Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression

I. Ying Kuo, Ching Chi Wu, Jia Ming Chang, Yu Lin Huang, Chien Hsun Lin, Jing Jou Yan, Bor Shyang Sheu, Pei Jung Lu, Wei Lun Chang, Wu Wei Lai, Yi Ching Wang

Research output: Contribution to journalArticle

36 Citations (Scopus)

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. What's new? While the SOX17 gene is known to encode a transcription factor important for esophagus tissue development, the transcriptional network of SOX17 and the prognostic impact of SOX17 protein expression in human cancers both remain largely unclear. Here, the authors discovered the first transcriptional network of SOX17 in cancer and verified the novel transcriptional repression target genes of SOX17 involved in migration and invasion of esophageal cancer. They provided evidence for metastasis suppression by SOX17 in an animal model and identified low SOX17 expression as a prognosis marker in esophageal cancer patients, indicating SOX17 as a potential target for therapeutic intervention.

Original languageEnglish
Pages (from-to)563-573
Number of pages11
JournalInternational Journal of Cancer
Volume135
Issue number3
DOIs
Publication statusPublished - 2014 Aug 1

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Esophageal Neoplasms
Gene Regulatory Networks
Genes
Proteins
Neoplasm Metastasis
Cell Movement
Neoplasms
Esophageal Squamous Cell Carcinoma
Chromatin Immunoprecipitation
Growth
Heterografts
Esophagus
Transcription Factors
Animal Models
Biomarkers
Polymerase Chain Reaction
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{c766995d84c44cfabd04582a520a6414,
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. What's new? While the SOX17 gene is known to encode a transcription factor important for esophagus tissue development, the transcriptional network of SOX17 and the prognostic impact of SOX17 protein expression in human cancers both remain largely unclear. Here, the authors discovered the first transcriptional network of SOX17 in cancer and verified the novel transcriptional repression target genes of SOX17 involved in migration and invasion of esophageal cancer. They provided evidence for metastasis suppression by SOX17 in an animal model and identified low SOX17 expression as a prognosis marker in esophageal cancer patients, indicating SOX17 as a potential target for therapeutic intervention.",
author = "Kuo, {I. Ying} and Wu, {Ching Chi} and Chang, {Jia Ming} and Huang, {Yu Lin} and Lin, {Chien Hsun} and Yan, {Jing Jou} and Sheu, {Bor Shyang} and Lu, {Pei Jung} and Chang, {Wei Lun} and Lai, {Wu Wei} and Wang, {Yi Ching}",
year = "2014",
month = "8",
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doi = "10.1002/ijc.28695",
language = "English",
volume = "135",
pages = "563--573",
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Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression. / Kuo, I. Ying; Wu, Ching Chi; Chang, Jia Ming; Huang, Yu Lin; Lin, Chien Hsun; Yan, Jing Jou; Sheu, Bor Shyang; Lu, Pei Jung; Chang, Wei Lun; Lai, Wu Wei; Wang, Yi Ching.

In: International Journal of Cancer, Vol. 135, No. 3, 01.08.2014, p. 563-573.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression

AU - Kuo, I. Ying

AU - Wu, Ching Chi

AU - Chang, Jia Ming

AU - Huang, Yu Lin

AU - Lin, Chien Hsun

AU - Yan, Jing Jou

AU - Sheu, Bor Shyang

AU - Lu, Pei Jung

AU - Chang, Wei Lun

AU - Lai, Wu Wei

AU - Wang, Yi Ching

PY - 2014/8/1

Y1 - 2014/8/1

N2 - 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. What's new? While the SOX17 gene is known to encode a transcription factor important for esophagus tissue development, the transcriptional network of SOX17 and the prognostic impact of SOX17 protein expression in human cancers both remain largely unclear. Here, the authors discovered the first transcriptional network of SOX17 in cancer and verified the novel transcriptional repression target genes of SOX17 involved in migration and invasion of esophageal cancer. They provided evidence for metastasis suppression by SOX17 in an animal model and identified low SOX17 expression as a prognosis marker in esophageal cancer patients, indicating SOX17 as a potential target for therapeutic intervention.

AB - 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. What's new? While the SOX17 gene is known to encode a transcription factor important for esophagus tissue development, the transcriptional network of SOX17 and the prognostic impact of SOX17 protein expression in human cancers both remain largely unclear. Here, the authors discovered the first transcriptional network of SOX17 in cancer and verified the novel transcriptional repression target genes of SOX17 involved in migration and invasion of esophageal cancer. They provided evidence for metastasis suppression by SOX17 in an animal model and identified low SOX17 expression as a prognosis marker in esophageal cancer patients, indicating SOX17 as a potential target for therapeutic intervention.

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