GDNF increases cell motility in human colon cancer through VEGF-VEGFR1 interaction
GDNF increases cell motility in human colon cancer through VEGF-VEGFR1 interaction
复制标题
DOI：
10.1530/erc-13-0351
复制
发表时间：
2014-02-01
影响因子：
3.9
通讯作者：
Lu, Dah-Yuu
中科院分区：
文献类型：
--
作者：
Huang, Ssu-Ming;Chen, Tzu-Sheng;Lu, Dah-Yuu
胶质细胞源性神经营养因子（GDNF）是一种有效的神经营养因子，已被证明可以影响癌细胞的转移和侵袭。然而，GDNF 诱导结肠癌细胞迁移的分子机制仍不清楚。研究发现 GDNF 与人类结肠癌患者的恶性肿瘤呈正相关。两种人类结肠癌细胞系 HCT116 和 SW480 的迁移活性被发现在人类 GDNF 存在下增强。血管内皮生长因子 (VEGF) 的表达以及 VEGF mRNA 的表达和转录活性也随着 GDNF 的刺激而增加。 GDNF 诱导的癌细胞迁移的增强被 VEGF 中和抗体拮抗。我们的结果还表明，GDNF 刺激后 VEGF 受体 1 (VEGFR1) 的表达增加，而 VEGFR 抑制剂则减少 GDNF 诱导的癌细胞迁移。 GDNF 诱导的 VEGF 表达受到 p38 和 PI3K/Akt 信号通路的调节。 GDNF 治疗以时间依赖性方式增加核缺氧诱导因子 1 α (HIF1 α) 的积累及其转录活性。此外，GDNF 增加了含有缺氧反应元件 (HRE) 的 VEGF 启动子转录活性，但不增加 HRE 缺失 VEGF 启动子构建体的转录活性。药物抑制剂或显性失活突变体对 HIF1 α 的抑制降低了 GDNF 诱导的人结肠癌细胞的迁移活性。这些结果表明，GDNF通过增加VEGF-VEGFR相互作用来增强结肠癌细胞的迁移，该相互作用主要受p38、PI3K/Akt和HIF1α信号通路的调节。
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 alpha (HIF1 alpha) 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 HIF1 alpha by a pharmacological inhibitor or dominant-negative mutant reduced theGDNF-inducedmigratory 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 HIF1 alpha signaling pathways.