Huang Ssu-Ming, Lin Chingju, Lin Hsiao-Yun, Chiu Chien-Ming, Fang Chia-Wei, Liao Kuan-Fu, Chen Dar-Ren, Yeh Wei-Lan
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
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.
Endocr Relat Cancer. 2015 Jun;22(3):455-64. doi: 10.1530/ERC-15-0007. Epub 2015 Apr 15.
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.
脑源性神经营养因子（BDNF）是一种强效神经营养因子，已被证明可影响癌细胞的转移和迁移。在本研究中，我们调查了BDNF诱导结肠癌细胞迁移的机制。发现在人BDNF存在的情况下，两种结肠癌细胞系HCT116和SW480的迁移活性增加。血红素加氧酶-1（HO）-1已知参与肿瘤的发生和发展。然而，HO-1在调节结肠癌细胞迁移中所涉及的分子机制仍不清楚。HO-1蛋白和mRNA的表达在BDNF刺激下增加。HO-1抑制剂和HO-1 siRNA可拮抗BDNF诱导的细胞迁移增加。此外，血管内皮生长因子（VEGF）的表达在BDNF刺激下也增加，VEGF mRNA表达和转录活性同样增加。VEGF中和抗体可拮抗BDNF诱导的癌细胞迁移增加。此外，用HO-1 siRNA转染可有效降低BDNF诱导的VEGF表达增加。BDNF诱导的细胞迁移受ERK、p38和Akt信号通路调节。此外，ERK、p38和AKT药理抑制剂以及显性负突变体可抑制BDNF增加的HO-1和VEGF启动子转录活性。这些结果表明，BDNF通过ERK、p38和PI3K/Akt信号通路调节VEGF/HO-1激活，从而增加结肠癌细胞的迁移。本研究结果可能为我们理解BDNF促进结肠癌细胞运动的分子机制提供相关贡献。
