Kozlova Nina, Wottawa Marieke, Katschinski Dörthe Magdalena, Kristiansen Glen, Kietzmann Thomas
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
Oncotarget. 2017 Feb 7;8(6):9885-9898. doi: 10.18632/oncotarget.14241.
Clinical studies in breast cancer suggest important associations between intratumoral hypoxia, the upregulation of epidermal growth factor receptor (EGFR or HER1), hypoxia-inducible factor 1α (HIF-1α), and reduced patient survival. However, direct molecular links between EGFR and the hypoxia signaling system are not yet established. Since the oxygen sensor hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is considered to be the main HIF-1α regulator, we hypothesized that PHD2 and EGFR may be interconnected at the molecular level. By analyzing samples from 313 breast cancer patients, we found that EGFR is a first clinicopathological parameter positively correlating with PHD2. Mechanistically, we identified PHD2 as a direct binding partner of EGFR and show that PHD2 regulates EGFR stability as well as its subsequent signaling in breast carcinoma cells. Overall, we introduce for the first time the direct crosstalk between the oxygen sensor PHD2 and EGFR-mediated tumorigenesis in breast cancer.
乳腺癌的临床研究表明，肿瘤内缺氧、表皮生长因子受体（EGFR或HER1）上调、缺氧诱导因子1α（HIF-1α）与患者生存率降低之间存在重要关联。然而，EGFR与缺氧信号系统之间的直接分子联系尚未确立。由于氧传感器缺氧诱导因子脯氨酰羟化酶2（PHD2）被认为是主要的HIF-1α调节因子，我们推测PHD2和EGFR可能在分子水平上相互关联。通过分析313例乳腺癌患者的样本，我们发现EGFR是第一个与PHD2呈正相关的临床病理参数。从机制上讲，我们确定PHD2是EGFR的直接结合伴侣，并表明PHD2调节EGFR的稳定性及其在乳腺癌细胞中的后续信号传导。总体而言，我们首次介绍了氧传感器PHD2与EGFR介导的乳腺癌肿瘤发生之间的直接相互作用。
