KMT2A 和慢性炎症作为散发甲状旁腺腺瘤的潜在驱动因素。

BACKGROUND: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood. METHODS: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single-cell RNA-sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single-cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations. RESULTS: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone-lysine N-methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto-oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. CONCLUSIONS: We revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti-inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications. HIGHLIGHTS: Single-cell RNA-sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands. PA cells show a pervasive increase in gene expression linked to KMT2A upregulation. KMT2A-mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2. PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis.

背景：散发性甲状旁腺腺瘤（PA）是甲状旁腺功能亢进症的最常见原因，但发病机制中涉及的机制仍不完全清楚。

方法：使用 10× Genomics Chromium Droplet 平台和 Cell Ranger 软件对手术切除的 PA 样本和在甲状腺全切除术中偶然分离的正常甲状旁腺（PG）组织进行单细胞 RNA 测序分析。进行基因集变异分析以描述标志性途径基因特征，并利用单细胞调控网络推断和聚类分析转录因子调控元件。进行免疫组织化学和免疫荧光染色以验证 PA 组织的细胞成分。进行 siRNA 敲低和基因过表达，以及定量聚合酶链反应、Western blot 和细胞增殖测定，以进行功能研究。

结果：与 PG 细胞相比，PA 细胞中的基因转录普遍增加。这与组蛋白赖氨酸 N-甲基转移酶 2A（KMT2A）的高表达有关。高 KMT2A 水平可能通过上调原癌基因 CCND2 促进 PAC 增殖，这是由转录因子信号转导和转录激活因子 3（STAT3）和 GATA 结合蛋白 3（GATA3）介导的。PA 组织被髓样细胞大量浸润，而与 PG 组织相比，PA 组织中的成纤维细胞、内皮细胞和巨噬细胞通常富含促炎基因特征。

结论：我们揭示了 KMT2A-STAT3/GATA3-CCND2 轴和慢性炎症在 PA 发病机制中的先前未被充分认识的作用。这些发现强调了 KMT2A 抑制和抗炎策略的治疗潜力，突出了将这些分子见解转化为实际应用的未来研究的必要性。

重点：单细胞 RNA 测序揭示了比较散发性甲状旁腺腺瘤（PA）与正常甲状旁腺的转录组目录。PA 细胞显示出普遍增加的基因表达，与 KMT2A 的上调有关。KMT2A 介导的 STAT3 和 GATA3 的上调是通过细胞周期蛋白 D2 促进 PA 细胞增殖的关键。PA 表现出促炎微环境，表明慢性炎症在 PA 发病机制中可能起作用。