Methylated BNIP3 gene in colorectal cancer prognosis

Sayaka Shimizu, Satoru Iida, Megumi Ishiguro, Hiroyuki Uetake, Toshiaki Ishikawa, Yoko Takagi, Hirotoshi Kobayashi, Tetsuro Higuchi, Masayuki Enomoto, Kaoru Mogushi, Hiroshi Mizushima, Hiroshi Tanaka, Kenichi Sugihara

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


The DNA methylation of apoptosis-related genes in various cancers contributes to the disruption of the apoptotic pathway and results in resistance to chemotherapeutic agents. Irinotecan (CPT-11) is one of the key chemotherapy drugs used to treat metastatic colorectal cancer (CRC). However, a number of metastatic CRC patients do not benefit from this drug. Thus, the identification of molecular genetic parameters associated with the response to CPT-11 is of interest. To identify apoptosis-related genes that may contribute to CPT-11 resistance, microarray analysis was conducted using colon cancer cells in which 5-aza-2'deoxycytidine (DAC) enhanced sensitivity to CPT-11. Microarray analysis identified 10 apoptosis-related genes that were up-regulated following treatment with DAC. Among the genes, Bcl-2/adenovirus E1B 19 kDa protein interacting protein 3 (BNIP3), a Bcl-2 family pro-apoptotic protein, was identified as being involved in CPT-11 resistance following methylation of its promoter. An analysis of 112 primary CRC cases revealed that approximately 58% of cases showed BNIP3 methylation, and that patients with methylation exhibited a poorer outcome compared to those without methylation. In addition, in 30 patients who received first-line CPT-11 chemotherapy, patients with methylation exhibited resistance to chemotherapy compared to patients with no methylation. The results suggest that methylation of BNIP3 is a predictive factor in the prognosis and response to CPT-11 treatment in CRC patients.

Original languageEnglish
Pages (from-to)865-872
Number of pages8
JournalOncology Letters
Issue number5
Publication statusPublished - 2010 Sep


  • Apoptosis
  • Colorectal cancer
  • Irinotecan
  • Methylation
  • Prognosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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