Shinmura Kazuya, Kato Hisami, Kawanishi Yuichi, Yoshimura Kimio, Igarashi Hisaki, Goto Masanori, Tao Hong, Inoue Yusuke, Sugiyama Takayuki, Furuse Hiroshi, Ozono Seiichiro, Sugimura Haruhiko
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Research Equipment Center, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Mol Carcinog. 2017 Feb;56(2):781-788. doi: 10.1002/mc.22509. Epub 2016 Jun 10.
8-Hydroxyguanine (8OHG), a major oxidative DNA lesion, is known to accumulate in prostate cancer; however, the status of one of its repair enzymes, MUTYH, in prostate cancer remains to be elucidated. In this study, we showed that the expression levels of MUTYH mRNA and protein were significantly lower in prostate cancer than in non-cancerous prostatic tissue by examining two independent, publicly available databases and by performing an immunohistochemical analysis of prostate cancer specimens obtained at our hospital, respectively. About two-thirds of the prostate cancers exhibited a reduced MUTYH expression. When the effect of reduced MUTYH expression in prostate adenocarcinoma on the somatic mutation load was examined using data from the Cancer Genome Atlas (TCGA) database, the numbers of total somatic mutations and somatic G:C to T:A mutations were significantly higher in the reduced MUTYH expression group than in the other group (P < 0.0001 and P = 0.0013, respectively). To determine the reason why reduced MUTYH expression leads to somatic mutation loads in prostate adenocarcinoma, we compared the DNA repair capacities between PC-3 prostatic cell line derived clones with different MUTYH expression levels. Both the capacities to cleave DNA containing adenine:8OHG mispairs and to suppress mutations caused by 8OHG were significantly lower in prostatic cell lines with lower MUTYH expression than in prostatic cell lines with higher MUTYH expression. These results suggested that reduced MUTYH expression is associated with somatic mutation loads via a reduction in DNA repair capacity in prostate adenocarcinoma. © 2016 Wiley Periodicals, Inc.
8-羟基鸟嘌呤（8OHG）是一种主要的氧化性DNA损伤，已知其在前列腺癌中会积累；然而，其修复酶之一MUTYH在前列腺癌中的状态仍有待阐明。在本研究中，我们通过分别检查两个独立的公开可用数据库以及对我院获取的前列腺癌标本进行免疫组织化学分析，发现前列腺癌中MUTYH mRNA和蛋白的表达水平显著低于非癌性前列腺组织。约三分之二的前列腺癌表现出MUTYH表达降低。当使用癌症基因组图谱（TCGA）数据库的数据检查前列腺腺癌中MUTYH表达降低对体细胞突变负荷的影响时，MUTYH表达降低组的总体细胞突变数和体细胞G:C到T:A突变数显著高于另一组（分别为P < 0.0001和P = 0.0013）。为了确定MUTYH表达降低导致前列腺腺癌体细胞突变负荷的原因，我们比较了具有不同MUTYH表达水平的PC-3前列腺癌细胞系衍生克隆之间的DNA修复能力。MUTYH表达较低的前列腺细胞系中，切割含有腺嘌呤:8OHG错配的DNA的能力以及抑制由8OHG引起的突变的能力均显著低于MUTYH表达较高的前列腺细胞系。这些结果表明，MUTYH表达降低通过降低前列腺腺癌中的DNA修复能力与体细胞突变负荷相关。© 2016威利期刊公司。
