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Tumor Biology

, Volume 37, Issue 4, pp 5621–5632 | Cite as

Methylation-mediated repression of potential tumor suppressor miR-203a and miR-203b contributes to esophageal squamous cell carcinoma development

  • Yibing Liu
  • Zhiming Dong
  • Jia Liang
  • Yanli Guo
  • Xin Guo
  • Supeng Shen
  • Gang Kuang
  • Wei Guo
Original Article

Abstract

MiRNAs regulate gene expression and play pivotal roles in biological processes. MiRNAs can be inactivated by epigenetic mechanisms, such as DNA hypermethylation of CpG sites within CpG islands. Here, we investigated the role and methylation status of miR-203a and miR-203b in esophageal cancer cell lines and primary esophageal squamous cell carcinoma (ESCC) tumors and further elucidate the role of both miRNAs in the prognosis of ESCC. The present study revealed a strong downregulation of miR-203a and miR-203b in esophageal cancer cell lines and primary ESCC samples. Treatment of esophageal cancer cells with demethylating agent 5-Aza-dC led to increased miR-203a and miR-203b expression, confirming the epigenetic regulation of both miRNAs. The inhibition of proliferation and invasiveness in esophageal cancer cells after treated with 5-Aza-dC or transfected with miR-203a or miR-203b mimics, suggesting the tumor suppressor role of both miRNAs in esophageal cancer. Furthermore, the critical CpG sites of miR-203a and miR-203b were found to be located in proximal promoter region, and the proximal promoter hypermethylation of both miRNAs was found to influence transcriptional activity. Downregulation and hypermethylation of miR-203a and miR-203b were associated with TNM stage, pathological differentiation, and lymph node metastasis. ESCC patients in stages III and IV, with reduced expression of miR-203a or hypermethylation of miR-203a or miR-203b, demonstrated poor patient survival. In summary, our results suggest that miR-203a and miR-203b may function as tumor-suppressive miRNAs that are inactivated through proximal promoter hypermethylation and miR-203a expression and methylation may be useful prognostic marker in ESCC patients.

Keywords

miR-203a miR-203b Esophageal squamous cell carcinoma Expression Methylation 

Notes

Acknowledgments

We thank the patients for taking part in this study. This research was supported by the National Natural Science Foundation (no. 81472335).

Compliance with ethical standards

Conflicts of interest

None

Supplementary material

13277_2015_4432_MOESM1_ESM.docx (15 kb)
Supplementary Table 1 Clinicopathologic characteristics of esophageal squamous cell carcinoma cases (DOCX 15 kb)
13277_2015_4432_MOESM2_ESM.docx (17 kb)
Supplementary Table 2 Primer sequences and reaction conditions of miR-203a and miR-203b used in this study (DOCX 16 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yibing Liu
    • 1
  • Zhiming Dong
    • 2
  • Jia Liang
    • 2
  • Yanli Guo
    • 2
  • Xin Guo
    • 2
  • Supeng Shen
    • 2
  • Gang Kuang
    • 2
  • Wei Guo
    • 2
  1. 1.Department of Internal Medicine-Oncologythe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
  2. 2.Laboratory of Pathology, Hebei Cancer Institutethe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina

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