SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells
Abstract Objective Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor mi...
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Springer
2025-02-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-024-03914-z |
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| author | Tianci Han Xiaoqi Guo Junwei Xie Wei Tong Liang Zhang |
| author_facet | Tianci Han Xiaoqi Guo Junwei Xie Wei Tong Liang Zhang |
| author_sort | Tianci Han |
| collection | DOAJ |
| description | Abstract Objective Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME. Methods Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay. Results In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C–C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1. Conclusions Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC. |
| format | Article |
| id | doaj-art-b2262c91c1904f408a9108686462a2cb |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-b2262c91c1904f408a9108686462a2cb2025-02-02T12:26:24ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311710.1007/s00262-024-03914-zSUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cellsTianci Han0Xiaoqi Guo1Junwei Xie2Wei Tong3Liang Zhang4Department of Thoracic Surgery, Cancer Hospital of Dalian University of TechnologyLiaoning University of Traditional Chinese MedicineDepartment of Thoracic Surgery, Cancer Hospital of Dalian University of TechnologyDepartment of Thoracic Surgery, Cancer Hospital of Dalian University of TechnologyDepartment of Thoracic Surgery, Cancer Hospital of Dalian University of TechnologyAbstract Objective Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME. Methods Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay. Results In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C–C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1. Conclusions Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC.https://doi.org/10.1007/s00262-024-03914-zEsophageal squamous cell carcinomaTumor-associated macrophagesETV1CCL2SUMO modificationUBC9 |
| spellingShingle | Tianci Han Xiaoqi Guo Junwei Xie Wei Tong Liang Zhang SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells Cancer Immunology, Immunotherapy Esophageal squamous cell carcinoma Tumor-associated macrophages ETV1 CCL2 SUMO modification UBC9 |
| title | SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells |
| title_full | SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells |
| title_fullStr | SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells |
| title_full_unstemmed | SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells |
| title_short | SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells |
| title_sort | sumo modified etv1 promotes m2 polarized tumor associated macrophage infiltration and cancer progression by facilitating ccl2 transcription in esophageal squamous cell carcinoma cells |
| topic | Esophageal squamous cell carcinoma Tumor-associated macrophages ETV1 CCL2 SUMO modification UBC9 |
| url | https://doi.org/10.1007/s00262-024-03914-z |
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