SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes
Abstract Background Prognosis of esophageal squamous cell carcinoma (ESCC) patients is poor and the concurrent chemoradiation therapy (CCRT) provided to ESCC patients often failed due to resistance. Therefore, development of biomarkers for predicting CCRT response is immensely important. In this stu...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-02-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | http://link.springer.com/article/10.1186/s12929-019-0510-4 |
| _version_ | 1818297357706461184 |
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| author | I-Ying Kuo Yu-Lin Huang Chien-Yu Lin Chien-Hsun Lin Wei-Lun Chang Wu-Wei Lai Yi-Ching Wang |
| author_facet | I-Ying Kuo Yu-Lin Huang Chien-Yu Lin Chien-Hsun Lin Wei-Lun Chang Wu-Wei Lai Yi-Ching Wang |
| author_sort | I-Ying Kuo |
| collection | DOAJ |
| description | Abstract Background Prognosis of esophageal squamous cell carcinoma (ESCC) patients is poor and the concurrent chemoradiation therapy (CCRT) provided to ESCC patients often failed due to resistance. Therefore, development of biomarkers for predicting CCRT response is immensely important. In this study, we evaluated the predicting value of SRY (sex determining region Y)-box 17 (SOX17) protein during CCRT and its dysregulation of transcriptional targets in CCRT resistance in ESCC. Methods Pyrosequencing methylation, RT-qPCR and immunohistochemistry assays were performed to examine the DNA methylation, mRNA expression and protein expression levels of SOX17 in endoscopic biopsy from a total of 70 ESCC patients received CCRT. Cell proliferation, clonogenic survival and xenograft growth were used to confirm the sensitization of ESCC cell line KYSE510 in response to cisplatin, radiation or CCRT treatment by SOX17 overexpression in vitro and in vivo. Luciferase activity, RT-qPCR and ChIP-qPCR assays were conducted to examine transcription regulation of SOX17 in KYSE510 parental, KYSE510 radio-resistant cells and their derived xenografts. Results High DNA methylation coincided with low mRNA and protein expression levels of SOX17 in pre-treatment endoscopic biopsy from ESCC patients with poor CCRT response. SOX17 protein expression exhibited a good prediction performance in discriminating poor CCRT responders from good responder. Overexpression of SOX17 sensitized KYSE510 radio-resistant cells to cisplatin, radiation or CCRT treatment in cell and xenograft models. Importantly, SOX17 transcriptionally down-regulated DNA repair and damage response-related genes including BRCA1, BRCA2, RAD51, KU80 DNAPK, p21, SIRT1, NFAT5 and REV3L in KYSE510 radio-resistant cells to achieve the sensitization effect to anti-cancer treatment. Low expression of BRCA1, DNAPK, p21, RAD51 and SIRT1 was confirmed in SOX17 sensitized xenograft tissues derived from radio-resistant ESCC cells. Conclusions Our study reveals a novel mechanism by which SOX17 transcriptionally inactivates DNA repair and damage response-related genes to sensitize ESCC cell or xenograft to CCRT treatment. In addition, we establish a proof-of-concept CCRT prediction biomarker using SOX17 immunohistochemical staining in pre-treatment endoscopic biopsies to identify ESCC patients who are at high risk of CCRT failure and need intensive care. |
| first_indexed | 2024-12-13T04:18:09Z |
| format | Article |
| id | doaj.art-b8627b0348134ae5a2634eff53ad8a20 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-12-13T04:18:09Z |
| publishDate | 2019-02-01 |
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| spelling | doaj.art-b8627b0348134ae5a2634eff53ad8a202022-12-21T23:59:50ZengBMCJournal of Biomedical Science1423-01272019-02-0126111410.1186/s12929-019-0510-4SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genesI-Ying Kuo0Yu-Lin Huang1Chien-Yu Lin2Chien-Hsun Lin3Wei-Lun Chang4Wu-Wei Lai5Yi-Ching Wang6Department of Pharmacology, College of Medicine, National Cheng Kung UniversityDepartment of Pharmacology, College of Medicine, National Cheng Kung UniversityDepartment of Pharmacology, College of Medicine, National Cheng Kung UniversityDepartment of Pharmacology, College of Medicine, National Cheng Kung UniversityDepartment of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Pharmacology, College of Medicine, National Cheng Kung UniversityAbstract Background Prognosis of esophageal squamous cell carcinoma (ESCC) patients is poor and the concurrent chemoradiation therapy (CCRT) provided to ESCC patients often failed due to resistance. Therefore, development of biomarkers for predicting CCRT response is immensely important. In this study, we evaluated the predicting value of SRY (sex determining region Y)-box 17 (SOX17) protein during CCRT and its dysregulation of transcriptional targets in CCRT resistance in ESCC. Methods Pyrosequencing methylation, RT-qPCR and immunohistochemistry assays were performed to examine the DNA methylation, mRNA expression and protein expression levels of SOX17 in endoscopic biopsy from a total of 70 ESCC patients received CCRT. Cell proliferation, clonogenic survival and xenograft growth were used to confirm the sensitization of ESCC cell line KYSE510 in response to cisplatin, radiation or CCRT treatment by SOX17 overexpression in vitro and in vivo. Luciferase activity, RT-qPCR and ChIP-qPCR assays were conducted to examine transcription regulation of SOX17 in KYSE510 parental, KYSE510 radio-resistant cells and their derived xenografts. Results High DNA methylation coincided with low mRNA and protein expression levels of SOX17 in pre-treatment endoscopic biopsy from ESCC patients with poor CCRT response. SOX17 protein expression exhibited a good prediction performance in discriminating poor CCRT responders from good responder. Overexpression of SOX17 sensitized KYSE510 radio-resistant cells to cisplatin, radiation or CCRT treatment in cell and xenograft models. Importantly, SOX17 transcriptionally down-regulated DNA repair and damage response-related genes including BRCA1, BRCA2, RAD51, KU80 DNAPK, p21, SIRT1, NFAT5 and REV3L in KYSE510 radio-resistant cells to achieve the sensitization effect to anti-cancer treatment. Low expression of BRCA1, DNAPK, p21, RAD51 and SIRT1 was confirmed in SOX17 sensitized xenograft tissues derived from radio-resistant ESCC cells. Conclusions Our study reveals a novel mechanism by which SOX17 transcriptionally inactivates DNA repair and damage response-related genes to sensitize ESCC cell or xenograft to CCRT treatment. In addition, we establish a proof-of-concept CCRT prediction biomarker using SOX17 immunohistochemical staining in pre-treatment endoscopic biopsies to identify ESCC patients who are at high risk of CCRT failure and need intensive care.http://link.springer.com/article/10.1186/s12929-019-0510-4SOX17Transcription regulationResistanceDNA repairConcurrent chemoradiation therapyEsophageal cancer |
| spellingShingle | I-Ying Kuo Yu-Lin Huang Chien-Yu Lin Chien-Hsun Lin Wei-Lun Chang Wu-Wei Lai Yi-Ching Wang SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes Journal of Biomedical Science SOX17 Transcription regulation Resistance DNA repair Concurrent chemoradiation therapy Esophageal cancer |
| title | SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes |
| title_full | SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes |
| title_fullStr | SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes |
| title_full_unstemmed | SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes |
| title_short | SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes |
| title_sort | sox17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down regulation of dna repair and damage response genes |
| topic | SOX17 Transcription regulation Resistance DNA repair Concurrent chemoradiation therapy Esophageal cancer |
| url | http://link.springer.com/article/10.1186/s12929-019-0510-4 |
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