Progesterone receptor isoform B expression in pulmonary neuroendocrine cells decreases cell proliferation. Issue 190 (June 2019)

• Record Type: Journal Article
• Authors: Asavasupreechar, Teeranut; Saito, Ryoko; Edwards, Dean P.; Sasano, Hironobu; Boonyaratanakornkit, Viroj
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 190(2019)
• Page Start: 212
• Page End: 223
• Publication Date: 2019-06
• Subjects: Progesterone receptor isoforms A and B -- Pulmonary neuroendocrine cell -- Isoform-specific antibody; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.03.022
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Roles of progesterone receptor (PR) and PR isoforms in lung neuroendocrine cells are not well understood. In vitro, PRB expression significantly decreases lung neuroendocrine cell proliferation, independent of ligand. PR and PRB immunolocalized to pulmonary endocrine cells in the fetal and adult lung. In the fetal and adult lung, PRB expression is associated with a decrease in pulmonary neuroendocrine cell proliferation. Abstract: 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.