Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Department of Food and Nutritional Environment, Kinjo Gakuin University of Human Life and Environment, Nagoya, Aichi, Japan.
Free Radic Res. 2020 Mar;54(2-3):195-205. doi: 10.1080/10715762.2020.1743285.
Exposure to asbestos fiber is central to mesothelial carcinogenesis. Recent sequencing studies on human and rodent malignant mesothelioma (MM) revealed frequently mutated genes, including , and . Crocidolite directly or indirectly catalyses the generation of hydroxyl radicals, which appears to be the major driving force for mesothelial mutations. DNA base modification is an oxidative DNA damage mechanism, where 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the most abundant modification both physiologically and pathologically. Multiple distinct mechanisms work together to decrease the genomic level of 8-OHdG through the enzymatic activities of and . Knockout of one or multiple enzymes is not lethal but increases the incidence of tumors. Here, we used single knockout (KO) mice to test whether the deficiency of these three genes affects the incidence and prognosis of asbestos-induced MM. Intraperitoneal injection of 3 mg crocidolite induced MM at a fraction of 14.8% (4/27) in KO, 41.4% (12/29) in KO and 24.0% (6/25) in KO mice, whereas 31.7% (20/63) induction was observed in wild-type (Wt) mice. The lifespan of female KO mice was longer than that of female Wt mice ( = 0.0468). Whole genome scanning of MM with array-based comparative genomic hybridization revealed rare genomic alterations compared to MM in rats and humans. These results indicate that neither Mutyh deficiency nor Ogg1 deficiency promotes crocidolite-induced MM in mice, but the sanitizing nucleotide pool with Mth1 is advantageous in crocidolite-induced mesothelial carcinogenesis.
暴露于石棉纤维是间皮瘤发生的核心。最近对人类和啮齿动物恶性间皮瘤（MM）的测序研究揭示了经常发生突变的基因，包括 、 和 。青石棉直接或间接催化羟自由基的产生，这似乎是间皮突变的主要驱动力。DNA 碱基修饰是一种氧化 DNA 损伤机制，其中 8-羟基-2'-脱氧鸟苷（8-OHdG）在生理和病理上都是最丰富的修饰物。多种不同的机制共同作用，通过 和 的酶活性降低基因组水平的 8-OHdG。敲除一个或多个酶并不致命，但会增加肿瘤的发生率。在这里，我们使用单基因敲除（KO）小鼠来测试这三个基因的缺失是否会影响石棉诱导的 MM 的发生率和预后。腹腔注射 3mg 青石棉诱导 MM 的发生率分别为 KO 组的 14.8%（4/27）、 KO 组的 41.4%（12/29）和 KO 组的 24.0%（6/25），而 Wt 组的诱导率为 31.7%（20/63）。 KO 组雌性小鼠的寿命长于 Wt 组雌性小鼠（ = 0.0468）。基于阵列比较基因组杂交的 MM 全基因组扫描显示，与大鼠和人类的 MM 相比，基因组改变罕见。这些结果表明，Mutyh 缺陷或 Ogg1 缺陷都不会促进小鼠青石棉诱导的 MM，但具有 Mth1 的清洁核苷酸池在青石棉诱导的间皮细胞癌变中是有利的。
