维生素 D 受体激活是一种可行的治疗靶点，可损害肾上腺皮质肿瘤的发生。
Vitamin D receptor activation is a feasible therapeutic target to impair adrenocortical tumorigenesis.
机构信息
Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
出版信息
Mol Cell Endocrinol. 2022 Dec 1;558:111757. doi: 10.1016/j.mce.2022.111757. Epub 2022 Aug 29.
OBJECTIVE
To evaluate the therapeutic potential of vitamin D receptor (VDR) signaling in adrenocortical carcinoma (ACC) cells.
METHODS
We evaluated VDR's methylation pattern in H295R ACC cells, and investigated the effects of calcitriol and seocalcitol treatments on adrenocortical tumorigenesis.
RESULTS
VDR was hypermethylated and underexpressed in basal H295R cells. Treatments with calcitriol and seocalcitol restored VDR signaling, resulted in antiproliferative effects, and impaired Wnt/B-catenin signaling. RNAseq of treated cells demonstrated VDR activation on steroid hormones biosynthesis and Rap1 signaling, among others. In vivo, seocalcitol constrained the growth of H295R xenografts and reduced autonomous tumor steroid secretion without hypercalcemia-associated side effects.
CONCLUSIONS
H295R cells present VDR hypermethylation, which can be responsible for its underexpression and signaling inactivation under basal conditions. VDR signaling promoted antiproliferative effects in vitro and in vivo, suggesting that it may be a potential therapeutic target for ACC and a valuable tool for patient's clinical management.
目的
评估维生素 D 受体 (VDR) 信号在肾上腺皮质癌 (ACC) 细胞中的治疗潜力。
方法
我们评估了 H295R ACC 细胞中 VDR 的甲基化模式，并研究了骨化三醇和西奥钙醇治疗对肾上腺皮质肿瘤发生的影响。
结果
VDR 在基础 H295R 细胞中呈高甲基化和低表达。骨化三醇和西奥钙醇治疗恢复了 VDR 信号，导致抗增殖作用，并损害了 Wnt/B-连环蛋白信号。处理细胞的 RNAseq 表明 VDR 激活了类固醇激素生物合成和 Rap1 信号等。在体内，西奥钙醇限制了 H295R 异种移植物的生长，并减少了自主肿瘤类固醇分泌，而没有与高钙血症相关的副作用。
结论
H295R 细胞存在 VDR 高甲基化，这可能是其在基础条件下低表达和信号失活的原因。VDR 信号在体外和体内均促进了抗增殖作用，表明其可能是 ACC 的潜在治疗靶点，也是患者临床管理的有价值工具。
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