Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α
Abstract Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involve...
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Nature Portfolio
2024-12-01
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| Online Access: | https://doi.org/10.1038/s41598-024-80280-x |
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| author | Daisuke Umeda Akikazu Harada Daisuke Motooka Shinichiro Tahara Masako Kurashige Kansuke Kido Tsuyoshi Takashima Hiroki Kiyokawa Koto Ukon Takahiro Matsui Shinji Matsumoto Yasushi Shintani Daisuke Okuzaki Akira Kikuchi Satoshi Nojima Eiichi Morii |
| author_facet | Daisuke Umeda Akikazu Harada Daisuke Motooka Shinichiro Tahara Masako Kurashige Kansuke Kido Tsuyoshi Takashima Hiroki Kiyokawa Koto Ukon Takahiro Matsui Shinji Matsumoto Yasushi Shintani Daisuke Okuzaki Akira Kikuchi Satoshi Nojima Eiichi Morii |
| author_sort | Daisuke Umeda |
| collection | DOAJ |
| description | Abstract Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC. |
| format | Article |
| id | doaj-art-d1e8bc3c46d5426a93f805fe3c3bc7ca |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-d1e8bc3c46d5426a93f805fe3c3bc7ca2025-01-05T12:28:41ZengNature PortfolioScientific Reports2045-23222024-12-0114111510.1038/s41598-024-80280-xHypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1αDaisuke Umeda0Akikazu Harada1Daisuke Motooka2Shinichiro Tahara3Masako Kurashige4Kansuke Kido5Tsuyoshi Takashima6Hiroki Kiyokawa7Koto Ukon8Takahiro Matsui9Shinji Matsumoto10Yasushi Shintani11Daisuke Okuzaki12Akira Kikuchi13Satoshi Nojima14Eiichi Morii15Department of Pathology, Osaka University Graduate School of MedicineDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka UniversityIntegrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University Institute for Open and Transdisciplinary Research Initiatives, Osaka UniversityDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka UniversityDepartment of General Thoracic Surgery, Osaka University Graduate School of MedicineIntegrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University Institute for Open and Transdisciplinary Research Initiatives, Osaka UniversityCenter for Infectious Disease Education and Research, Osaka UniversityDepartment of Pathology, Osaka University Graduate School of MedicineDepartment of Pathology, Osaka University Graduate School of MedicineAbstract Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC.https://doi.org/10.1038/s41598-024-80280-xLung micropapillary adenocarcinomaHypoxiaMatrigelThree-dimensional cell cultureHypoxia-inducible factor-1αMUC1 |
| spellingShingle | Daisuke Umeda Akikazu Harada Daisuke Motooka Shinichiro Tahara Masako Kurashige Kansuke Kido Tsuyoshi Takashima Hiroki Kiyokawa Koto Ukon Takahiro Matsui Shinji Matsumoto Yasushi Shintani Daisuke Okuzaki Akira Kikuchi Satoshi Nojima Eiichi Morii Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α Scientific Reports Lung micropapillary adenocarcinoma Hypoxia Matrigel Three-dimensional cell culture Hypoxia-inducible factor-1α MUC1 |
| title | Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α |
| title_full | Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α |
| title_fullStr | Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α |
| title_full_unstemmed | Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α |
| title_short | Hypoxia drives the formation of lung micropapillary adenocarcinoma-like structure through hypoxia-inducible factor-1α |
| title_sort | hypoxia drives the formation of lung micropapillary adenocarcinoma like structure through hypoxia inducible factor 1α |
| topic | Lung micropapillary adenocarcinoma Hypoxia Matrigel Three-dimensional cell culture Hypoxia-inducible factor-1α MUC1 |
| url | https://doi.org/10.1038/s41598-024-80280-x |
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