Division of Life and Pharmaceutical Sciences, Ewha Women's University, Seoul, Korea.
J Natl Cancer Inst. 2010 Mar 17;102(6):426-42. doi: 10.1093/jnci/djq026. Epub 2010 Mar 1.
Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A(225)) acetylates HIF-1alpha, triggering its degradation, and thus may play a role in decreased expression of VEGFA.
We generated Apc(Min/+)/mARD1A(225) transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A(225) were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A(225) acetylation of Lys532 in HIF-1alpha, we injected B16F10-mARD1A(225) cell lines stably expressing mutant HIF-1alpha/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.
Apc(Min/+)/mARD1A(225) transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc(Min/+) mice (n = 21) (number of intestinal polyps per mouse: Apc(Min/+) mice vs Apc(Min/+)/mARD1A(225) transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A(225)-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A(225) decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and Apc(Min/+) intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1alpha in B16F10-mARD1A(225) cells prevented HIF-1alpha degradation and inhibited the antimetastatic effect of mARD1A(225) (P < .001).
mARD1A(225) may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis.
血管内皮生长因子 A（VEGFA）是肿瘤血管生成的关键介质，是缺氧诱导因子 1（HIF-1）的一个特征靶点。鼠 ARD1A（mARD1A(225)）蛋白可乙酰化 HIF-1α，触发其降解，从而可能在 VEGFA 表达降低中发挥作用。
我们生成了 Apc(Min/+)/mARD1A(225) 转基因小鼠，并量化了肠息肉的生长情况。将过表达 mARD1A(225)的人胃癌 MKN74 和鼠黑色素瘤 B16F10 细胞注入小鼠体内，测量肿瘤生长和转移情况。使用免疫组织化学法评估肿瘤中 VEGFA 表达和微血管密度。为了评估 mARD1A(225)对 HIF-1α赖氨酸 532 乙酰化的作用，我们将稳定表达突变 HIF-1α/K532R 的 B16F10-mARD1A(225)细胞系注入小鼠体内，并测量转移情况。所有统计检验均为双侧检验，P 值小于 0.05 被认为具有统计学意义。
Apc(Min/+)/mARD1A(225) 转基因小鼠（n = 25）的肠息肉数量明显少于 Apc(Min/+) 小鼠（n = 21）（每只小鼠的肠息肉数量：Apc(Min/+) 小鼠 vs Apc(Min/+)/mARD1A(225) 转基因小鼠，平均值 = 83.4 个 vs 38.0 个息肉，差异 = 45.4 个息肉，95%置信区间[CI] = 41.8 至 48.6；P < 0.001）。与对照组相比，注射 mARD1A(225)过表达细胞的小鼠的移植瘤生长和转移也明显减少（P < 0.01）。此外，mARD1A(225)的过表达降低了肿瘤异种移植物中的 VEGFA 表达和微血管密度（P < 0.04）和 Apc(Min/+)肠息肉中的 VEGFA 表达和微血管密度（P = 0.001）。B16F10-mARD1A(225) 细胞中 HIF-1α赖氨酸 532 的突变阻止了 HIF-1α 的降解，并抑制了 mARD1A(225)的抗转移作用（P < 0.001）。
mARD1A(225) 可能是一种阻断 VEGFA 表达和肿瘤相关血管生成的新型上游靶点。
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