Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer.
Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer.
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DOI：
10.1158/1541-7786.mcr-16-0218
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发表时间：
2017-07
期刊：
影响因子：
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通讯作者：
Torres-Ramos CA
中科院分区：
文献类型：
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作者：
Ballista-Hernández J;Martínez-Ferrer M;Vélez R;Climent C;Sánchez-Vázquez MM;Torres C;Rodríguez-Muñoz A;Ayala-Peña S;Torres-Ramos CA
许多癌症中都报道了线粒体 DNA (mtDNA) 完整性的变化，然而，mtDNA 完整性对肿瘤发生的贡献尚不清楚。我们使用了无嘌呤/无嘧啶核酸内切酶 1 (Apex1+/-) 基因单倍体不足的转基因小鼠模型，该基因编码碱基切除修复 (BER) 酶 APE1，以确定其在保护 mtDNA 免受氧化偶氮甲烷 (AOM)（一种用于诱发结直肠癌 (CRC) 的致癌物质）影响中的作用。在单次 AOM 剂量后，使用定量 PCR 评估 AOM 诱导的 mtDNA 损伤的修复动力学，并观察到野生型 (WT) 和 Apex1+/- 动物的结肠隐窝中 mtDNA 损伤的显着诱导。然而，Apex1+/- 小鼠除了线粒体 DNA 丰度降低外，修复动力学也较慢。还使用多个 AOM 剂量诱导肿瘤，WT 和 Apex1+/- 动物均表现出 mtDNA 丰度显着损失。令人惊讶的是，在 WT 和 Apex1+/- 动物的肿瘤中没有观察到 mtDNA 损伤的重大差异，而在 Apex1+/- 小鼠的肿瘤中检测到核 DNA 损伤的显着增加。最后，Apex1+/-小鼠的肿瘤表现出增殖指数增加和组织学异常。总而言之，这些结果表明 APE1 对于防止 AOM 诱导的 CRC 期间 mtDNA 完整性的变化非常重要。影响：氧化偶氮甲烷是一种结直肠癌致癌物，会对线粒体基因组造成损害，并且需要 BER 酶 APE1 来维持其完整性。
Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers, however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (Apex1+/-) gene, which encodes the base excision repair (BER) enzyme APE1, to determine its role in protecting mtDNA from the effects of azoxymethane (AOM), a carcinogen used to induce colorectal cancer (CRC). Repair kinetics of AOM-induced mtDNA damage was evaluated using quantitative PCR after a single AOM dose and a significant induction in mtDNA lesions in colonic crypts from both wild type (WT) and Apex1+/-animals were observed. However, Apex1+/- mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses and both WT and Apex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and Apex1+/-animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from Apex1+/- mice. Finally, tumors from Apex1+/-mice displayed an increased proliferative index and histological abnormalities. Taken together, these results demonstrate that APE1 is important for preventing changes in mtDNA integrity during AOM-induced CRC. Implications: Azoxymethane, a colorectal cancer carcinogen, generates damage to the mitochondrial genome and the BER enzyme APE1 is required to maintain its integrity.