Brain-derived neurotrophic factor regulates cell motility in human colon cancer
Brain-derived neurotrophic factor regulates cell motility in human colon cancer
复制标题
DOI：
10.1530/erc-15-0007
复制
发表时间：
2015-06-01
影响因子：
3.9
通讯作者：
Yeh, Wei-Lan
中科院分区：
文献类型：
--
作者：
Huang, Ssu-Ming;Lin, Chingju;Yeh, Wei-Lan
脑源性神经营养因子(BDNF)是一种强有力的神经营养因子，已被证明可影响癌细胞的转移和迁移。在本研究中，我们研究了BDNF诱导结肠癌细胞迁移的机制。两种结肠癌细胞系HCT116和SW480的迁移活性在人BDNF存在时被增强。血红素氧合酶-1(HO)-1与肿瘤的发生发展密切相关。然而，HO-1调控结肠癌细胞迁移的分子机制仍不清楚。脑源性神经营养因子刺激后，HO-1蛋白和mRNA表达增加。BDNF诱导的细胞迁移增加可被HO-1抑制剂和HO-1 siRNA拮抗。此外，血管内皮生长因子(VEGF)的表达也随着BDNF刺激的增加而增加，VEGFmRNA的表达和转录活性也增加。BDNF诱导的癌细胞迁移增加可被血管内皮生长因子中和抗体所拮抗。此外，HO-1 siRNA可有效抑制BDNF诱导的血管内皮细胞生长因子表达增加。BDNF诱导的细胞迁移受ERK、p38和Akt信号通路的调控。此外，在结肠癌细胞中，ERK、p38和AKT药物抑制剂和显性负性突变体可以抑制BDNF增加的HO-1和VEGF启动子的转录活性。这些结果表明，BDNF通过ERK、p38和PI3K/Akt信号通路调节VEGF/HO-1的激活，从而促进结肠癌细胞的迁移。本研究的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的贡献。
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.