Angelousi Anna, Nasiri-Ansari Narjes, Karapanagioti Angeliki, Kyriakopoulos Georgios, Aggeli Chrysanthi, Zografos Giorgos, Choreftaki Theodosia, Parianos Christos, Kounadi Theodora, Alexandraki Krystallenia, Randeva Harpal S, Kaltsas Gregory, Papavassiliou Athanasios G, Kassi Eva
1st Department of Internal Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527, Athens, Greece.
Endocrine. 2020 Jun;68(3):650-659. doi: 10.1007/s12020-020-02246-z. Epub 2020 Mar 8.
Although the effect of the central clock system on adrenal function has been extensively studied, the role of the peripheral clock system in adrenal tumorigenesis remains largely unexplored. In this study we investigated the expression of clock-related genes in normal adrenocortical tissue and adrenocortical tumors. Twenty-seven fresh frozen human adrenal tissues including 13 cortisol secreting adenomas (CSA), seven aldosterone producing adenomas (APA), and seven adrenocortical carcinomas (ACC) were collected. CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα mRNA and protein expression were determined by qPCR and immunoblotting in pathological tissues and compared with the adjacent normal adrenal tissues. A significant downregulation of PER1, CRY1, and Rev-ERB compared with their normal tissue was demonstrated in CSA. All clock-related genes were overexpressed in APA compared with their normal tissue, albeit not significantly. A significant upregulation of CRY1 and PER1 and downregulation of BMAL1, RORα, and Rev-ERB compared with normal adrenal tissue was observed in ACC. BMAL1 and PER1 were significantly downregulated in APA compared with CSA. CLOCK, CRY1, and PER1 were upregulated, whereas BMAL1, RORα, and Rev-ERB were downregulated in ACC compared with CSA. Our study demonstrated the expression of CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα in normal and pathological human adrenal tissues. Adrenal tumors exhibited altered expression of these genes compared with normal tissue, with specific differences between benign and malignant lesions and between benign tumors arising from glomerulosa vs fasciculata zone. Further studies should clarify whether these alterations could be implicated in adrenocortical tumorigenesis.
尽管中枢时钟系统对肾上腺功能的影响已得到广泛研究，但外周时钟系统在肾上腺肿瘤发生中的作用仍 largely 未被探索。在本研究中，我们调查了正常肾上腺皮质组织和肾上腺皮质肿瘤中时钟相关基因的表达。收集了 27 份新鲜冷冻的人类肾上腺组织，包括 13 例分泌皮质醇腺瘤（CSA）、7 例醛固酮分泌腺瘤（APA）和 7 例肾上腺皮质癌（ACC）。通过 qPCR 和免疫印迹法测定病理组织中 CLOCK、BMAL1、PER1、CRY1、Rev-ERB 和 RORα 的 mRNA 和蛋白表达，并与相邻的正常肾上腺组织进行比较。CSA 中 PER1、CRY1 和 Rev-ERB 与其正常组织相比显著下调。与正常组织相比，APA 中所有时钟相关基因均有过表达，尽管不显著。ACC 中与正常肾上腺组织相比，CRY1 和 PER1 显著上调，而 BMAL1、RORα 和 Rev-ERB 下调。与 CSA 相比，APA 中 BMAL1 和 PER1 显著下调。与 CSA 相比，ACC 中 CLOCK、CRY1 和 PER1 上调，而 BMAL1、RORα 和 Rev-ERB 下调。我们的研究证明了 CLOCK、BMAL1、PER1、CRY1、Rev-ERB 和 RORα 在正常和病理人类肾上腺组织中的表达。与正常组织相比肾上腺肿瘤这些基因的表达发生改变，良性和恶性病变之间以及来自球状带与束状带的良性肿瘤之间存在特定差异。进一步的研究应阐明这些改变是否与肾上腺皮质肿瘤发生有关。
