Morotti Annamaria, Forno Irene, Verdelli Chiara, Guarnieri Vito, Cetani Filomena, Terrasi Andrea, Silipigni Rosamaria, Guerneri Silvana, Andrè Valentina, Scillitani Alfredo, Vicentini Leonardo, Ferrero Stefano, Corbetta Sabrina, Vaira Valentina
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Division of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
J Bone Miner Res. 2020 Dec;35(12):2423-2431. doi: 10.1002/jbmr.4154. Epub 2020 Sep 23.
A role for long non-coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss-of-heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds-derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild-type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild-type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild-type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR).
长链非编码RNA（lncRNA）在内分泌癌发病机制中的作用正逐渐显现。然而，关于它们在甲状旁腺肿瘤中的表达模式、与已知基因缺陷的相关性以及临床意义仍不清楚。在此，我们在第一组正常甲状旁腺（PaN = 2）、腺瘤性甲状旁腺（PAd = 12）和癌性甲状旁腺（PCa = 4）中分析了90种已知的lncRNA，并使用另一组独立患者（PaN = 4；PAd = 26；PCa = 9）证实了11种lncRNA的失调。lncRNA的表达与细胞遗传学异常、多内分泌腺瘤1型（MEN1）和细胞分裂周期73（CDC73）基因状态或临床特征相关。总体而言，lncRNA可根据组织组织学进行区分。BC200能持续区分甲状旁腺癌与腺瘤和非典型腺瘤。1号、11号、15号、21号和22号染色体上的杂合性缺失（LOH）显著影响PAd中lncRNA的表达。关键甲状旁腺基因MEN1的沉默可调节原代PAd来源培养物中六种lncRNA的表达。与野生型MEN1的PAd相比，MEN1基因突变的PAd中lncRNA水平相似。同样，CDC七三突变的癌在lncRNA表达方面与野生型蛋白的PCa不同。与野生型癌相比，携带CDC七三突变的PCa过表达BC200。总体而言，这些发现揭示了人类甲状旁腺肿瘤中lncRNA的失调，并提出lncRNA与肿瘤抑制因子MEN1或CDC七三之间的回路可能作为表观遗传调节剂在甲状旁腺肿瘤发生中起作用。©️2020美国骨与矿物质研究学会（ASBMR）。
