EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma
Abstract Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PD...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-02-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-021-00855-2 |
| _version_ | 1798023918557069312 |
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| author | Qu-Jing Gai Zhen Fu Jiang He Min Mao Xiao-Xue Yao Yan Qin Xi Lan Lin Zhang Jing-Ya Miao Yan-Xia Wang Jiang Zhu Fei-Cheng Yang Hui-Min Lu Ze-Xuan Yan Fang-Lin Chen Yu Shi Yi-Fang Ping You-Hong Cui Xia Zhang Xindong Liu Xiao-Hong Yao Sheng-Qing Lv Xiu-Wu Bian Yan Wang |
| author_facet | Qu-Jing Gai Zhen Fu Jiang He Min Mao Xiao-Xue Yao Yan Qin Xi Lan Lin Zhang Jing-Ya Miao Yan-Xia Wang Jiang Zhu Fei-Cheng Yang Hui-Min Lu Ze-Xuan Yan Fang-Lin Chen Yu Shi Yi-Fang Ping You-Hong Cui Xia Zhang Xindong Liu Xiao-Hong Yao Sheng-Qing Lv Xiu-Wu Bian Yan Wang |
| author_sort | Qu-Jing Gai |
| collection | DOAJ |
| description | Abstract Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment. |
| first_indexed | 2024-04-11T17:54:08Z |
| format | Article |
| id | doaj.art-405264fc1e9d490c8dafcef11c97de0f |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-11T17:54:08Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-405264fc1e9d490c8dafcef11c97de0f2022-12-22T04:10:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352022-02-017111210.1038/s41392-021-00855-2EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastomaQu-Jing Gai0Zhen Fu1Jiang He2Min Mao3Xiao-Xue Yao4Yan Qin5Xi Lan6Lin Zhang7Jing-Ya Miao8Yan-Xia Wang9Jiang Zhu10Fei-Cheng Yang11Hui-Min Lu12Ze-Xuan Yan13Fang-Lin Chen14Yu Shi15Yi-Fang Ping16You-Hong Cui17Xia Zhang18Xindong Liu19Xiao-Hong Yao20Sheng-Qing Lv21Xiu-Wu Bian22Yan Wang23Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Department of Neurosurgery, Xinqiao Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University)Abstract Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment.https://doi.org/10.1038/s41392-021-00855-2 |
| spellingShingle | Qu-Jing Gai Zhen Fu Jiang He Min Mao Xiao-Xue Yao Yan Qin Xi Lan Lin Zhang Jing-Ya Miao Yan-Xia Wang Jiang Zhu Fei-Cheng Yang Hui-Min Lu Ze-Xuan Yan Fang-Lin Chen Yu Shi Yi-Fang Ping You-Hong Cui Xia Zhang Xindong Liu Xiao-Hong Yao Sheng-Qing Lv Xiu-Wu Bian Yan Wang EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma Signal Transduction and Targeted Therapy |
| title | EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma |
| title_full | EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma |
| title_fullStr | EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma |
| title_full_unstemmed | EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma |
| title_short | EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma |
| title_sort | epha2 mediates pdgfa activity and functions together with pdgfra as prognostic marker and therapeutic target in glioblastoma |
| url | https://doi.org/10.1038/s41392-021-00855-2 |
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