title: Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression.
abstract: The transcriptional network of the SRY (sex determining region Y)-box 17 (SOX17) and the prognostic impact of SOX17 protein expression in human cancers remain largely unclear. In this study, we evaluated the prognostic effect of low SOX17 protein expression and its dysregulation of transcriptional network in esophageal squamous cell carcinoma (ESCC). Low SOX17 protein expression was found in 47.4% (73 of 154) of ESCC patients with predicted poor prognosis. Re-expression of SOX17 in ESCC cells caused reduced foci formation, cell motility, decreased ESCC xenograft growth and metastasis in animals. Knockdown of SOX17 increased foci formation in ESCC and normal esophageal cells. Notably, 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. Using quantitative chromatin immunoprecipitation-PCR and promoter activity assays, we confirmed that MACC1, MALAT1, NBN, NFAT5, CSNK1A1, FN1 and SERBP1 genes were suppressed by SOX17 via the SRY binding-mediated transcriptional regulation. Overexpression of FN1 and MACC1 abolished SOX17-mediated migration and invasion suppression. The inverse correlation between SOX17 and FN1 protein expression in ESCC clinical samples further strengthened our conclusion that FN1 is a transcriptional repression target gene of SOX17. This study provides compelling 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 suppressive downstream genes of SOX17 which can be potential therapeutic targets for ESCC.
authors.affiliation: Institute of Basic Medical Sciences College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: I-Ying
authors.initials: IY
authors.lastname: Kuo
authors.forename: Ching-Chi
authors.initials: CC
authors.lastname: Wu
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Huang
authors.forename: Chien-Hsun
authors.initials: CH
authors.lastname: Lin
authors.forename: Jing-Jou
authors.initials: JJ
authors.lastname: Yan
authors.forename: Bor-Shyang
authors.initials: BS
authors.lastname: Sheu
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Chang
authors.forename: Wu-Wei
authors.initials: WW
authors.lastname: Lai
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics*; D015996:Survival Rate; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C067625:FN1 protein, human; D005353:Fibronectins; C544162:MACC1 protein, human; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors
keywords: SOX17; esophageal squamous cell carcinoma; prognosis; transcriptional network; tumor suppressor