Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden.
Endocr Relat Cancer. 2011 Oct 27;18(6):643-55. doi: 10.1530/ERC-11-0082. Print 2011 Oct.
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.
肾上腺皮质癌（ACC）是一种具有侵袭性的肿瘤，常发生转移且预后不良。尽管最近对 ACC 的全基因组研究有助于我们了解该疾病，但在诊断和预后评估方面仍存在重大挑战。本研究旨在确定与 ACC 患者恶性程度和生存相关的特定 microRNAs（miRNAs）。采用微阵列技术检测一系列 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，ACC 中有一些 miRNA 表现出明显不同的表达模式。其中，miR-483-3p、miR-483-5p、miR-210 和 miR-21 表达上调，而 miR-195、miR-497 和 miR-1974 表达下调。在人 NCI-H295R ACC 细胞中，抑制 miR-483-3p 或 miR-483-5p 并过表达 miR-195 或 miR-497 可降低细胞增殖。此外，下调 miR-483-3p 但不下调 miR-483-5p，以及增加 miR-195 或 miR-497 的表达，可导致细胞死亡显著增加。潜在靶标 miR-483-3p 的凋亡上调调节剂（PUMA）的蛋白表达在 ACC 中显著降低，且与 miR-483-3p 的表达呈负相关。此外，miR-503、miR-1202 和 miR-1275 的高表达与 ACC 患者总生存时间显著缩短显著相关（P 值分别为 0.006、0.005 和 0.042）。总之，我们确定了与 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 PUMA（miR-483-3p 的靶标）在肾上腺皮质肿瘤中的潜在作用，并发现了与 ACC 患者生存相关的新 miRNAs。
