Carcinogenesis studies with MTH1-deficient mice

MTH1 缺陷小鼠的致癌研究

• 批准号: 11138239
• 负责人: TSUZUKI Teruhisa
• 金额: $ 6.4万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11138239/
• 关键词: Reactive oxygen; Oxidative stress; Mutation; Carcinogenesis; 8-oxo-dGTPase; 8-oxo-guanine; DNA repair; Mutator; 8-oxo-dGTPase

Oxidative DNA damage is thought to contribute to carcinogenesis, aging, and neurological degeneration. Studies have shown that oxidative DNA damage accumulates in cancerous tissue. For example, higher levels of oxidative base damage were observed in lung cancer tissue compared with surrounding normal tissue. Further, the cumulative risk of cancer increases dramatically with age in humans. In genreal terms cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoG.8-Oxo-7, 8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When incorporated into DNA, 8-oxo-dGTP causes mutation. Organisms posseces 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP.By means of gene targeting, we established mouse lines deficient in the MTH1 gene, and 8-oxo-dGTPase activi … More ty. An approximately 2-fold higher frequency of spontaneous mutations in the HPRT gene was observed in two independently isolated MTH1^<-/-> ES cell lines, compared with the value of MTH1^<+/+> cells. We then examined susceptibility of the derived mutant mice to spontaneous tumorigenesis. Wild type or mutant mice consisting of approximately 50 male and 50 female were maintained under SPF conditions and necropsied after 1.5 years. No significant difference in survival rates of MTH1^<+/+> and MTH1^<-/-> mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. A distinct difference in the frequency of tumor formation in lungs between wild-type and mutant mice was observed while more tumors were likely to be formed in the stomach and in liver of MTH1^<-/-> mice as well. 8-Oxo-dGTPase appears to play an important role to protect animals from the spontaneous tumorigenesis caused by the oxygen-induced DNA damage. To study the enhancing effect of chronic inflammation in carcinogenesis, we investigated the spontaneous gastric carcinogenesis in MTH1 deficient mice infected with Helicobacter pylori (H.P.). MTH1^<-/-> mouse and wild type were inocculated intragastrically with H.pylori. After 1.5 year of obserbvation, chrronic gastritis was observed histologically in infected mouse of both MTH1 status. The incidence rate of hyperplastic elevated lesion was augmented by H.P.infection. Moreover, the incidence rate of atypical hyperplastic lesion was augmented especially in MTH1^<-/-> mouse infected with H.pylori. Less

氧化性DNA损伤被认为有助于致癌、衰老和神经退行性变。研究表明，氧化性DNA损伤在癌组织中积累。例如，与周围正常组织相比，在肺癌组织中观察到更高水平的氧化性碱损伤。此外，癌症的累积风险随着人类年龄的增长而急剧增加。一般而言，癌症可被视为一种老化的退化性疾病。基于主要测量8-氧代-7，8-二氢-2 ′-脱氧鸟苷5 ′-三磷酸（8-氧代-dGTP）增加的研究，存在氧化性DNA损伤随年龄积累的证据。在正常细胞代谢期间，在细胞的核苷酸库中形成8-氧代-7，8-二氢-2 ′-脱氧鸟苷5 ′-三磷酸（8-氧代-dGTP）。当掺入DNA时，8-oxo-dGTP引起突变。生物体具有8-oxo-dGT 3，一种特异性降解8-oxo-dGTP为8-oxo-dGMP的酶。通过基因打靶，我们建立了MTH 1基因缺陷的小鼠品系，并在小鼠中检测到8-oxo-dGT 3活性。 ...更多信息 泰与MTH 1 ^<+/+>细胞相比，在两个独立分离的MTH 1 ^<-/-> ES细胞系中观察到HPRT基因的自发突变频率高出约2倍。然后，我们检查了衍生的突变小鼠对自发性肿瘤发生的易感性。将由约50只雄性和50只雌性组成的野生型或突变型小鼠维持在SPF条件下，并在1.5年后进行尸检。MTH 1 ^<+/+>和MTH 1 ^<-/->小鼠的存活率无显著差异。然而，病理学检查显示肿瘤发生率有统计学显著差异。观察到野生型和突变小鼠之间肺中肿瘤形成频率的明显差异，而MTH 1 ^<-/->小鼠的胃和肝中也可能形成更多的肿瘤。8-Oxo-dGTdR在保护动物免受氧诱导的DNA损伤引起的自发性肿瘤发生中起重要作用。为了研究慢性炎症在胃癌发生中的促进作用，我们研究了MTH 1缺陷小鼠感染幽门螺杆菌（H. P.）后自发性胃癌的发生。用幽门螺杆菌胃内接种MTH 1 ^-/->小鼠和野生型。感染1.5年后，组织学上观察到两种MTH 1状态的感染小鼠的慢性胃炎。HP感染增加了增生性隆起病变的发生率。此外，不典型增生性病变的发生率增加，尤其是在MTH 1 ^<-/->小鼠感染H. pylori后。少

项目成果

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Akiyosi, S., Kanda, H., Okazaki, Y., Akama, T., Nomura, K., Hayashizaki, Y.and Kitagawa, T.: "A genetic linkage map of the MSM japanese wild mouse strain with restriction landmark genomic scanning (RLGS)."Mamm.Genome. (in press).

Akiyosi, S.、Kanda, H.、Okazaki, Y.、Akama, T.、Nomura, K.、Hayashizaki, Y. 和 Kitakawa, T.：“具有限制性标志的 MSM 日本野生小鼠品系的遗传连锁图

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