血清及甲状腺组织中 let-7b 的水平及其与 Graves 病 TRAb 的相关性。
Serum and thyroid tissue level of let-7b and their correlation with TRAb in Graves' disease.
机构信息
Department of Endocrinology, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University Medical School, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
出版信息
J Transl Med. 2018 Jul 5;16(1):188. doi: 10.1186/s12967-018-1565-9.
BACKGROUND
Abnormal microRNAs (miRNAs) were reported to be involved in the mechanism of Graves' disease (GD). Dysregulated miRNAs may be overlapping in different cells and can be secreted to circulation. We chose miRNAs which were previously reported to be differentially expressed in peripheral blood mononuclear cells (PBMCs) in patients with GD with different disease stage, detected the expression of those miRNAs in serum, corroborated the findings in thyroid tissue, and validated the target gene in vitro to investigate the possible role of circulating miRNAs in GD.
METHODS
A total of 54 individuals with untreated GD, 12 individuals with GD in remission and 14 disease-free controls were enrolled. The expression of miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b was detected in the serum. Ten thyroid tissue samples from patients with GD and six disease-free thyroid samples were used for further validation. The potential target genes were identified and validated in vitro.
RESULTS
miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b were present in serum and two of them (miR-142-3p and let-7b) were significantly increased in serum of patients with untreated GD (for serum miR-142-3p, P = 0.033, for serum let-7b, P = 0.026) and gradually decreased to normal levels in patients with GD in remission. Correlation analysis showed that let-7b level was strongly correlated with TRAb level (r = 0.305, P = 0.001). let-7b directly inhibited promyelocytic leukemia zinc finger (PLZF) expression and increased the expression of TSHR in thyroid cells in vitro. Furthermore, let-7b levels in GD thyroid tissue were found to be inversely correlated with PLZF levels (r = - 0.849, P = 0.033). Decreased PLZF and increased TSHR was validated in thyroid tissue in patients with GD.
CONCLUSIONS
The present study confirmed that a portion of miRNAs in PBMCs were also presented and differentially expressed in serum and thyroid tissue. Upregulated in all these three compartments, let-7b may be used as a disease biomarker and therapeutic targets in patients with GD. Circulating let-7b had a strong correlation with disease severity and let-7b may participate in the production of TRAb via targeting PLZF in patients with GD.
背景
异常的 microRNAs（miRNAs）被报道参与格雷夫斯病（GD）的发病机制。失调的 miRNAs 可能在不同的细胞中重叠，并可以分泌到循环中。我们选择了之前报道在 GD 患者外周血单核细胞（PBMCs）中差异表达的 miRNAs，检测了它们在血清中的表达，在甲状腺组织中证实了这些发现，并在体外验证了靶基因，以研究循环 miRNAs 在 GD 中的可能作用。
方法
共纳入 54 例未经治疗的 GD 患者、12 例 GD 缓解患者和 14 例无病对照者。检测血清中 miR-142-3p、miR-154-3p、miR-431-3p、miR-590-5p 和 let-7b 的表达。用 10 例 GD 患者和 6 例无病甲状腺样本进行进一步验证。鉴定和验证潜在的靶基因。
结果
miR-142-3p、miR-154-3p、miR-431-3p、miR-590-5p 和 let-7b 存在于血清中，其中两种（miR-142-3p 和 let-7b）在未经治疗的 GD 患者血清中显著升高（血清 miR-142-3p，P=0.033，血清 let-7b，P=0.026），并在 GD 缓解患者中逐渐降至正常水平。相关性分析显示，let-7b 水平与 TRAb 水平呈强相关（r=0.305，P=0.001）。let-7b 直接抑制早幼粒细胞白血病锌指（PLZF）表达，并增加甲状腺细胞中 TSHR 的表达。此外，GD 甲状腺组织中 let-7b 水平与 PLZF 水平呈负相关（r=-0.849，P=0.033）。在 GD 患者的甲状腺组织中验证了 PLZF 减少和 TSHR 增加。
结论
本研究证实，PBMC 中的一部分 miRNAs 也存在于血清和甲状腺组织中，并呈现出差异表达。在这三个部位均上调的 let-7b 可作为 GD 患者的疾病生物标志物和治疗靶点。循环 let-7b 与疾病严重程度密切相关，可能通过靶向 PLZF 参与 GD 患者 TRAb 的产生。
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