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d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro
BACKGROUND: PM(2.5) exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM(2.5) exposure, and aimed to find a potential intervention for peo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741803/ https://www.ncbi.nlm.nih.gov/pubmed/36496421 http://dx.doi.org/10.1186/s12931-022-02270-9 |
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author | Zhu, Tengteng Li, Yangyang Feng, Tienan Yang, Yuqing Zhang, Kai Gao, Jing Quan, Xiaowei Qian, Ying Yu, Herbert Qian, Biyun |
author_facet | Zhu, Tengteng Li, Yangyang Feng, Tienan Yang, Yuqing Zhang, Kai Gao, Jing Quan, Xiaowei Qian, Ying Yu, Herbert Qian, Biyun |
author_sort | Zhu, Tengteng |
collection | PubMed |
description | BACKGROUND: PM(2.5) exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM(2.5) exposure, and aimed to find a potential intervention for people living in PM(2.5) polluted regions. METHODS: Electron microscopy and oil-red staining were conducted to examine the lipid droplet accumulation. Masson’s trichrome staining, colony forming, scratch assay and transwell experiment were conducted to evaluate the effect of PM(2.5) exposure and d-limonene intervention on the occurrence and progression of LUAD. Potential intervention targets were found by RNA-Seq and verified by luciferase reporter assay. MiR-195 KO mice constructed with CRISPR/Cas9 technology were used to investigate the pivotal role of d-limonene-miR-195-SREBP1/FASN axis. Cohort analysis of lung cancer patients, human LUAD tissues staining and human intervention trial were also conducted to validate the results of cell and animal experiments. RESULTS: Our results showed that PM(2.5) exposure induced accumulation of lipid droplets in LUAD cells which accompanied by increased malignant cellular behaviors. PM(2.5) exposure led to cleaved N-SREBP1 translocation into nucleus, which activated the de novo lipogenesis pathway. Same changes were also observed in normal lung epithelial cells and normal lung tissue, and mice developed pulmonary fibrosis after long-term exposure to PM(2.5). Furthermore, in a cohort of 11,712 lung cancer patients, significant lipid metabolism disorders were observed in higher PM(2.5) polluted areas. In view of that, d-limonene was found to inhibit the changes in lipid metabolism through upregulating the expression of miR-195, which inhibited the expression of lipogenic genes (SREBF1/FASN/ACACA) specifically. And a small human intervention trial showed that serum miR-195 was upregulated after oral intake of d-limonene. CONCLUSION: Our findings reveal a new mechanism of pulmonary fibrosis and LUAD that is related to PM(2.5) exposure-induced lipid droplet accumulation. We also demonstrate that d-limonene-miR-195-SREBP1/FASN axis is a potential preventive intervention for mediating the progression and development of LUAD induced by PM(2.5) exposure. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030200. Registered 25 February 2020, http://www.chictr.org.cn/showproj.aspx?proj=48013 GRAPHICAL ABSTRACT: [Image: see text] |
format | Online Article Text |
id | pubmed-9741803 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-97418032022-12-12 d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro Zhu, Tengteng Li, Yangyang Feng, Tienan Yang, Yuqing Zhang, Kai Gao, Jing Quan, Xiaowei Qian, Ying Yu, Herbert Qian, Biyun Respir Res Research BACKGROUND: PM(2.5) exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM(2.5) exposure, and aimed to find a potential intervention for people living in PM(2.5) polluted regions. METHODS: Electron microscopy and oil-red staining were conducted to examine the lipid droplet accumulation. Masson’s trichrome staining, colony forming, scratch assay and transwell experiment were conducted to evaluate the effect of PM(2.5) exposure and d-limonene intervention on the occurrence and progression of LUAD. Potential intervention targets were found by RNA-Seq and verified by luciferase reporter assay. MiR-195 KO mice constructed with CRISPR/Cas9 technology were used to investigate the pivotal role of d-limonene-miR-195-SREBP1/FASN axis. Cohort analysis of lung cancer patients, human LUAD tissues staining and human intervention trial were also conducted to validate the results of cell and animal experiments. RESULTS: Our results showed that PM(2.5) exposure induced accumulation of lipid droplets in LUAD cells which accompanied by increased malignant cellular behaviors. PM(2.5) exposure led to cleaved N-SREBP1 translocation into nucleus, which activated the de novo lipogenesis pathway. Same changes were also observed in normal lung epithelial cells and normal lung tissue, and mice developed pulmonary fibrosis after long-term exposure to PM(2.5). Furthermore, in a cohort of 11,712 lung cancer patients, significant lipid metabolism disorders were observed in higher PM(2.5) polluted areas. In view of that, d-limonene was found to inhibit the changes in lipid metabolism through upregulating the expression of miR-195, which inhibited the expression of lipogenic genes (SREBF1/FASN/ACACA) specifically. And a small human intervention trial showed that serum miR-195 was upregulated after oral intake of d-limonene. CONCLUSION: Our findings reveal a new mechanism of pulmonary fibrosis and LUAD that is related to PM(2.5) exposure-induced lipid droplet accumulation. We also demonstrate that d-limonene-miR-195-SREBP1/FASN axis is a potential preventive intervention for mediating the progression and development of LUAD induced by PM(2.5) exposure. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030200. Registered 25 February 2020, http://www.chictr.org.cn/showproj.aspx?proj=48013 GRAPHICAL ABSTRACT: [Image: see text] BioMed Central 2022-12-10 2022 /pmc/articles/PMC9741803/ /pubmed/36496421 http://dx.doi.org/10.1186/s12931-022-02270-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhu, Tengteng Li, Yangyang Feng, Tienan Yang, Yuqing Zhang, Kai Gao, Jing Quan, Xiaowei Qian, Ying Yu, Herbert Qian, Biyun d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro |
title | d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro |
title_full | d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro |
title_fullStr | d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro |
title_full_unstemmed | d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro |
title_short | d-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM(2.5) exposure in vivo and in vitro |
title_sort | d-limonene inhibits the occurrence and progression of luad through suppressing lipid droplet accumulation induced by pm(2.5) exposure in vivo and in vitro |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741803/ https://www.ncbi.nlm.nih.gov/pubmed/36496421 http://dx.doi.org/10.1186/s12931-022-02270-9 |
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