Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer.
Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer.
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2005-02
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通讯作者：
M. Murai;M. Toyota;Hiromu Suzuki;A. Satoh;Y. Sasaki;K. Akino;M. Ueno;F. Takahashi;M. Kusano;H. Mita;K. Yanagihara;T. Endo;Y. Hinoda;T. Tokino;K. Imai
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作者：
M. Murai;M. Toyota;Hiromu Suzuki;A. Satoh;Y. Sasaki;K. Akino;M. Ueno;F. Takahashi;M. Kusano;H. Mita;K. Yanagihara;T. Endo;Y. Hinoda;T. Tokino;K. Imai
BNIP 3蛋白是Bcl-2家族的促凋亡成员，其在肿瘤的缺氧区域中表达。为了研究BNIP 3基因在胃肠道肿瘤进展中的作用，我们检测了一组结直肠癌和胃癌细胞系中BNIP 3基因的表达和DNA甲基化状态。BNIP 3在测试的24个细胞系中的14个中不表达，并且其缺失不是由基因突变或低氧诱导因子-1（调节BNIP 3表达的关键转录因子）的表达改变引起的。另一方面，BNIP 3的5' CpG岛甲基化与基因沉默密切相关。此外，用甲基转移酶抑制剂5-氮杂-2 '-脱氧胞苷处理甲基化的细胞恢复了缺氧诱导的BNIP 3 mRNA和蛋白的表达，这反过来导致细胞死亡。在66%的原发性结直肠癌和49%的原发性胃癌中也检测到BNIP 3的异常甲基化，但在从肿瘤附近区域收集的正常组织样本中没有检测到。显然，BNIP 3的表观遗传改变是一种常见的癌症特异性事件，这表明BNIP 3的失活可能在某些胃肠道癌症的进展中起关键作用，并且它可能是一种有用的治疗分子靶点。
BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5' CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.