Carcinogenesis studies with MTH1-deficient mice

氧化DNA损伤被认为是导致癌症、衰老和神经退化的原因。研究表明，DNA氧化损伤会在癌组织中积累。例如，与周围正常组织相比，肺癌组织中观察到的氧化碱基损伤水平更高。此外，人类患癌症的累积风险随着年龄的增长而急剧增加。从基因的角度来说，癌症可以被认为是一种衰老的退行性疾病。根据主要测量8-oxo-7，8-二氢-2‘-脱氧鸟苷5’-三磷酸(8-oxo-dGTP)在正常细胞代谢过程中在细胞的核苷酸池中形成的研究，有证据表明氧化DNA损伤随着年龄的增加而积累。当8-oxo-dGTP结合到DNA中时，会导致突变。8-oxo-dGTP酶是一种能将8-oxo-dGTP特异性降解为8-oxo-dGMP的酶。通过基因打靶的方法，我们建立了mth1基因缺陷的小鼠系，8-oxo-dGTP酶激活了…更多的TY。在两个独立分离的MTH1^&lt；-/-&gt；ES细胞系中观察到HPRT基因自发突变的频率比MTH1^&lt；/&gt；细胞的值高约2倍。然后，我们检查了衍生的突变小鼠对自发肿瘤发生的敏感性。由大约50只雄性和50只雌性组成的野生型或突变小鼠被保存在SPF条件下，并在1.5年后解剖。MTH1^&lt；/&gt；和MTH1^&lt；-/-&gt；小鼠存活率无显著差异。然而，病理检查显示，肿瘤的发生率在统计学上有显著差异。野生型和突变型小鼠在肺部的肿瘤形成频率有明显差异，而MTH1；-/-&gt；小鼠的胃和肝脏也可能形成更多的肿瘤。8-oxo-dGTP酶在保护动物免受氧诱导的DNA损伤所致的自发性肿瘤发生中起着重要作用。为了研究慢性炎症在肿瘤发生中的促进作用，我们研究了MTH1基因缺陷小鼠感染幽门螺杆菌(H.P.)后的自发胃癌发生。给MTH1小鼠和野生型小鼠灌胃接种幽门螺杆菌。观察1.5年后，两种MTH1状态的感染小鼠均出现慢性胃炎。Hp感染可增加增生性隆起病变的发生率。此外，非典型增生性病变的发生率增加，尤其是在感染幽门螺杆菌的MTH1；-/-&gt；小鼠。较少

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