Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma
Background: Recent research has shown that lysosomes play a critical role in the onset and progression of malignancy by regulating tumor cell death through several mechanisms. Nevertheless, the involvement of lysosome-associated genes (LSAGs) in lung adenocarcinoma (LUAD) is still not well understoo...
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Elsevier
2024-03-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024036065 |
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| author | Zi-Ming Wang Zhi-Lin Ning Chao Ma Tang-Bin Liu Bo Tao Liang Guo |
| author_facet | Zi-Ming Wang Zhi-Lin Ning Chao Ma Tang-Bin Liu Bo Tao Liang Guo |
| author_sort | Zi-Ming Wang |
| collection | DOAJ |
| description | Background: Recent research has shown that lysosomes play a critical role in the onset and progression of malignancy by regulating tumor cell death through several mechanisms. Nevertheless, the involvement of lysosome-associated genes (LSAGs) in lung adenocarcinoma (LUAD) is still not well understood. Methods: LSAGs were identified in malignant lung epithelial cells, as well as biologically and functionally annotated by the comprehensive integration of single-cell and bulk RNA-sequencing data. Prognostic characterization of LSAGs was established, of which the accuracy and reliability were assessed by one-way Cox and LASSO regression. Correlations between LSAG properties and immune cell infiltration, chemotherapy, and immunotherapy were analyzed by integrated omics data. Finally, we characterized the expression of three LSAGs (KCNE1, NPC2, and SFTPD) in malignant lung epithelium and assessed their impact on tumor malignancy related phenotypes. Results: We identified 18 LSAGs associated with prognosis, of which 3 LSAGs were used to construct prognostic models. High-risk patients had worse survival and the model predicted it better than other clinical indicators. Based on the functional enrichment analyses, LSAGs were associated with binding and molecular activity functions, inhibition of DNA damage repair and tumor growth, IL7 signaling pathway, and glycolysis. M0 macrophages and M1 macrophages were substantially enriched in high-risk patients. Conversely, there was a considerable enrichment of resting dendritic cells and M2 macrophages in patients at low risk. We also found that risk scores predicted the outcome of immunotherapy. In vitro, we found that KCNE1, NPC2, and SFTPD were lowly expressed in malignant epithelial cells and patients with low expression of KCNE1, NPC2, and SFTPD had a higher percentage of M2 macrophage infiltration. Overexpression of KCNE1, NPC2, and SFTPD suppressed the proliferation and invasion of malignant cells, and M0 macrophages remarkably reduced M2 macrophage polarization and cellular secretion of pro-tumor cytokines. Conclusions: We used three LASGs—KCNE1, NPC2, and SFTPD—to develop and validate a predictive signature for LUAD patients. Furthermore, we found that low expression of KCNE1, NPC2, and SFTPD promotes lung cancer cell proliferation and invasion and M2 macrophage polarization. Our study may provide fresh perspectives for customized immunotherapy. |
| first_indexed | 2024-04-24T13:48:50Z |
| format | Article |
| id | doaj.art-03367d4f0cab49279e0f28b4f6202c13 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-24T13:48:50Z |
| publishDate | 2024-03-01 |
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| series | Heliyon |
| spelling | doaj.art-03367d4f0cab49279e0f28b4f6202c132024-04-04T05:05:11ZengElsevierHeliyon2405-84402024-03-01106e27575Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinomaZi-Ming Wang0Zhi-Lin Ning1Chao Ma2Tang-Bin Liu3Bo Tao4Liang Guo5Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200443, ChinaKey Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaDepartment of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, Henan, ChinaDepartment of Thoracic surgery, Anhui Chest Hospital, Hefei 230061, Anhui, ChinaDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200443, China; Corresponding author. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, No. 507 Zhengmin Road, Shanghai 200443, China.Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200443, China; Corresponding author. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, No. 507 Zhengmin Road, Shanghai 200443, China.Background: Recent research has shown that lysosomes play a critical role in the onset and progression of malignancy by regulating tumor cell death through several mechanisms. Nevertheless, the involvement of lysosome-associated genes (LSAGs) in lung adenocarcinoma (LUAD) is still not well understood. Methods: LSAGs were identified in malignant lung epithelial cells, as well as biologically and functionally annotated by the comprehensive integration of single-cell and bulk RNA-sequencing data. Prognostic characterization of LSAGs was established, of which the accuracy and reliability were assessed by one-way Cox and LASSO regression. Correlations between LSAG properties and immune cell infiltration, chemotherapy, and immunotherapy were analyzed by integrated omics data. Finally, we characterized the expression of three LSAGs (KCNE1, NPC2, and SFTPD) in malignant lung epithelium and assessed their impact on tumor malignancy related phenotypes. Results: We identified 18 LSAGs associated with prognosis, of which 3 LSAGs were used to construct prognostic models. High-risk patients had worse survival and the model predicted it better than other clinical indicators. Based on the functional enrichment analyses, LSAGs were associated with binding and molecular activity functions, inhibition of DNA damage repair and tumor growth, IL7 signaling pathway, and glycolysis. M0 macrophages and M1 macrophages were substantially enriched in high-risk patients. Conversely, there was a considerable enrichment of resting dendritic cells and M2 macrophages in patients at low risk. We also found that risk scores predicted the outcome of immunotherapy. In vitro, we found that KCNE1, NPC2, and SFTPD were lowly expressed in malignant epithelial cells and patients with low expression of KCNE1, NPC2, and SFTPD had a higher percentage of M2 macrophage infiltration. Overexpression of KCNE1, NPC2, and SFTPD suppressed the proliferation and invasion of malignant cells, and M0 macrophages remarkably reduced M2 macrophage polarization and cellular secretion of pro-tumor cytokines. Conclusions: We used three LASGs—KCNE1, NPC2, and SFTPD—to develop and validate a predictive signature for LUAD patients. Furthermore, we found that low expression of KCNE1, NPC2, and SFTPD promotes lung cancer cell proliferation and invasion and M2 macrophage polarization. Our study may provide fresh perspectives for customized immunotherapy.http://www.sciencedirect.com/science/article/pii/S2405844024036065Lung cancerLysosomePrognosisImmunotherapyMacrophage |
| spellingShingle | Zi-Ming Wang Zhi-Lin Ning Chao Ma Tang-Bin Liu Bo Tao Liang Guo Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma Heliyon Lung cancer Lysosome Prognosis Immunotherapy Macrophage |
| title | Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma |
| title_full | Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma |
| title_fullStr | Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma |
| title_full_unstemmed | Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma |
| title_short | Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma |
| title_sort | low expression of lysosome related genes kcne1 npc2 and sftpd promote cancer cell proliferation and tumor associated m2 macrophage polarization in lung adenocarcinoma |
| topic | Lung cancer Lysosome Prognosis Immunotherapy Macrophage |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024036065 |
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