Reduced protein expression of the phosphodiesterases PDE4A4 and PDE4A8 in AIP mutation positive somatotroph adenomas
Reduced protein expression of the phosphodiesterases PDE4A4 and PDE4A8 in AIP mutation positive somatotroph adenomas
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DOI：
10.1016/j.mce.2018.04.014
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发表时间：
2018-11-15
影响因子：
4.1
通讯作者：
Korbonits, Marta
中科院分区：
文献类型：
--
作者：
Bizzi, Mariana Ferreira;Brant Pinheiro, Sergio Veloso;Korbonits, Marta
大 PDE 酶超家族的 4 型磷酸二酯酶 (PDE4) 对 cAMP 具有独特的特异性，因此可能与生长激素肿瘤的发生有关。生长激素细胞腺瘤通常过度表达 PDE，这可能是降低 cAMP 水平的补偿机制的一部分。大鼠 PDE4A5 异构体（人类同源物 PDE4A4）与 AIP 蛋白相互作用，该蛋白由家族性孤立性垂体腺瘤 (FIPA) 亚组中突变的肿瘤抑制基因编码。 PDE4A8 是 PDE4A4 最相关的亚型。我们的目的是评估 AIP 突变腺瘤 GH 细胞中 PDE4A4 和 PDE4A8 的表达，并将它们的表达与散发性 AIP 突变阴性 GH 分泌腺瘤的 GH 细胞中的表达进行比较，我们之前已经证明 PDE4A4 和 PDE4A8 亚型均过表达。共聚焦免疫荧光分析显示，与散发性 GH 分泌肿瘤相比，AIP 突变的生长激素瘤样本中 PDE4A8 和 PDE4A4 的表达均较低（两者 P < 0.0001）。基于 PDE4A4 和 PDE4A8 低表达与种系 AIP 突变阳性样本的关联，我们认为 AIP 的缺乏阻碍了散发性生长激素瘤中 PDE4A8 和 PDE4A4 蛋白的上调。这些数据表明 AIP 突变阳性腺瘤中 cAMP-PDE 通路存在独特的紊乱，这可能有助于解释其对生长抑素类似物的不良反应。
Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.