Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea.
Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Cancer Res Treat. 2016 Jan;48(1):345-54. doi: 10.4143/crt.2014.247. Epub 2015 Mar 3.
We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1.
Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues.
In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues.
Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.
我们之前曾报道过，O 类 1 叉头转录因子（FOXO1）在胃癌（GC）中的表达与血管生成相关分子有关。然而，FOXO1 在 GC 中直接作用的实验证据很少。在本研究中，我们研究了 FOXO1 对 GC 发生和血管生成的影响及其与 SIRT1 的关系。
通过慢病毒转染稳定的 GC 细胞系（SNU-638 和 SNU-601），建立用于动物研究和细胞培养实验的细胞系。我们使用裸鼠异种移植肿瘤来评估 FOXO1 沉默对肿瘤生长和血管生成的影响。此外，我们通过对 471 例人 GC 标本的免疫组织化学组织阵列分析和异种移植瘤组织的 Western blot 分析，检查了 FOXO1 和 SIRT1 之间的关联。
在细胞培养中，FOXO1 沉默增强了缺氧诱导因子-1α（HIF-1α）在缺氧条件下的表达和 GC 细胞的生长，但在常氧条件下没有。在异种移植研究中，FOXO1 下调增强了肿瘤生长、微血管面积、HIF-1α 激活和血管内皮生长因子（VEGF）表达。此外，在人 GC 组织和异种移植瘤组织中，失活的 FOXO1 表达与 SIRT1 表达相关。
我们的研究结果表明，FOXO1 通过失活 HIF-1α-VEGF 通路抑制缺氧条件下的 GC 生长和血管生成，可能与 SIRT1 有关。因此，开发针对该通路的治疗方法可能对治疗 GC 有用。
