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Epigenetic Status of CDO1 Gene May Reflect Chemosensitivity in Colon Cancer with Postoperative Adjuvant Chemotherapy

  • Keigo Yokoi
  • Hiroki Harada
  • Kazuko Yokota
  • Satoru Ishii
  • Toshimichi Tanaka
  • Nobuyuki Nishizawa
  • Masashi Shimazu
  • Ken Kojo
  • Hirohisa Miura
  • Takahiro Yamanashi
  • Takeo Sato
  • Takatoshi Nakamura
  • Masahiko Watanabe
  • Keishi Yamashita
Translational Research and Biomarkers

Abstract

Background

Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor gene, and its expression is regulated by promoter DNA methylation in human cancer. The metabolic product mediated by CDO1 enzyme increases mitochondrial membrane potential (MMP), putatively representing chemoresistance. The aim of this study is to investigate the functional relevance of CDO1 gene in colon cancer with chemotherapy.

Patients and Methods

We investigated 170 stage III colon cancer patients for CDO1 methylation by using quantitative methylation-specific polymerase chain reaction (PCR). To elucidate the functional role of CDO1 gene in colorectal cancer (CRC) biology, we established cell lines that stably express CDO1 gene and evaluated chemosensitivity, MMP, and tolerability assay including anaerobic environment.

Results

Hypermethylation of CDO1 gene was an independent prognostic factor for stage III colon cancer on multivariate prognostic analysis. Surprisingly, patients with CDO1 hypermethylation exhibited better prognosis than those with CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy (P = 0.03); however, a similar finding was not seen in those without postoperative chemotherapy. In some CRC cell lines, forced expression of CDO1 gene increased MMP accompanied by chemoresistance and/or tolerance under hypoxia.

Conclusion

CDO1 methylation may be a useful biomarker to increase the number of stage III colon cancer patients who can be saved by adjuvant therapy. Such clinical relevance may represent the functionally oncogenic property of CDO1 gene through MMP activity.

Notes

Disclosure

None of the authors has any conflicts of interest to declare regarding this study.

Supplementary material

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Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Keigo Yokoi
    • 1
  • Hiroki Harada
    • 1
  • Kazuko Yokota
    • 1
  • Satoru Ishii
    • 1
  • Toshimichi Tanaka
    • 1
  • Nobuyuki Nishizawa
    • 1
  • Masashi Shimazu
    • 1
  • Ken Kojo
    • 1
  • Hirohisa Miura
    • 1
  • Takahiro Yamanashi
    • 1
  • Takeo Sato
    • 1
  • Takatoshi Nakamura
    • 1
  • Masahiko Watanabe
    • 1
  • Keishi Yamashita
    • 1
    • 2
  1. 1.Department of SurgeryKitasato University School of MedicineSagamiharaJapan
  2. 2.Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical FrontiersKitasato University School of MedicineSagamiharaJapan

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