Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

BackgroundPrimary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.
Methodology/Principal FindingsPRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.
ConclusionsWe demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.

【背景】原发性甲状旁腺功能亢进症（primary hyperparathyroidism, PHPT）是一种常见的内分泌紊乱性疾病，好发于女性，提示女性激素及其受体在甲状旁腺腺瘤的发生发展中可能发挥关键作用。本研究针对与乳腺及其他器官肿瘤相关的催乳素受体（prolactin receptor, PRLr）展开了系统性探究。

【方法学与主要研究结果】本研究纳入37例散发性甲状旁腺肿瘤患者队列，检测了PRLr在上述肿瘤组织中的表达特征，并在体外培养的甲状旁腺肿瘤细胞中验证其功能活性。与其他正常组织及乳腺癌细胞相比，甲状旁腺组织中催乳素受体基因（PRLR）的转录本水平显著升高。所有纳入的甲状旁腺肿瘤组织均高表达分子量为60/70 kDa的PRLr蛋白产物；此外，本研究还检测到不同表达水平的80 kDa PRLr剪接变体，该变体已被证实具有促细胞增殖活性。在甲状旁腺肿瘤组织中，PRLr免疫反应活性定位于细胞质（所有病例，n=36）、细胞质颗粒（n=16）、细胞膜（n=12）或肿大的溶酶体（n=4）。而在28例正常甲状旁腺边缘组织中，PRLr均匀表达于细胞质与细胞质颗粒内。在短期体外培养的人甲状旁腺肿瘤细胞实验中，催乳素刺激可引发JAK/STAT、RIG-I样受体（RIG-I like receptor）及II型干扰素信号通路的显著转录变化，该结果通过基因表达谱分析得以证实。此外，甲状旁腺肿瘤中PRLR基因的表达水平与患者血浆钙浓度呈负相关。

【结论】本研究证实，催乳素受体在人甲状旁腺组织中呈高表达状态，且甲状旁腺肿瘤中PRLr剪接变体的表达模式及其亚细胞定位均发生异常改变。在生理浓度催乳素的刺激下，PRLr可介导甲状旁腺肿瘤细胞的甲状旁腺激素（parathyroid hormone, PTH）分泌增加，并引发基因转录谱的显著改变，具体表现为RIG-I样受体、JAK-STAT及II型干扰素信号通路的激活上调。上述实验数据提示，催乳素受体在甲状旁腺腺瘤的发生发展过程中发挥着重要的调控作用。