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Digestive Diseases and Sciences

, Volume 58, Issue 12, pp 3503–3515 | Cite as

Hypoxia-Induced Snail Expression Through Transcriptional Regulation by HIF-1α in Pancreatic Cancer Cells

  • Guang-hui Zhu
  • Chen Huang
  • Zheng-zhong Feng
  • Xiu-hong Lv
  • Zheng-jun QiuEmail author
Original Article

Abstract

Background

Intratumoral hypoxia and epithelial–mesenchymal transition are involved in tumor invasion and metastasis.

Aims

This study investigated the molecular mechanisms that relay the hypoxia signal into the epithelial–mesenchymal transition and metastasis.

Methods

Morphology analysis and tumor cell migration and invasion assays were performed to detect phenotypic changes of pancreatic cancer cells under normoxic and hypoxic conditions after lentiviral HIF-1α shRNA transfection. Quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry were used to detect gene expression in pancreatic cancer cell lines and tissues or normal pancreatic tissues. Luciferase, gel shift, and ChIP assays were used to assess gene regulation.

Results

Under hypoxic conditions, these tumor cells underwent typical morphological and molecular changes to epithelial–mesenchymal transition. Moreover, Snail expression was induced by hypoxic conditions and was regulated by HIF-1α expression at the transcriptional level through HIF-1α-binding to the second site of hypoxia-responsive elements of the Snail gene promoter. In addition, Snail expression was associated with HIF-1α expression in pancreatic cancer tissues, and expression of both was associated with tumor metastasis and poor patient survival.

Conclusions

Our study provides key evidence that HIF-1α and Snail are responsible for hypoxia-induced metastasis phenotypes in pancreatic cancer and that HIF-1α and Snail expression can be used as biomarkers to predict tumor metastasis and patient survival.

Keywords

Hypoxia Epithelial–mesenchymal transition HIF-1α Snail Metastasis 

Notes

Acknowledgments

This work was supported by a grant (no. 09QA1404600) awarded by the fund for scientific research of Science and Technology Commission of Shanghai Municipality.

Conflict of interest

None.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Guang-hui Zhu
    • 1
  • Chen Huang
    • 2
    • 4
    • 5
  • Zheng-zhong Feng
    • 3
  • Xiu-hong Lv
    • 3
  • Zheng-jun Qiu
    • 2
    • 4
    • 5
    Email author
  1. 1.Department of General SurgeryFengxian Central HospitalShanghaiChina
  2. 2.Departments of General Surgery, Affiliated First People’s HospitalShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Departments of Pathology, Affiliated First People’s HospitalShanghai Jiao Tong UniversityShanghaiChina
  4. 4.Shanghai Key Laboratory of Pancreatic DiseasesShanghaiChina
  5. 5.Pancreatic Cancer Center of Shanghai Jiaotong UniversityShanghaiChina

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