Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas.
Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas.
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DOI：
10.1530/erc-17-0112
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发表时间：
2017-08
影响因子：
3.9
通讯作者：
Vassallo J
中科院分区：
文献类型：
--
作者：
Formosa R;Borg J;Vassallo J
垂体腺瘤（PA）是颅内肿瘤中最大的一组，但驱动这种疾病的分子机制仍在很大程度上未知。本研究的目的是使用高通量筛选方法来确定可能在PA中发挥重要和一致作用的分子途径。使用微阵列对8个本地PA的RNA分析确定了芳烃受体（AHR）信号通路作为所有PA类型中下调的关键经典通路。这在31个肿瘤中通过实时PCR得到证实。AHR已被证明可以调节各种细胞类型的细胞周期进程;然而，其在垂体组织中的作用从未被研究过。为了验证AHR在PA行为中的作用，进行了进一步的功能研究。GH 3细胞中AHR的过表达揭示了肿瘤抑制潜力，其独立于苯并α-芘（B α P）的外源配体激活。细胞周期分析和细胞周期调控基因的定量PCR结果显示，无论是未经刺激的还是经B α P刺激的AHR均能降低E2 F驱动的转录，改变细胞周期调控基因的表达，从而使G0/G1期细胞比例增加，细胞增殖速率减慢。免疫共沉淀证实了AHR和视网膜母细胞瘤（Rb 1）蛋白之间的相互作用，支持这是所观察到的减少的功能机制。使用沉默RNA的内源性Ahr减少证实了Ahr的肿瘤抑制功能。这些数据支持一个机制的途径，为推定的肿瘤抑制作用的AHR特别是在PA，可能通过其作为细胞周期的共同调节，即使在没有外源性配体的作用。
Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however, its role in pituitary tissue has never been investigated. In order to validate the role of AHR in PA behaviour, further functional studies were undertaken. Over-expression of AHR in GH3 cells revealed a tumour suppressor potential independent of exogenous ligand activation by benzo α-pyrene (BαP). Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BαP-stimulated AHR reduced E2F-driven transcription and altered expression of cell cycle regulator genes, thus increasing the percentage of cells in G0/G1 phase and slowing the proliferation rate of GH3 cells. Co-immunoprecipitation confirmed the interaction between AHR and retinoblastoma (Rb1) protein supporting this as a functional mechanism for the observed reduction. Endogenous Ahr reduction using silencing RNA confirmed the tumour suppressive function of the Ahr. These data support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands.