Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian, China.
Mol Biol Rep. 2012 Apr;39(4):4127-34. doi: 10.1007/s11033-011-1195-2. Epub 2011 Jul 17.
Increasing evidence indicates that in gastric epithelial cells, induction of TFF3 by hypoxia is mediated by HIF-1. Since VEGF is one of the most important angiogenic factors on cancer progression, we have started to investigate the possible link among HIF-1α, VEGF, and TFF3 in gastric cancer cells. We induced the hypoxic condition in SGC-7901cells using hypoxia-mimetic agent of CoCI2. SGC7901 cells were transfected with pcPUR + U6 plasmid carrying RNAi targeted to human TFF3 and selected puromycin-resistant pools to establish the stable knockdown of TFF3 cells. Our results showed the induction of HIF-1a via hypoxia and consequences of increased expressions of the TFF3 and VEGF in gastric cancer SGC-7901 cells. Overexpression of TFF3 upregulated the mRNA expressions of VEGF and HIF-1a induced by hypoxia, and stable knockdown of TFF3 impaired the mRNA upregulations of VEGF and HIF-1a induced by hypoxia. Furthermore, knockdown of TFF3 reduced the VEGF protein secretion: as VEGF secretion was increased time dependent manner in response to the hypoxia induction in TFF3-WT cells; however, VEGF production was significantly decreased in TFF3-KD cells (621 ± 89 vs. 264 ± 73 at 6 h and 969 ± 97 vs. 508 ± 69 at 12 h, P < 0.05). Our data demonstrated the TFF3 mediated regulation of VEGF expression induced by hypoxia, and implicated that TFF3 might be applied as a potential anti-angiogenic target for treatment of gastric cancer.
越来越多的证据表明，在胃上皮细胞中，缺氧诱导 TFF3 的产生是由 HIF-1 介导的。由于 VEGF 是癌症进展过程中最重要的血管生成因子之一，我们开始研究胃癌细胞中 HIF-1α、VEGF 和 TFF3 之间的可能联系。我们使用缺氧模拟剂 CoCI2 诱导 SGC-7901 细胞缺氧。将靶向人 TFF3 的 RNAi 的 pcPUR+U6 质粒转染到 SGC7901 细胞中，并选择嘌呤霉素抗性池来建立 TFF3 细胞的稳定敲低。我们的结果表明，缺氧诱导 HIF-1a 以及 TFF3 和 VEGF 在胃癌 SGC-7901 细胞中的表达增加。TFF3 的过表达上调了缺氧诱导的 VEGF 和 HIF-1a 的 mRNA 表达，而 TFF3 的稳定敲低则削弱了缺氧诱导的 VEGF 和 HIF-1a 的 mRNA 上调。此外，TFF3 的敲低减少了 VEGF 蛋白的分泌：在 TFF3-WT 细胞中，随着缺氧诱导，VEGF 分泌呈时间依赖性增加；然而，在 TFF3-KD 细胞中，VEGF 产生显著减少（6 小时时分别为 621±89 与 264±73，12 小时时分别为 969±97 与 508±69，P<0.05）。我们的数据表明，TFF3 介导了缺氧诱导的 VEGF 表达的调节，并暗示 TFF3 可能作为治疗胃癌的潜在抗血管生成靶标。
