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FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome

BACKGROUND: Birt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gen...

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Autores principales: Min, Haiyan, Ma, Dehua, Zou, Wei, Wu, Yongzheng, Ding, Yibing, Zhu, Chengchu, Lin, Anqi, Song, Shiyu, Liang, Qiao, Chen, Baofu, Zhang, Bin, Wan, Yueming, Ye, Minhua, Pan, Yanqing, Wen, Yanting, Yi, long, Gao, Qian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279199/
https://www.ncbi.nlm.nih.gov/pubmed/32184379
http://dx.doi.org/10.1136/thoraxjnl-2019-213225
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author Min, Haiyan
Ma, Dehua
Zou, Wei
Wu, Yongzheng
Ding, Yibing
Zhu, Chengchu
Lin, Anqi
Song, Shiyu
Liang, Qiao
Chen, Baofu
Zhang, Bin
Wan, Yueming
Ye, Minhua
Pan, Yanqing
Wen, Yanting
Yi, long
Gao, Qian
author_facet Min, Haiyan
Ma, Dehua
Zou, Wei
Wu, Yongzheng
Ding, Yibing
Zhu, Chengchu
Lin, Anqi
Song, Shiyu
Liang, Qiao
Chen, Baofu
Zhang, Bin
Wan, Yueming
Ye, Minhua
Pan, Yanqing
Wen, Yanting
Yi, long
Gao, Qian
author_sort Min, Haiyan
collection PubMed
description BACKGROUND: Birt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma. METHODS: The expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts. RESULTS: Cystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424–5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424–5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency. CONCLUSION: The upregulation of miR-424–5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.
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spelling pubmed-72791992020-06-15 FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome Min, Haiyan Ma, Dehua Zou, Wei Wu, Yongzheng Ding, Yibing Zhu, Chengchu Lin, Anqi Song, Shiyu Liang, Qiao Chen, Baofu Zhang, Bin Wan, Yueming Ye, Minhua Pan, Yanqing Wen, Yanting Yi, long Gao, Qian Thorax Orphan Lung Disease BACKGROUND: Birt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma. METHODS: The expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts. RESULTS: Cystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424–5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424–5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency. CONCLUSION: The upregulation of miR-424–5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients. BMJ Publishing Group 2020-06 2020-03-17 /pmc/articles/PMC7279199/ /pubmed/32184379 http://dx.doi.org/10.1136/thoraxjnl-2019-213225 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Orphan Lung Disease
Min, Haiyan
Ma, Dehua
Zou, Wei
Wu, Yongzheng
Ding, Yibing
Zhu, Chengchu
Lin, Anqi
Song, Shiyu
Liang, Qiao
Chen, Baofu
Zhang, Bin
Wan, Yueming
Ye, Minhua
Pan, Yanqing
Wen, Yanting
Yi, long
Gao, Qian
FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome
title FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome
title_full FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome
title_fullStr FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome
title_full_unstemmed FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome
title_short FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome
title_sort flcn-regulated mirnas suppressed reparative response in cells and pulmonary lesions of birt-hogg-dubé syndrome
topic Orphan Lung Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279199/
https://www.ncbi.nlm.nih.gov/pubmed/32184379
http://dx.doi.org/10.1136/thoraxjnl-2019-213225
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