Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
J Steroid Biochem Mol Biol. 2019 Jun;190:212-223. doi: 10.1016/j.jsbmb.2019.03.022. Epub 2019 Mar 26.
The progesterone receptor (PR) has been reported to play important roles in lung development and function, such as alveolarization, alveolar fluid clearance (AFC) and upper airway dilator muscle activity. In the lung, pulmonary neuroendocrine cells (PNECs) are important in the etiology and progression of lung neuroendocrine tumors (NETs). Women with lung NETs had significantly better survival rates than men, suggesting that sex steroids and their receptors, such as the PR, could be involved in the progression of lung NETs. The PR exists as two major isoforms, PRA and PRB. How the expression of different PR isoforms affects proliferation and the development of lung NETs is not well understood. To determine the role of the PR isoforms in PNECs, we constructed H727 lung NET cell models expressing PRB, PRA, Green Fluorescence Protein (GFP) (control). The expression of PRB significantly inhibited H727 cell proliferation better than that of PRA in the absence of progestin. The expression of the unrelated protein, GFP, had little to no effect on H727 cell proliferation. To better understand the role of the PR isoform in PNECs, we examined PR isoform expression in PNECs in lung tissues. A monoclonal antibody specific to the N-terminus of PRB (250H11 mAb) was developed to specifically recognize PRB, while a monoclonal antibody specific to a common N-terminus epitope present in both PRA and PRB (1294 mAb) was used to detect both PRA and PRB. Using these PR and PRB-specific antibodies, we demonstrated that PR (PRA&PRB) and PRB were expressed in the PNECs of the normal fetal and adult lung, with significantly higher PR expression in the fetal lung. Interestingly, PRB expression in the normal lung was associated with lower cell proliferation than PR expression, suggesting a distinct role of PRB in the PNECs. A better understanding of the molecular mechanism of PR and PR isoform signaling in lung NET cells may help in developing novel therapeutic strategies that will benefit lung NET patients in the future.
孕激素受体（PR）在肺发育和功能中发挥着重要作用，如肺泡化、肺泡液清除（AFC）和上呼吸道扩张肌活动。在肺部，肺神经内分泌细胞（PNECs）在肺神经内分泌肿瘤（NETs）的病因和进展中起着重要作用。患有肺 NET 的女性的生存率明显高于男性，这表明性激素及其受体，如 PR，可能参与了肺 NET 的进展。PR 存在两种主要的亚型，即 PRA 和 PRB。不同 PR 亚型的表达如何影响肺 NET 的增殖和发展尚不清楚。为了确定 PR 亚型在 PNECs 中的作用，我们构建了表达 PRB、PRA、绿色荧光蛋白（GFP）（对照）的 H727 肺 NET 细胞模型。在没有孕激素的情况下，PRB 的表达显著抑制 H727 细胞增殖的效果优于 PRA。不相关蛋白 GFP 的表达对 H727 细胞增殖几乎没有影响。为了更好地理解 PR 亚型在 PNECs 中的作用，我们研究了肺组织中 PNECs 中 PR 亚型的表达。开发了一种针对 PRB N 端的单克隆抗体（250H11 mAb）特异性识别 PRB，而一种针对 PRA 和 PRB 中存在的共同 N 端表位的单克隆抗体（1294 mAb）用于检测 PRA 和 PRB。使用这些 PR 和 PRB 特异性抗体，我们证明 PR（PRA&PRB）和 PRB 在正常胎儿和成人肺的 PNECs 中表达，胎儿肺中的 PR 表达显著更高。有趣的是，正常肺中 PRB 的表达与细胞增殖较低相关，提示 PRB 在 PNECs 中具有独特的作用。更好地理解 PR 和 PR 亚型在肺 NET 细胞中的信号转导分子机制可能有助于开发新的治疗策略，从而使未来的肺 NET 患者受益。
