Gene signature driving invasive mucinous adenocarcinoma of the lung
Abstract Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Muc...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606711 |
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| author | Minzhe Guo Koichi Tomoshige Michael Meister Thomas Muley Takuya Fukazawa Tomoshi Tsuchiya Rebekah Karns Arne Warth Iris M Fink‐Baldauf Takeshi Nagayasu Yoshio Naomoto Yan Xu Marcus A Mall Yutaka Maeda |
| author_facet | Minzhe Guo Koichi Tomoshige Michael Meister Thomas Muley Takuya Fukazawa Tomoshi Tsuchiya Rebekah Karns Arne Warth Iris M Fink‐Baldauf Takeshi Nagayasu Yoshio Naomoto Yan Xu Marcus A Mall Yutaka Maeda |
| author_sort | Minzhe Guo |
| collection | DOAJ |
| description | Abstract Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung Tumor Signature of 143 genes, which was unexpectedly enriched in mucin‐producing gastrointestinal, pancreatic, and breast cancers. The signature genes included transcription factors FOXA3, SPDEF, HNF4A, mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1/B7‐H4 (but not PD‐L1/B7‐H1). Importantly, induction of FOXA3 or SPDEF along with mutant KRAS in lung epithelium was sufficient to develop benign or malignant mucinous lung tumors, respectively, in transgenic mice. FOXA3 and SPDEF induced MUC5AC and MUC5B, while HNF4A induced MUC3 in human mucinous lung cancer cells harboring a KRAS mutation. ChIP‐seq combined with CRISPR/Cas9 determined that upstream enhancer regions of the mucin genes MUC5AC and MUC5B, which were bound by SPDEF, were required for the expression of the mucin genes. Here, we report the molecular signature and gene regulatory network driving mucinous lung tumors. |
| format | Article |
| id | doaj-art-0d624d3b6a504f8eae00181f7c7fcdae |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-0d624d3b6a504f8eae00181f7c7fcdae2025-08-20T04:02:56ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-03-019446248110.15252/emmm.201606711Gene signature driving invasive mucinous adenocarcinoma of the lungMinzhe Guo0Koichi Tomoshige1Michael Meister2Thomas Muley3Takuya Fukazawa4Tomoshi Tsuchiya5Rebekah Karns6Arne Warth7Iris M Fink‐Baldauf8Takeshi Nagayasu9Yoshio Naomoto10Yan Xu11Marcus A Mall12Yutaka Maeda13Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of MedicinePerinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of MedicineTranslational Research Unit, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL)Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL)Department of General Surgery, Kawasaki Medical SchoolDepartment of Surgical Oncology, Nagasaki University Graduate School of Biomedical SciencesDivision of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of MedicineInstitute of Pathology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of HeidelbergPerinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of MedicineDepartment of Surgical Oncology, Nagasaki University Graduate School of Biomedical SciencesDepartment of General Surgery, Kawasaki Medical SchoolPerinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of MedicineDepartment of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of HeidelbergPerinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of MedicineAbstract Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung Tumor Signature of 143 genes, which was unexpectedly enriched in mucin‐producing gastrointestinal, pancreatic, and breast cancers. The signature genes included transcription factors FOXA3, SPDEF, HNF4A, mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1/B7‐H4 (but not PD‐L1/B7‐H1). Importantly, induction of FOXA3 or SPDEF along with mutant KRAS in lung epithelium was sufficient to develop benign or malignant mucinous lung tumors, respectively, in transgenic mice. FOXA3 and SPDEF induced MUC5AC and MUC5B, while HNF4A induced MUC3 in human mucinous lung cancer cells harboring a KRAS mutation. ChIP‐seq combined with CRISPR/Cas9 determined that upstream enhancer regions of the mucin genes MUC5AC and MUC5B, which were bound by SPDEF, were required for the expression of the mucin genes. Here, we report the molecular signature and gene regulatory network driving mucinous lung tumors.https://doi.org/10.15252/emmm.201606711FOXA3IMAMUC5AC/5BSPDEFVTCN1 |
| spellingShingle | Minzhe Guo Koichi Tomoshige Michael Meister Thomas Muley Takuya Fukazawa Tomoshi Tsuchiya Rebekah Karns Arne Warth Iris M Fink‐Baldauf Takeshi Nagayasu Yoshio Naomoto Yan Xu Marcus A Mall Yutaka Maeda Gene signature driving invasive mucinous adenocarcinoma of the lung EMBO Molecular Medicine FOXA3 IMA MUC5AC/5B SPDEF VTCN1 |
| title | Gene signature driving invasive mucinous adenocarcinoma of the lung |
| title_full | Gene signature driving invasive mucinous adenocarcinoma of the lung |
| title_fullStr | Gene signature driving invasive mucinous adenocarcinoma of the lung |
| title_full_unstemmed | Gene signature driving invasive mucinous adenocarcinoma of the lung |
| title_short | Gene signature driving invasive mucinous adenocarcinoma of the lung |
| title_sort | gene signature driving invasive mucinous adenocarcinoma of the lung |
| topic | FOXA3 IMA MUC5AC/5B SPDEF VTCN1 |
| url | https://doi.org/10.15252/emmm.201606711 |
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