Aberrant promoter methylation, expression and function of RASSF1A gene in a series of Italian parathyroid tumors.

IF 3 3区医学 Q2 ENDOCRINOLOGY & METABOLISM Endocrine Pub Date : 2025-03-01 Epub Date: 2024-11-28 DOI:10.1007/s12020-024-04113-7

Chiara Verdelli, Federico Pio Fabrizio, Paola Maroni, Annamaria Morotti, Giulia Stefania Tavanti, Silvia Carrara, Vito Guarnieri, Filomena Cetani, Alfredo Scillitani, Riccardo Maggiore, Francesca Perticone, Valentina Vaira, Lucia Anna Muscarella, Sabrina Corbetta

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引用次数: 0

Abstract

Purpose: Aberrant epigenetic features are key events involved in parathyroid tumorigenesis, including DNA methylation, histone methylation, and non-coding RNAs. Ras Association Domain Family Protein1 Isoform A (RASSF1A) and Adenomatous Polyposis of Colon (APC) are frequently downregulated in human cancers. Here, we investigated their deregulated expression and the potential role in parathyroid neoplasms.

Methods: methylation of RASSF1A and APC promoters was analyzed in a series of parathyroid adenomas (PAds, n = 80) and parathyroid carcinomas (PCas, n = 9) from Italian patients with primary hyperparathyroidism, RESULTS: RASSF1A and APC promoter methylation occurred in about 90% of PAds samples. PCas displayed RASSF1A promoter methylation, while APC promoter was methylated only in 2 samples. Of note, RASSF1A promoter methylation negatively correlated with PAds tumor size. However, RASSF1A transcript and protein levels were reduced in PAds and PCas compared with parathyroid normal glands. Investigating the potential mechanism involved in RASSF1A promoter methylation, we found that DNA methyltransferases (DNMTs) activity was variable in PAds and inversely correlated with RASSF1A protein levels. In addition, the RASSF1A promoter methylation negatively correlated with long-non-coding Antisense Intronic Noncoding RASSF1A (ANRASSF1A) mRNA levels, excluding the involvement of ANRASSF1 in RASSF1A regulation. In HEK293A cells transfected with the calcium sensing receptor (CASR), loss of RASSF1A increased basal phosphorylated Extracellular signal-regulated kinase (pERK/ERK) levels blunting the CASR-induced increases.

Conclusion: RASSF1A and APC promoter methylation is a hallmark of parathyroid tumors; deregulation of DNMTs activity contributes to modulation of RASSF1A expression. Loss of RASSF1A may be involved in the tuning of ERK pathway in parathyroid tumors.

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一系列意大利甲状旁腺肿瘤中RASSF1A基因启动子甲基化、表达和功能的异常。

目的：表观遗传特征异常是甲状旁腺肿瘤发生的关键事件，包括DNA甲基化、组蛋白甲基化和非编码RNA。Ras关联域家族蛋白1异构体A（RASSF1A）和结肠腺瘤性息肉病（APC）经常在人类癌症中被下调。方法：在一系列原发性甲状旁腺功能亢进症意大利患者的甲状旁腺腺瘤（PAds，n = 80）和甲状旁腺癌（PCas，n = 9）中分析了RASSF1A和APC启动子的甲基化。PCas 显示 RASSF1A 启动子甲基化，而 APC 启动子甲基化仅出现在 2 个样本中。值得注意的是，RASSF1A 启动子甲基化与 PAds 肿瘤大小呈负相关。然而，与甲状旁腺正常腺体相比，PAds 和 PCas 中的 RASSF1A 转录物和蛋白水平均有所降低。在研究RASSF1A启动子甲基化的潜在机制时，我们发现DNA甲基转移酶（DNMTs）的活性在PAds中存在差异，并且与RASSF1A蛋白水平成反比。此外，RASSF1A 启动子甲基化与长非编码反义非编码 RASSF1A（ANRASSF1A）mRNA 水平呈负相关，排除了 ANRASSF1 参与 RASSF1A 调控的可能性。在转染了钙传感受体（CASR）的 HEK293A 细胞中，RASSF1A 的缺失会增加基础磷酸化细胞外信号调节激酶（pERK/ERK）水平，削弱 CASR 诱导的增加：结论：RASSF1A和APC启动子甲基化是甲状旁腺肿瘤的特征之一；DNMTs活性的失调有助于调节RASSF1A的表达。RASSF1A的缺失可能与甲状旁腺肿瘤中ERK通路的调整有关。

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来源期刊

Endocrine ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

5.40%

发文量

295

审稿时长

1.5 months

期刊介绍： Well-established as a major journal in today’s rapidly advancing experimental and clinical research areas, Endocrine publishes original articles devoted to basic (including molecular, cellular and physiological studies), translational and clinical research in all the different fields of endocrinology and metabolism. Articles will be accepted based on peer-reviews, priority, and editorial decision. Invited reviews, mini-reviews and viewpoints on relevant pathophysiological and clinical topics, as well as Editorials on articles appearing in the Journal, are published. Unsolicited Editorials will be evaluated by the editorial team. Outcomes of scientific meetings, as well as guidelines and position statements, may be submitted. The Journal also considers special feature articles in the field of endocrine genetics and epigenetics, as well as articles devoted to novel methods and techniques in endocrinology. Endocrine covers controversial, clinical endocrine issues. Meta-analyses on endocrine and metabolic topics are also accepted. Descriptions of single clinical cases and/or small patients studies are not published unless of exceptional interest. However, reports of novel imaging studies and endocrine side effects in single patients may be considered. Research letters and letters to the editor related or unrelated to recently published articles can be submitted. Endocrine covers leading topics in endocrinology such as neuroendocrinology, pituitary and hypothalamic peptides, thyroid physiological and clinical aspects, bone and mineral metabolism and osteoporosis, obesity, lipid and energy metabolism and food intake control, insulin, Type 1 and Type 2 diabetes, hormones of male and female reproduction, adrenal diseases pediatric and geriatric endocrinology, endocrine hypertension and endocrine oncology.