Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells
Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells
复制标题
DOI：
10.1023/a:1006764100867
复制
发表时间：
2000-01-01
影响因子：
4
通讯作者：
Eccles, SA
中科院分区：
文献类型：
--
作者：
O-charoenrat, P;Rhys-Evans, P;Eccles, SA
酪氨酸激酶如c-erbB和EGFR的异常表达有助于头颈部鳞状细胞癌（HNSCC）的进展。一种机制可能是血管生成的增强，因为已经描述了通过表皮生长因子受体（EGFR）和/或c-erbB-2的活化上调血管内皮生长因子（VEGF）表达。首先，我们证明了VEGF家族的所有4个成员在一组过表达一种或多种c-erbB受体的15种HNSCC细胞系中的表达。然后，我们探索了三种主要配体对所选HNSCC系中VEGF-A、B、C和D表达的调节作用，这些配体具有不同的与c-erbB B受体结合的选择性（即转化生长因子-α（TGF-α）、β细胞素（BTC）和调蛋白-β 1（HRG-β 1））。使用半定量逆转录-PCR，我们发现所有三种c-erbB配体上调VEGF-A mRNA（所有亚型）和VEGF-C（BTC最大值为1-10 nM; TGF-α和HRG-beta1最大值为10-100 nM），但对VEGF-B没有影响。有趣的是，所有配体同时下调VEGF-D mRNA的表达。阻断EGFR配体结合的单克隆抗体（mAb）（ICR 62）下调VEGF-A（所有亚型）和VEGF-C的基础水平，对VEGF-B没有可检测的影响，并增加VEGF-D。ICR 62还逆转了所有三种erbB配体（TGF-α、BTC和HRG-β 1）对VEGF-A、VEGF-C和VEGF-D表达的影响。抗c-erbB-2 mAb（ICR 12）对这些细胞系中VEGF的基础或配体调节表达显示出相似的作用，尽管程度较低。我们的研究结果表明，四个VEGF基因的调节c-erbB信号通路在一个显着不同的方式，这表明他们服务不同的，虽然可能是互补的（VEGF-A和VEGF-C）或拮抗（VEGF-D）功能。EGFR和c-erbB-2信号通路在HNSCC中的VEGF调节中起作用，尽管EGFR似乎在该细胞类型中占主导地位。
Aberrant expression of tyrosine kinases such as c-erbB and EGFR contributes to the progression of head and neck squamous cell carcinomas (HNSCCs). One mechanism may be potentiation of angiogenesis, since upregulation of vascular endothelial growth factor (VEGF) expression by activation of epidermal growth factor receptor (EGFR) and/or c-erbB-2 has been described. Firstly, we demonstrated expression of all 4 members of the VEGF family in a panel of 15 HNSCC cell lines which over-express one or more c-erbB receptors. We then explored the regulatory roles of three major ligands with different selectivity of binding to c-erbB receptors (namely transforming growth factor-alpha (TGF-alpha), betacellulin (BTC) and heregulin-beta1 (HRG-beta1)) on VEGF-A, B, C and D expression in selected HNSCC lines. Using semi-quantitative reverse transcription-PCR, we showed that all three c-erbB ligands up-regulated VEGF-A mRNA (all isoforms) and VEGF-C (BTC max at 1-10 nM; TGF-alpha and HRG-beta1 max at 10-100 nM) but had no effect on VEGF-B. Interestingly, all ligands simultaneously down-regulated the expression of VEGF-D mRNA. A monoclonal antibody (mAb) which blocks EGFR ligand binding (ICR62) down-regulated the basal levels of VEGF-A (all isoforms) and VEGF-C, had no detectable effects on VEGF-B and increased VEGF-D. ICR62 also reversed the effects of all three erbB ligands (TGF-alpha, BTC and HRG-beta1) on VEGF-A, VEGF-C and VEGF-D expression. An anti-c-erbB-2 mAb (ICR12) showed similar effects on basal or ligand-modulated expression of VEGF in these cell lines, although to a lesser extent. Our results reveal that the four VEGF genes are regulated by c-erbB signaling pathways in a strikingly different manner, suggesting that they serve distinct, although perhaps complimentary (VEGF-A and VEGF-C) or antagonistic (VEGF-D) functions. The EGFR and c-erbB-2 signaling pathway(s) plays a role in VEGF regulation in HNSCC, although EGFR would appear to be dominant in this cell type.