Comparison of the frequency of mtDNA mutation in primary and metastatic lesions of human malignant tumors

人类恶性肿瘤原发灶和转移灶mtDNA突变频率比较

• 批准号: 21590349
• 负责人: KOSHIKAWA Nobuko
• 金额: $ 3万
• 依托单位: Chiba Cancer Center (Research Institute)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590349/
• 关键词: mtDNA変異; 肺癌; 大腸癌; 原発巣; 転移巣; 神経膠腫; 髄液播種; ラマンバンド; ROS; 転移能; 肺癌・大腸癌; 癌部と非癌部; 神経膠芽腫; mtDNA; 変異; ヒト腫瘍

We showed that ROS-generating pathogenic mutations in NADH dehydrogenase subunit 6(ND6) gene of mitochondrial DNA(mtDNA), which is a subunit of complex I of the electron transport chain, can regulate tumor cell metastasis in mouse models. In this study, we compared the status of mutations and nonsynonymous single nucleotide polymorphisms(SNPs) of the genes encoding complex I subunits(ND1, ND2, ND3, ND4L and ND6) between primary and metastatic lesions of human lung and colon carcinomas. The combined frequency of appearance of nonsynonymous SNPs and mutations related to mtDNA base substitution disease such as LHON and novel mutations of Grantham value> 50 in the genes encoding complex I was considerably higher in metastatic lesions than in primary lesions. It may be possible that such mtDNA SNPs and mutations contribute to metastasis in human cancers.

我们发现，ROS产生的线粒体DNA（mtDNA）的NADH脱氢酶亚基6（ND6）基因的致病性突变，这是一个复合物I的电子传递链的亚基，可以调节小鼠模型中的肿瘤细胞转移。在这项研究中，我们比较了人类肺癌和结肠癌原发灶和转移灶之间编码复合物I亚单位（ND1，ND2，ND3，ND4L和ND6）的基因的突变和非同义单核苷酸多态性（SNP）的状态。与原发性病变相比，转移性病变中出现非同义SNP和与mtDNA碱基置换疾病相关的突变（如LHON）以及编码复合物I的基因中Grantham值> 50的新突变的组合频率明显更高。这种mtDNA SNP和突变可能有助于人类癌症的转移。

项目成果

Reactive oxygen speciesgenerating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1 alpha gene transcription via phosphatid ylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway

活性氧产生线粒体 DNA 突变通过磷脂酰肌醇 3-激酶-Akt/蛋白激酶 C/组蛋白脱乙酰酶途径上调缺氧诱导因子 1 α 基因转录

• 发表时间: 2009
• 期刊: Journal of Biological Chemistry
• 影响因子: 4.8
• 作者: Koshikawa N;Hayashi J;Nakagawara A;Takenaga K
• 通讯作者: Takenaga K

低酸素、ミトコンドリアとがんの転移

缺氧、线粒体与癌症转移

• 发表时间: 2009
• 作者: 竹永啓三

MCL-1V, a novel mouse antiapoptotic MCL-1 variant, generated by RNA splicing at a non-canonical splicing pair.

• DOI: 10.1016/j.bbrc.2009.11.086
• 发表时间: 2010
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: S. Kojima;Akira Hyakutake;N. Koshikawa;A. Nakagawara;K. Takenaga

Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-lalpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway

产生活性氧的线粒体 DNA 突变通过磷脂酰肌醇 3-激酶-Akt/蛋白激酶 C/组蛋白脱乙酰酶途径上调缺氧诱导因子-lalpha 基因转录

• 发表时间: 2009
• 期刊: Joarnal of Biological Chemistry 284
• 作者: Koshikawa N;Hayashi J;Nakagawara A;Takenaga K
• 通讯作者: Takenaga K

ヒト肺癌及び大腸癌の原発巣と転移巣におけるmtDNA変異頻度

人肺癌和结直肠癌原发性和转移性肿瘤mtDNA突变频率

• 发表时间: 2010
• 作者: 越川信子;木村秀樹;飯笹俊彦;井内俊彦;滝口伸浩;竹永啓三;中川原章
• 通讯作者: 中川原章