protein, human
HMOX1 protein, human
Heme Oxygenase-1