Volume 28 Issue 2 - December 19, 2014 PDF
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Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression
I-Ying Kuo1, Ching-Chi Wu2, Jia-Ming Chang3,4, Yu-Lin Huang2, Chien-Hsun Lin2, Jing-Jou Yan5, Bor-Shyang Sheu6, Pei-Jung Lu3, Wei-Lun Chang6, Wu-Wei Lai7, Yi-Ching Wang1,2,*
1 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
2 Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan
3 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4 Department of Surgery, Chia-Yi Christian Hospital, Chiayi, Taiwan
5 Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
6 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
7 Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
 
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Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. The SRY (sex determining region Y)-box 17 (SOX17) gene, encoding a transcription factor containing a high-mobility group DNA-binding domain, is hypermethylated in many cancers. Here we show the low protein expression of SOX17 and its dysregulation of transcriptional network in ESCC. SOX17 protein expression was examined in ESCC patients, and its effects on tumor growth and metastasis were determined in cell and animal models. Expression array, quantitative chromatin immunoprecipitation-polymerase chain reaction and promoter activity assays were conducted to identify novel transcriptional targets of SOX17. Re-expression of SOX17 in ESCC cells reduced colony formation, cell motility and decreased ESCC xenograft growth and metastasis in animals. A total of 489 significantly differential genes involved in cell growth and motility controls were identified by expression array upon SOX17 overexpression and 47 genes contained putative SRY element in their promoters. MACC1, MALAT1, NBN, NFAT5, CSNK1A1, FN1 and SERBP1 genes were suppressed by SOX17-mediated transcriptional regulation. Overexpression of FN1 and MACC1 abolished SOX17-mediated migration and invasion suppression in ESCC. Clinically, FN1 protein expression inversely correlated with SOX17 protein expression (Fig. 1A). SOX17 protein low expression was found in 47.4% (73 of 154) of ESCC patients with predicted poor survival (Fig. 1B). This study provides the first clinical evidence that low SOX17 protein expression is a prognostic biomarker and novel cell and animal data of SOX17-mediated suppression of ESCC metastasis. We establish the first transcriptional network and identify new SOX17 suppressive downstream genes such as FN1 gene (Fig. 1C) which can be potential therapeutic targets for ESCC.

Figure 1. The clinical correlation between SOX17 and FN1 protein expression in ESCC patients. (A) The representative immunohistochemistry figures for SOX17 and FN1 protein are shown for four ESCC patients. (B) Kaplan-Meier curves showing ESCC patients with SOX17 protein low expression had significantly poorer overall survival than those with normal expression. (C) An inverse correlation between SOX17 and FN1 protein expression was found in 48 ESCC patients analyzed. Y axis, percent of cases; X axis, type of comparison. Positive (+) and negative (−) expression status of protein are noted. The percentage in the inverse correlation group (gray columns) and non-inverse correlation group (white columns) is indicated above. P values are shown as indicated.
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