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
Department of Surgical Oncology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Oncol Lett. 2010 Sep;1(5):865-872. doi: 10.3892/ol_00000153. Epub 2010 Sep 1.
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.
各种癌症中凋亡相关基因的DNA甲基化会导致凋亡途径的破坏，并产生对化疗药物的耐药性。伊立替康（CPT-11）是用于治疗转移性结直肠癌（CRC）的关键化疗药物之一。然而，许多转移性CRC患者并未从该药物中获益。因此，确定与CPT-11反应相关的分子遗传参数备受关注。为了鉴定可能导致CPT-11耐药的凋亡相关基因，使用5-氮杂-2'-脱氧胞苷（DAC）增强对CPT-11敏感性的结肠癌细胞进行了微阵列分析。微阵列分析确定了10个在DAC处理后上调的凋亡相关基因。在这些基因中，Bcl-2/腺病毒E1B 19 kDa蛋白相互作用蛋白3（BNIP3），一种Bcl-2家族促凋亡蛋白，被确定在其启动子甲基化后参与CPT-11耐药。对112例原发性CRC病例的分析显示，约58%的病例显示BNIP3甲基化，与未甲基化的患者相比，甲基化患者的预后较差。此外，在30例接受一线CPT-11化疗的患者中，与未甲基化的患者相比，甲基化患者对化疗表现出耐药性。结果表明，BNIP3甲基化是CRC患者预后和对CPT-11治疗反应的预测因素。
