Prolyl-4-hydroxylase PHD2-and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis
Prolyl-4-hydroxylase PHD2-and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis
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DOI：
10.1038/onc.2010.433
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发表时间：
2011-02-01
期刊：
影响因子：
8
通讯作者：
Camenisch, G.
中科院分区：
文献类型：
--
作者：
Bordoli, M. R.;Stiehl, D. P.;Camenisch, G.
缺氧引起的肿瘤细胞适应对于肿瘤生长和癌症进展至关重要。尽管有充足的证据表明缺氧诱导因子 (HIF) 与肿瘤形成、转移和不良预后之间存在正相关，但 HIF-α 蛋白稳定性调节脯氨酰 4-羟化酶结构域酶 PHD2 在致癌作用中的功能尚不清楚。在这项研究中，我们证明 PHD2 的下调会导致激素依赖性乳腺癌小鼠模型中肿瘤生长增加。对 281 个人类乳腺癌临床样本中 PHD2 蛋白表达的组织微阵列分析显示，低水平 PHD2 肿瘤患者 10 年生存时间显着缩短。血管生成相关抗体阵列发现，双调蛋白在 PHD2 不存在的情况下会增加，并在 PHD2 重建后恢复正常。在源自 PHD2 下调细胞的条件培养基中培养内皮细胞，导致管形成增强，而添加中和性抗双调蛋白抗体可阻断这一增强。从功能上讲，双调蛋白在转录水平上受 HIF-2 而非 HIF-1 特异性调节。我们的数据表明，PHD2/HIF-2/双调蛋白信号在乳腺肿瘤进展的调节中具有关键作用，并提出 PHD2 作为乳腺癌的潜在肿瘤抑制因子。癌基因 (2011) 30, 548-560; doi：10.1038/onc.2010.433； 2010 年 9 月 20 日在线发布
Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxia-inducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-alpha protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer. Oncogene (2011) 30, 548-560; doi: 10.1038/onc.2010.433; published online 20 September 2010