Methylation of BNIP3 in pancreatic cancer inhibits the induction of mitochondrial-mediated tumor cell apoptosis.
Methylation of BNIP3 in pancreatic cancer inhibits the induction of mitochondrial-mediated tumor cell apoptosis.
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DOI：
10.18632/oncotarget.18736
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
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作者：
Li Y;Zhang X;Yang J;Zhang Y;Zhu D;Zhang L;Zhu Y;Li D;Zhou J
Bcl-2 相互作用蛋白 3 (BNIP3) 参与多种细胞过程，被认为是缺氧诱导细胞凋亡的关键调节因子。本研究旨在探讨BNIP3在胰腺癌组织中的表达情况、与临床病理特征和预后的相关性以及该蛋白在胰腺癌细胞株中诱导细胞凋亡的调控作用。与正常上皮细胞相比，BNIP3在胰腺癌组织中的表达显着降低，并且与肿瘤大小、临床分期和淋巴结转移相关。 BNIP3 的表达与促凋亡蛋白 Bax 呈正相关，与抗凋亡蛋白 Bcl-2 呈负相关，而 BNIP3 诱导细胞凋亡与 caspase 3 和 9 激活无关。体外胰腺癌细胞中 BNIP3 表达的恢复导致 ΔΨm 损失、ROS 产生增加和细胞凋亡诱导。通过 RNAi 沉默 BNIP3 后，在胰腺癌细胞中观察到相反的效果。胰腺癌细胞中 BNIP3 表达的缺失与抑制 HIF-1α 与 BNIP3 启动子结合的基因甲基化有关，而 5-Aza-2'-脱氧胞苷 (Aza-dC) 治疗可恢复 BNIP3 表达并使胰腺癌细胞对 BNIP3 诱导的细胞凋亡敏感。研究结果表明，BNIP3 在胰腺癌中显着下调，导致细胞凋亡诱导减少。 BNIP3 表达的沉默与缺氧反应元件 (HRE) 位点的甲基化相关，后者反过来抑制 HIF-1α 与 BNIP3 启动子的结合。数据表明 BNIP3 重新激活是胰腺癌治疗干预的潜在目标。
Bcl-2 interacting protein 3 (BNIP3) is involved in various cellular processes and is considered a key regulator of hypoxia-induced apoptosis. In the present study, the expression of BNIP3 in pancreatic cancer tissues, the correlation with clinicopathological characteristics and prognosis and the regulation of this protein in pancreatic cancer cell lines with regard to the induction of apoptosis were investigated. BNIP3 expression was significantly lower in pancreatic cancer tissues compared with normal epithelia and was associated with tumor size, clinical stage, and lymph node metastasis. The expression of BNIP3 correlated positively to the proapoptotic protein Bax and negatively to the antiapoptotic protein Bcl-2, whereas the induction of apoptosis by BNIP3 was independent of caspase 3 and 9 activation. The restoration of BNIP3 expression in pancreatic cancer cells in vitro, caused loss of ΔΨm, increase in ROS production, and apoptosis induction. The opposite effect was observed in pancreatic cancer cells, following BNIP3 silencing by RNAi. The absence of BNIP3 expression in pancreatic cancer cells was related to gene methylation that suppressed binding of HIF-1α to the BNIP3 promoter, whereas 5-Aza-2′-deoxycytidine (Aza-dC) treatment restored BNIP3 expression and sensitized pancreatic cancer cells to BNIP3-induced apoptosis. The findings indicated that BNIP3 was significantly downregulated in pancreatic cancer resulting in reduced apoptosis induction. Silencing of BNIP3 expression was associated with methylation of the hypoxia-responsive element (HRE) site that in turn inhibited the binding of HIF-1α to the BNIP3 promoter. The data suggest that BNIP3 reactivation is a potential target for therapeutic intervention against pancreatic cancer.