Endocrinology and Diabetology Unit, Department of Medical-Surgical Sciences, Università di Milano, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy.
Endocr Relat Cancer. 2010 Feb 18;17(1):135-46. doi: 10.1677/ERC-09-0134. Print 2010 Mar.
Parathyroid carcinoma (PaC) is a rare cause of primary hyperparathyroidism. Though the loss of the oncosuppressor CDC73/HRPT2 gene product, parafibromin, has been involved in the hyperparathyroidism-jaw tumor syndrome and in a consistent set of sporadic PaCs, parathyroid carcinogenesis remains obscure. MicroRNAs are a new class of small, non-coding RNAs implicated in development of cancer, since their deregulation can induce aberrant expression of several target genes. The aim of the present study was to identify differentially expressed microRNAs in parathyroid cancers compared with normal tissues. We performed a TaqMan low-density array profiling of four parathyroid cancers harboring CDC73 inactivating mutations and negative for parafibromin immunostaining. Their microRNA profiling was compared with that of two normal parathyroid biopsies. Out of 362 human microRNAs assayed, 279 (77%) were successfully amplified. Fourteen and three microRNAs were significantly down- and over-expressed in parathyroid cancers respectively. Of these, miR-296 and miR-139 were down-regulated, and miR-503 and miR-222 were over-expressed with a null false discovery rate. Carcinomas could be discriminated from parathyroid adenomas by a computed score based on the expression levels of miR-296, miR-222, and miR-503 as miR-139 was similarly down-regulated in both cancers and adenomas. Finally, miR-296 and miR-222 levels negatively correlated with mRNA levels of the hepatocyte growth factor receptor-regulated tyrosine kinase substrate and p27/kip1 levels respectively. These results suggest the existence of an altered microRNA expression pattern in PaCs together with a potential role of miR-296 as novel oncosuppressor gene in these neoplasia.
甲状旁腺癌 (PaC) 是原发性甲状旁腺功能亢进的罕见原因。虽然抑癌基因 CDC73/HRPT2 基因产物 parafibromin 的缺失与甲状旁腺功能亢进-颌骨肿瘤综合征以及一组一致的散发性 PaC 有关，但甲状旁腺癌的发生机制仍不清楚。microRNAs 是一类新的小非编码 RNA，参与癌症的发生，因为它们的失调可以诱导几个靶基因的异常表达。本研究的目的是鉴定与正常组织相比在甲状旁腺癌中差异表达的 microRNAs。我们对四个携带 CDC73 失活突变且 parafibromin 免疫染色阴性的甲状旁腺癌进行了 TaqMan 低密度阵列分析。将其 microRNA 谱与两个正常甲状旁腺活检进行比较。在检测的 362 个人类 microRNAs 中，成功扩增了 279 个（77%）。甲状旁腺癌中分别有 14 个和 3 个 microRNAs 表达下调和上调。其中，miR-296 和 miR-139 下调，miR-503 和 miR-222 过表达，假发现率为零。基于 miR-296、miR-222 和 miR-503 的表达水平计算的得分可区分癌与甲状旁腺瘤，因为 miR-139 在两种癌症和腺瘤中均下调。最后，miR-296 和 miR-222 的水平分别与肝细胞生长因子受体调节的酪氨酸激酶底物和 p27/kip1 的 mRNA 水平呈负相关。这些结果表明，PaC 中存在异常的 microRNA 表达模式，并且 miR-296 可能作为这些肿瘤的新抑癌基因发挥作用。
