Phosphorylation of cAMP response element binding protein (CREB) as a marker of hypoxia in pituitary adenoma
Phosphorylation of cAMP response element binding protein (CREB) as a marker of hypoxia in pituitary adenoma
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DOI：
10.1007/s11060-006-9131-3
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发表时间：
2006-09-01
影响因子：
3.9
通讯作者：
Teramoto, Akira
中科院分区：
文献类型：
--
作者：
Morimoto, Daijiro;Yoshida, Daizo;Teramoto, Akira
缺氧似乎与垂体腺瘤有关。目前，没有生物标志物可用于术后评估患者样本中的缺氧情况。由于 cAMP 反应元件结合蛋白 (CREB) 在缺氧条件下被磷酸化，我们研究了 CREB 磷酸化水平是否可以用作垂体腺瘤组织缺氧的新型生物标志物。将HP-75人垂体腺瘤细胞在21%或1%氧（分别为常氧和缺氧）下培养，采用Western blotting比较CREB和磷酸化CREB（p-CREB）的水平。我们的结果表明，在 1% 的氧气下，p-CREB 水平显着升高，而总 CREB 浓度保持不变。我们进一步测试了这种磷酸化是否可用作 45 名患者（32 名女性和 13 名男性，22-78 岁）经蝶手术切除的垂体腺瘤组织缺氧的标志物。荧光双免疫组化数据显示，腺瘤组织中p-CREB显着升高，与Knosp分级呈正相关（Spearman等级相关；P = 0.0483，r = 0.3412），但与肿瘤亚型无显着相关性（Kruskal-Wallis分析，CREB，P = 0.1072；p-CREB，P = 0.1888； 磷酸化率，P = 0.4916）。我们的研究结果总体表明 CREB 磷酸化可用作缺氧的原位标记。此外，CREB的缺氧和/或磷酸化与垂体腺瘤的细胞侵袭性有关。
Hypoxia appears to be causatively related to pituitary adenoma. Currently, no biomarkers are available for the postoperative assessment of hypoxia in patient samples. Since the cAMP response element binding protein (CREB) is phosphorylated under hypoxic conditions, we examined whether CREB phosphorylation levels may be exploited as a novel biomarker for hypoxia in pituitary adenoma tissues. HP-75 human pituitary adenoma cells were incubated in 21% or 1% oxygen (normoxia and hypoxia, respectively), and Western blotting was employed to compare the levels of CREB and phosphorylated CREB (p-CREB). Our results show that p-CREB levels are significantly elevated under 1% oxygen, whereas the total CREB concentration remains unchanged. We further tested whether this phosphorylation is applicable as a marker of hypoxia in pituitary adenoma tissues removed by transsphenoidal surgery from 45 patients (32 females and 13 males, 22-78 years old). Fluorescence double immunohistochemistry data revealed that p-CREB in adenoma tissues is significantly elevated, and displays a positive correlation with Knosp grading (Spearman rank correlation; P = 0.0483, r = 0.3412), but no significant association with tumor subtype (Kruskal-Wallis analysis, CREB, P = 0.1072; p-CREB, P = 0.1888; phosphorylation ratio, P = 0.4916). Our findings collectively suggest that CREB phosphorylation may be employed as an in situ marker for hypoxia. Moreover, hypoxia and/or phosphorylation of CREB are associated with the cell invasiveness of pituitary adenomas.