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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 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.

SUBMITTER: Kuo IY

PROVIDER: S-EPMC6378712 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes.

Kuo I-Ying IY Huang Yu-Lin YL Lin Chien-Yu CY Lin Chien-Hsun CH Chang Wei-Lun WL Lai Wu-Wei WW Wang Yi-Ching YC

Journal of biomedical science 20190218 1

<h4>Background</h4>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.<h4>Methods</h4>Py ...[more]

PMID: 30777052

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Project description:PURPOSE:To examine the value of early changes in quantitative diffusion-weighted imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for discriminating complete pathologic response (pCR) to chemoradiation in esophageal cancer. METHODS AND MATERIALS:Twenty esophageal cancer patients treated with chemoradiation followed by surgery were prospectively enrolled. Patients underwent magnetic resonance imaging and FDG-PET/CT scans at baseline, interim (2 weeks after chemoradiation start), and first follow-up. On the basis of pathologic findings at surgery, patients were categorized into tumor regression groups (TRG1, TRG2, and TRG3+). Distributions of summary statistics in apparent diffusion coefficient (ADC) and FDG-PET at baseline and relative changes at interim and follow-up scans were compared between pCR/TRG1 and non-pCR/TRG2+ groups and across readers. Receiver operating characteristics were evaluated for summary measures to characterize discrimination of pCR from non-pCR. RESULTS:Relative changes in tumor volume ADC (?ADC) mean and 25th and 10th percentiles from baseline to interim were able to completely discriminate (area under the curve = 1, P < .0011) between pCR and non-pCR (thresholds = 27.7%, 29.2%, and 32.1%, respectively) and were found to have high interreader reliability (95% limits of agreement of 1.001, 0.944, and 0.940, respectively). Relative change in total lesion glycolysis (TLG) from baseline to interim was significantly different among pCR and non-pCR groups (P=.0117) and yielded an area under the curve of 0.947 (95% confidence interval 0.8505-1.043). An optimal threshold of 59% decrease in TLG provided optimal sensitivity (specificity) of 1.000 (0.867). Changes in ADC summary measures were negatively correlated with that of TLG (Spearman, -0.495, P=.027). CONCLUSIONS:Quantitative volume ?ADC and TLG during treatment may serve as early imaging biomarkers for discriminating pathologic response to chemoradiation in esophageal cancer. Validation of these data in larger, prospective, multicenter studies is essential.

Dataset Information

SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes.

Publications

SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes.

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