High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma
Background According to the histopathology, lung adenocarcinoma (LUAD) could be divided into five distinct pathological subtypes, categorized as high-risk (micropapillary and solid) group, intermediate-risk (acinar and papillary) group, and low-risk (lepidic) group. Despite this classification, ther...
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PeerJ Inc.
2023-10-01
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| Online Access: | https://peerj.com/articles/16306.pdf |
| _version_ | 1797419555828531200 |
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| author | Wei Fei Yan Yan Guangjun Liu Bo Peng Yuanyuan Liu Qiang Chen |
| author_facet | Wei Fei Yan Yan Guangjun Liu Bo Peng Yuanyuan Liu Qiang Chen |
| author_sort | Wei Fei |
| collection | DOAJ |
| description | Background According to the histopathology, lung adenocarcinoma (LUAD) could be divided into five distinct pathological subtypes, categorized as high-risk (micropapillary and solid) group, intermediate-risk (acinar and papillary) group, and low-risk (lepidic) group. Despite this classification, there is limited knowledge regarding the role of transcription factors (TFs) in the molecular regulation of LUAD histology patterns. Methods Publish data was mined to explore the candidate TFs associated with high-risk histopathology in LUAD, which was validated in tissue samples. Colony formation, CCK8, EdU, transwell, and matrigel assays were performed to determine the biological function of FAM83A in vitro. Subcutaneous tumor-bearing in BALB/c nude mice and xenograft perivitelline injection in zebrafish were utilized to unreal the function of FAM83A in vivo. We also performed chromatin immunoprecipitation (ChIP), dual-luciferase reporter, and rescue assays to uncover the underline mechanism of FAM83A. Immunohistochemistry (IHC) was performed to confirm the oncogenic role of FAM83A in clinical LUAD tissues. Results Screening the transcriptional expression data from TCGA-LUAD, we focus on the differentially expressed TFs across the divergent pathological subtypes, and identified that the expression of FAM83A is higher in patients with high-risk groups compared with those with intermediate or low-risk groups. The FAM83A expression is positively correlated with worse overall survival, progression-free survival, and advanced stages. Gain- and loss-of-function assays revealed that FAM83A promoted cell proliferation, invasion, and migration of tumor cell lines both in vivo and in vitro. Pathway enrichment analysis shows that FAM83A expression is significantly enriched in cell cycle-related pathways. The ChIP and luciferase reporter assays revealed that FAM83A hijacks the promoter of FOXM1 to progress the malignant LUAD, and the rescue assay uncovered that the function of FAM83A is partly dependent on FOXM1 regulation. Additionally, patients with high FAM83A expression positively correlated with higher IHC scores of Ki-67 and FOXM1, and patients with active FAM83A/FOXM1 axis had poor prognoses in LUAD. Conclusions Taken together, our study revealed that the high-risk histological subtype-related FAM83A hijacks FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma, which implies targeting FAM83A/FOXM1 is the therapeutic vulnerability. |
| first_indexed | 2024-03-09T06:49:19Z |
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| id | doaj.art-7692c105eadf4350bd18c93c07f70f2c |
| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T06:49:19Z |
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| spelling | doaj.art-7692c105eadf4350bd18c93c07f70f2c2023-12-03T10:30:18ZengPeerJ Inc.PeerJ2167-83592023-10-0111e1630610.7717/peerj.16306High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinomaWei Fei0Yan Yan1Guangjun Liu2Bo Peng3Yuanyuan Liu4Qiang Chen5Department of Clinical College, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Cardiovascular Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Clinical College, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Respiratory and Critical Care Medicine, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Clinical College, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBackground According to the histopathology, lung adenocarcinoma (LUAD) could be divided into five distinct pathological subtypes, categorized as high-risk (micropapillary and solid) group, intermediate-risk (acinar and papillary) group, and low-risk (lepidic) group. Despite this classification, there is limited knowledge regarding the role of transcription factors (TFs) in the molecular regulation of LUAD histology patterns. Methods Publish data was mined to explore the candidate TFs associated with high-risk histopathology in LUAD, which was validated in tissue samples. Colony formation, CCK8, EdU, transwell, and matrigel assays were performed to determine the biological function of FAM83A in vitro. Subcutaneous tumor-bearing in BALB/c nude mice and xenograft perivitelline injection in zebrafish were utilized to unreal the function of FAM83A in vivo. We also performed chromatin immunoprecipitation (ChIP), dual-luciferase reporter, and rescue assays to uncover the underline mechanism of FAM83A. Immunohistochemistry (IHC) was performed to confirm the oncogenic role of FAM83A in clinical LUAD tissues. Results Screening the transcriptional expression data from TCGA-LUAD, we focus on the differentially expressed TFs across the divergent pathological subtypes, and identified that the expression of FAM83A is higher in patients with high-risk groups compared with those with intermediate or low-risk groups. The FAM83A expression is positively correlated with worse overall survival, progression-free survival, and advanced stages. Gain- and loss-of-function assays revealed that FAM83A promoted cell proliferation, invasion, and migration of tumor cell lines both in vivo and in vitro. Pathway enrichment analysis shows that FAM83A expression is significantly enriched in cell cycle-related pathways. The ChIP and luciferase reporter assays revealed that FAM83A hijacks the promoter of FOXM1 to progress the malignant LUAD, and the rescue assay uncovered that the function of FAM83A is partly dependent on FOXM1 regulation. Additionally, patients with high FAM83A expression positively correlated with higher IHC scores of Ki-67 and FOXM1, and patients with active FAM83A/FOXM1 axis had poor prognoses in LUAD. Conclusions Taken together, our study revealed that the high-risk histological subtype-related FAM83A hijacks FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma, which implies targeting FAM83A/FOXM1 is the therapeutic vulnerability.https://peerj.com/articles/16306.pdfLUADFAM83AHistological pathology subtypeTranscription factors |
| spellingShingle | Wei Fei Yan Yan Guangjun Liu Bo Peng Yuanyuan Liu Qiang Chen High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma PeerJ LUAD FAM83A Histological pathology subtype Transcription factors |
| title | High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma |
| title_full | High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma |
| title_fullStr | High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma |
| title_full_unstemmed | High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma |
| title_short | High-risk histological subtype-related FAM83A hijacked FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma |
| title_sort | high risk histological subtype related fam83a hijacked foxm1 transcriptional regulation to promote malignant progression in lung adenocarcinoma |
| topic | LUAD FAM83A Histological pathology subtype Transcription factors |
| url | https://peerj.com/articles/16306.pdf |
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