Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop
Abstract Background Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remai...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02471-6 |
| _version_ | 1828356425941778432 |
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| author | Junjie Gu Yuanyuan Sun Jiahang Song Ruiling Zhao Xiaoke Di Yumeng Zhang Xiaolin Ge Shu Zhang Yun Gu Xinchen Sun |
| author_facet | Junjie Gu Yuanyuan Sun Jiahang Song Ruiling Zhao Xiaoke Di Yumeng Zhang Xiaolin Ge Shu Zhang Yun Gu Xinchen Sun |
| author_sort | Junjie Gu |
| collection | DOAJ |
| description | Abstract Background Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown. Methods We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms. Results DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-β1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-β1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy. Conclusions Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-β1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-β1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Graphical Abstract Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells. |
| first_indexed | 2024-04-14T02:59:23Z |
| format | Article |
| id | doaj.art-93cdad6401874ca2b3ad1b135f4a39a4 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-14T02:59:23Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-93cdad6401874ca2b3ad1b135f4a39a42022-12-22T02:15:59ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-08-0141112210.1186/s13046-022-02471-6Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loopJunjie Gu0Yuanyuan Sun1Jiahang Song2Ruiling Zhao3Xiaoke Di4Yumeng Zhang5Xiaolin Ge6Shu Zhang7Yun Gu8Xinchen Sun9The First School of Clinical Medicine, Nanjing Medical UniversityThe First School of Clinical Medicine, Nanjing Medical UniversityThe First School of Clinical Medicine, Nanjing Medical UniversityThe First School of Clinical Medicine, Nanjing Medical UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical UniversityThe First School of Clinical Medicine, Nanjing Medical UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical UniversityCore Facility Center, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Thoracic Surgery, Lian Shui People’s HospitalDepartment of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Background Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown. Methods We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms. Results DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-β1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-β1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy. Conclusions Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-β1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-β1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Graphical Abstract Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells.https://doi.org/10.1186/s13046-022-02471-6DJ-1TGF-β1HSC70Smad3TSP1Esophageal squamous cell carcinoma |
| spellingShingle | Junjie Gu Yuanyuan Sun Jiahang Song Ruiling Zhao Xiaoke Di Yumeng Zhang Xiaolin Ge Shu Zhang Yun Gu Xinchen Sun Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop Journal of Experimental & Clinical Cancer Research DJ-1 TGF-β1 HSC70 Smad3 TSP1 Esophageal squamous cell carcinoma |
| title | Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop |
| title_full | Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop |
| title_fullStr | Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop |
| title_full_unstemmed | Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop |
| title_short | Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop |
| title_sort | irradiation induces dj 1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a tgf β1 positive feedback loop |
| topic | DJ-1 TGF-β1 HSC70 Smad3 TSP1 Esophageal squamous cell carcinoma |
| url | https://doi.org/10.1186/s13046-022-02471-6 |
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