The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma.
The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma.
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DOI：
10.1530/erc-11-0082
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发表时间：
2011-10
影响因子：
3.9
通讯作者：
Lui WO
中科院分区：
文献类型：
--
作者：
Özata DM;Caramuta S;Velázquez-Fernández D;Akçakaya P;Xie H;Höög A;Zedenius J;Bäckdahl M;Larsson C;Lui WO
肾上腺皮质癌（ACC）是一种侵袭性肿瘤，表现出频繁的转移扩散和低生存率。尽管最近的ACC全基因组研究有助于我们对该疾病的理解，但诊断和预后评估仍面临重大挑战。本研究的目的是鉴定与ACC患者恶性程度和生存率相关的特异性microRNAs（miRNAs）。使用微阵列测定了一系列ACC、腺瘤和正常皮质中的miRNA表达谱。与肾上腺皮质和腺瘤相比，一个miRNA子集在ACC中显示出不同的表达模式。其中，发现miR-483- 3 p、miR-483- 5 p、miR-210和miR-21在ACC中过表达，而miR-195、miR-497和miR-1974在人NCI-H295 R ACC细胞中低表达。此外，下调miR-483- 3 p而非miR-483- 5 p，以及增加miR-195或miR-497的表达导致显著诱导细胞死亡。p53上调的凋亡调节因子（p53 modulator of apoptosis，p53）（miR-483- 3 p的潜在靶点）的蛋白表达在ACC中显著降低，并与miR-483- 3 p表达呈负相关。此外，发现miR-503、miR-1202和miR-1275的高表达与ACC患者的总生存期较短显著相关（P值分别为0.006、0.005和0.042）。总之，我们鉴定了与ACC相关的其他miRNAs，阐明了4种miRNAs在ACC细胞发病机制中的功能作用，证明了促凋亡因子β A（一种miR-483- 3 p靶标）在肾上腺皮质肿瘤中的潜在参与，并发现了与ACC存活相关的新型miRNAs。
Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC.