Abstract
Birt–Hogg–Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax. The possibility of FLCN haploinsufficiency in pleural mesothelial cells (PMCs) contributing to development of pneumothorax has not yet been clarified. Electron microscopy revealed exposed intercellular boundaries between PMCs on visceral pleura and decreased electron density around the adherens junctions in BHDS. To characterize cellular function of PMCs in BHDS patients (BHDS-PMCs), during surgery for pneumothorax, we established the flow cytometry-based methods of isolating high-purity PMCs from pleural lavage fluid. BHDS-PMCs showed impaired cell attachment and a significant decrease in proliferation and migration, but a significant increase in apoptosis compared with PMCs from primary spontaneous pneumothorax (PSP) patients (PSP-PMCs). Microarray analysis using isolated PMCs revealed a significant alteration in the expression of genes belonging to Gene Ontology terms “cell–cell adhesion junction” and “cell adhesion molecule binding”. Gene set enrichment analysis demonstrated that CDH1, encoding E-cadherin, was identified in the down-regulated leading edge of a plot in BHDS-PMCs. AMPK and LKB1 activation were significantly impaired in BHDS-PMCs compared with PSP-PMCs. Our findings indicate that FLCN haploinsufficiency may affect the E-cadherin-LKB1-AMPK axis and lead to abnormal cellular function in BHDS-PMCs.
Highlights
Birt–Hogg–Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax
To elucidate the possible morphological differences between primary spontaneous pneumothorax (PSP)- and BHDS-pleural mesothelial cells (PMCs), we initially examined visceral pleura in PSP and BHDS patients using scanning electron microscope (SEM) and transmission electron microscope (TEM)
Results of GSEA of BHDS-PMCs compared to PSP-PMCs utilizing the Gene Ontology (GO) terms “cell–cell adhesion junction”
Summary
Birt–Hogg–Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax. Gene set enrichment analysis demonstrated that CDH1, encoding E-cadherin, was identified in the down-regulated leading edge of a plot in BHDS-PMCs. AMPK and LKB1 activation were significantly impaired in BHDSPMCs compared with PSP-PMCs. Our findings indicate that FLCN haploinsufficiency may affect the E-cadherin-LKB1-AMPK axis and lead to abnormal cellular function in BHDS-PMCs. Birt–Hogg–Dubé syndrome (BHDS) is an autosomal dominant inheritance disorder characterized by skin fibrofolliculomas, renal tumors, multiple lung cysts, and spontaneous pneumothorax (SP)[1,2,3]. The purpose of this study was to examine whether FLCN haploinsufficiency affects the morphology of PMCs and characterize the cellular functions of PMCs in both BHDS and primary spontaneous pneumothorax (PSP) patients, using PSP-PMCs as a control. Our findings extend the knowledge of the mechanisms for development of BHDS-associated pneumothorax
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