Ruohola J K, Valve E M, Karkkainen M J, Joukov V, Alitalo K, Härkönen P L
Institute of Biomedicine, Department of Anatomy, University of Turku, Finland.
Mol Cell Endocrinol. 1999 Mar 25;149(1-2):29-40. doi: 10.1016/s0303-7207(99)00003-9.
Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and an important prognostic factor in breast cancer. Hypoxia is an important inducer of VEGF expression but less is known of the role of hormones in VEGF regulation. We have studied the regulation of VEGF, VEGF-B, VEGF-C, and VEGF-D mRNAs in human MCF-7 and mouse S115 breast carcinoma cells stimulated by estrogens and androgens, respectively. VEGF, VEGF-B, and VEGF-C were expressed in both cell lines, whereas VEGF-D was expressed only in S115 cells. Addition of estradiol (E2) caused a biphasic increase of VEGF mRNA in MCF-7 cells and led to accumulation of the VEGF protein in the culture medium. The VEGF-B mRNA was not affected, while a decrease occurred in VEGF-C mRNA. Similarly, testosterone upregulated the expression of VEGF mRNA in the S115 cells. Experiments with actinomycin D and cycloheximide suggested that estrogen induction of VEGF mRNA is dependent on the synthesis of new mRNA and increased mRNA half-life. The antiestrogen ICI 182.780 inhibited E2 stimulation of VEGF, suggesting that the effect was mediated by the estrogen receptor. In contrast, the antiestrogens tamoxifen and toremifene which inhibit MCF-7 cell growth in vivo and in vitro did not inhibit estrogen effect but induced VEGF mRNA expression when used alone. The antiandrogen cyprosterone acetate inhibited T induction of VEGF mRNA in S115 cells, thus suggesting that activation of androgen receptor must be involved in the increase of VEGF mRNA. Our results suggest that both estrogen and androgen stimulate the expression of VEGF by increasing gene transcription and mRNA stability. In addition, the antiestrogens tamoxifen and toremifene also increased VEGF expression. Estrogen and androgen induction of VEGF expression and promotion of new vessel formation may be an important paracrine mechanism by which these hormones contribute to the early phase of tumor growth of hormonal cancer.
血管内皮生长因子（VEGF）是肿瘤血管生成的主要诱导因子，也是乳腺癌的重要预后因素。缺氧是VEGF表达的重要诱导因素，但激素在VEGF调节中的作用尚鲜为人知。我们分别研究了雌激素和雄激素刺激下人MCF-7和小鼠S115乳腺癌细胞中VEGF、VEGF-B、VEGF-C和VEGF-D mRNA的调节情况。VEGF、VEGF-B和VEGF-C在两种细胞系中均有表达，而VEGF-D仅在S115细胞中表达。添加雌二醇（E2）导致MCF-7细胞中VEGF mRNA呈双相增加，并导致培养基中VEGF蛋白的积累。VEGF-B mRNA未受影响，而VEGF-C mRNA减少。同样，睾酮上调了S115细胞中VEGF mRNA的表达。用放线菌素D和环己酰亚胺进行的实验表明，雌激素诱导VEGF mRNA依赖于新mRNA的合成以及mRNA半衰期的延长。抗雌激素药物ICI 182.780抑制E2对VEGF的刺激，表明该作用是由雌激素受体介导的。相比之下，在体内和体外均能抑制MCF-7细胞生长的抗雌激素药物他莫昔芬和托瑞米芬并不抑制雌激素的作用，反而单独使用时可诱导VEGF mRNA表达。抗雄激素药物醋酸环丙孕酮抑制睾酮对S115细胞中VEGF mRNA的诱导，因此表明雄激素受体的激活必定参与了VEGF mRNA的增加。我们的结果表明，雌激素和雄激素均通过增加基因转录和mRNA稳定性来刺激VEGF的表达。此外，抗雌激素药物他莫昔芬和托瑞米芬也增加了VEGF的表达。雌激素和雄激素诱导VEGF表达以及促进新血管形成可能是这些激素促进激素依赖性癌症肿瘤生长早期阶段的重要旁分泌机制。
