Methylated BNIP3 gene in colorectal cancer prognosis

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

doi:10.3892/ol_00000153

Methylated BNIP3 gene in colorectal cancer prognosis

Authors:
- 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
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Affiliations: Department of Surgical Oncology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Published online on: September 1, 2010 https://doi.org/10.3892/ol_00000153
Pages: 865-872

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Abstract

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.

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