Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells

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 pneumoth...

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Autores principales:	Shouichi Okamoto, Hiroki Ebana, Masatoshi Kurihara, Keiko Mitani, Etsuko Kobayashi, Takuo Hayashi, Yasuhito Sekimoto, Koichi Nishino, Mizuto Otsuji, Toshio Kumasaka, Kazuhisa Takahashi, Kuniaki Seyama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd2ed7a6da7f482eb03fc71e356f40e6
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spelling	oai:doaj.org-article:cd2ed7a6da7f482eb03fc71e356f40e62021-12-02T14:49:18ZFolliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells10.1038/s41598-021-90184-92045-2322https://doaj.org/article/cd2ed7a6da7f482eb03fc71e356f40e62021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90184-9https://doaj.org/toc/2045-2322Abstract 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.Shouichi OkamotoHiroki EbanaMasatoshi KuriharaKeiko MitaniEtsuko KobayashiTakuo HayashiYasuhito SekimotoKoichi NishinoMizuto OtsujiToshio KumasakaKazuhisa TakahashiKuniaki SeyamaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shouichi Okamoto Hiroki Ebana Masatoshi Kurihara Keiko Mitani Etsuko Kobayashi Takuo Hayashi Yasuhito Sekimoto Koichi Nishino Mizuto Otsuji Toshio Kumasaka Kazuhisa Takahashi Kuniaki Seyama Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
description	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.
format	article
author	Shouichi Okamoto Hiroki Ebana Masatoshi Kurihara Keiko Mitani Etsuko Kobayashi Takuo Hayashi Yasuhito Sekimoto Koichi Nishino Mizuto Otsuji Toshio Kumasaka Kazuhisa Takahashi Kuniaki Seyama
author_facet	Shouichi Okamoto Hiroki Ebana Masatoshi Kurihara Keiko Mitani Etsuko Kobayashi Takuo Hayashi Yasuhito Sekimoto Koichi Nishino Mizuto Otsuji Toshio Kumasaka Kazuhisa Takahashi Kuniaki Seyama
author_sort	Shouichi Okamoto
title	Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
title_short	Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
title_full	Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
title_fullStr	Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
title_full_unstemmed	Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
title_sort	folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cd2ed7a6da7f482eb03fc71e356f40e6
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Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells

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