EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis.
EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis.
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DOI：
10.1210/js.2016-1053
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发表时间：
2017-02-01
影响因子：
4.1
通讯作者：
Melmed S
中科院分区：
文献类型：
--
作者：
Araki T;Liu X;Kameda H;Tone Y;Fukuoka H;Tone M;Melmed S
表皮生长因子受体（EGFR）在促肾上腺皮质激素（ACTH）分泌垂体腺瘤中表达，可引起库欣病，调节ACTH的产生和促肾上腺皮质激素细胞的增殖。为了阐明EGFR作为库欣病治疗靶点的效用，我们使用新构建的促皮质激素特异性启动子产生了具有促皮质激素特异性人EGFR表达的转基因（Tg）小鼠（皮质-EGFR-Tg）。2.5个月时观察到垂体特异性EGFR表达，8个月时观察到具有Crooke细胞特征的侵袭性ACTH分泌型垂体腺瘤，复发率为65%。与库欣表型一致的特征包括血浆ACTH和皮质酮水平升高、体重增加、葡萄糖耐受不良和肾上腺皮质增大。EGFR酪氨酸激酶抑制剂吉非替尼可抑制肿瘤POMC表达和下游EGFR肿瘤信号传导，ACTH和皮质酮水平分别降低80%和78%。E2 F1和磷酸化Ser-337 E2 F1在皮质-EGFR-Tg小鼠中均增加，并且在人垂体促肾上腺皮质激素细胞肿瘤样品中与人POMC（hPOMC）共定位。EGFR抑制逆转E2 F1的活性在体内，而E2 F1抑制抑制POMC和ACTH在培养的人垂体瘤细胞。皮质-EGFR-Tg表型重现了ACTH分泌型垂体腺瘤和库欣病，证实了EGFR与促肾上腺皮质激素肿瘤发生的相关性。E2 F1被认为是治疗ACTH依赖性库欣病的一个有前景的促皮质激素特异性靶点。Araki等人制备了一种促皮质激素特异性的EGFR表达转基因小鼠，重现了人垂体库欣病，并显示EGFR诱导的E2 F1是治疗库欣病的有希望的靶点。
The epidermal growth factor receptor (EGFR), expressed in adrenocorticotrophic hormone (ACTH)–secreting pituitary adenomas causing Cushing disease, regulates ACTH production and corticotroph proliferation. To elucidate the utility of EGFR as a therapeutic target for Cushing disease, we generated transgenic (Tg) mice with corticotroph-specific human EGFR expression (corti-EGFR-Tg) using a newly constructed corticotroph-specific promoter. Pituitary-specific EGFR expression was observed by 2.5 months, and aggressive ACTH-secreting pituitary adenomas with features of Crooke’s cells developed by 8 months with 65% penetrance observed. Features consistent with the Cushing phenotype included elevated plasma ACTH and corticosterone levels, increased body weight, glucose intolerance, and enlarged adrenal cortex. Gefitinib, an EGFR tyrosine kinase inhibitor, suppressed tumor POMC expression and downstream EGFR tumor signaling, and ACTH and corticosterone levels were attenuated by 80% and 78%, respectively. Both E2F1 and phosphorylated Ser-337 E2F1 were increased in corti-EGFR-Tg mice and also colocalized with human POMC (hPOMC) in human pituitary corticotroph tumor samples. EGFR inhibition reversed E2F1 activity in vivo, whereas E2F1 inhibition suppressed POMC and ACTH in cultured human pituitary tumor cells. The corti-EGFR-Tg phenotype recapitulates ACTH-secreting pituitary adenomas and Cushing disease, validating the relevance of EGFR to corticotroph tumorigenesis. E2F1 is identified as a promising corticotroph-specific target for ACTH-dependent Cushing disease. Araki et al. generated a corticotroph-specific, EGFR-expressing transgenic mouse recapitulating human pituitary Cushing disease and showed EGFR-induced E2F1 as a promising target for Cushing disease.