Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line
Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line
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DOI：
10.1096/fasebj.14.5.652
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发表时间：
2000-04-01
期刊：
影响因子：
4.8
通讯作者：
Del Bufalo, D
中科院分区：
文献类型：
--
作者：
Biroccio, A;Candiloro, A;Del Bufalo, D
我们以前已经证明，bcl-2过表达增强的MCF 7 Ablation人乳腺癌细胞系阿霉素耐药的转移潜力，诱导转移相关的属性。为了进一步阐明bcl-2表达与MCF 7 ADR细胞系转移潜能之间的关系，我们评估了bcl-2是否也参与了血管生成表型的调节。将四个bcl-2过表达克隆、对照转染子克隆和MCF 7 ADR亲本系用于体外和体内实验。Bcl-2过表达促进缺氧刺激的VEGF蛋白和mRNA的合成。北方印迹分析表明在bcl-2过表达的克隆中VEGF mRNA表达增加，逆转录-聚合酶链反应显示VEGF（121）和VEGF（165）mRNA亚型的水平更高，它们在引发血管生成中最活跃。当掺入基质胶，bcl-2转染细胞培养的上清液在缺氧条件下诱导C57 BL/6小鼠与对照克隆相比，增加血管生成反应。从bcl-2转染的肿瘤表现出增加的VEGF表达和新血管形成相比，父母线，而在体内异种移植的细胞凋亡是类似的控制和bcl-2转染。bcl-2对血管生成的影响不通过p53蛋白介导。这些结果表明，bcl-2和缺氧可协同作用以调节MCF 7 ADR系中的VEGF表达和体内血管生成反应-Biroccio，A.，Angloro，A.，Mottolese，M.，Sapora，O.，阿尔比尼，A.，Zupi，G.，Del Bufalo，D. Bcl-2过表达和缺氧协同调节乳腺癌细胞系血管内皮生长因子表达和体内血管生成
We have previously demonstrated that bcl-2 overexpression enhances the metastatic potential of the MCF7 ADIR human breast cancer cell line resistant to adriamycin by inducing metastasis-associated properties. To further elucidate the relationship between bcl-2 expression and the metastatic potential of the MCF7 ADR line, we evaluated whether bcl-2 could be also involved in the modulation of the angiogenic phenotype. Four bcl-2-overexpressing clones, a control transfectant clone, and the MCF7 ADR parental Line were used for in vitro and in vivo experiments. Bcl-2 overexpression enhanced the synthesis of the hypoxia-stimulated VEGF protein and mRNA. Northern blot analysis demonstrated an increased VEGF mRNA expression in bcl-2-overexpressing clones, and reverse transcription-polymerase chain reaction showed higher levels of the VEGF(121) and VEGF(165) mRNA isoforms, which are the most active in eliciting angiogenesis. When incorporated into matrigel, supernatants of bcl-2-transfected cells cultured under hypoxic conditions induced an increased angiogenic response in C57BL/6 mice compared with that of control clone. Tumors from bcl-2 transfectants demonstrated increased VEGF expression and neovascularization as compared to the parental line, whereas the apoptosis in in vivo xenografts was similar in control and bcl-2 transfectants. The effect of bcl-2 on angiogenesis was not mediated by p53 protein. These results demonstrate that bcl-2 and hypoxia can act synergistically to modulate VEGF expression and the in vivo angiogenic response in the MCF7 ADR line-Biroccio, A., Candiloro, A., Mottolese, M., Sapora, O., Albini, A., Zupi, G., Del Bufalo, D. Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line.