Genome-wide DNA hypomethylation and concomitant site-specific gene hypermethylation are among the most common molecular alterations in human neoplasia. Previous studies revealed that genetic reduction of the DNA methylation level results in opposing effects on tumor development, depending on the tumor cell type and on the different stages of the tumorigenesis. For instance, reduced levels of DNA methylation in mice strongly inhibited tumor development of the intestine, whereas they induced thymic lymphomas and liver tumors. In the present study, using DNA methyltrasferase 1 (Dnmt1) hypomorphic alleles to reduce genomic methylation, we examined the effects of DNA hypomethylation on a murine squamous carcinogenesis in the tongue and esophagus induced by 4-nitroquinoline 1-oxide. A ltered DNA methylation in the form of global hypomethylation and regional hypermethylation is one of the most consistent epigenetic changes in cancer.(1) Global DNA hypomethylation, which is frequently observed at early stages of tumorigenesis in human cancer, promotes tumor development in mouse models and causes chromosomal instability in cultured fibroblasts.(2) After the initial observation of DNA hypermethylation within the retinoblastoma tumor suppressor gene, a number of genes have been shown to be hypermethylated and transcriptionally silenced in tumors. Although the consequences of global hypomethylation and gene-specific hypermethylation have been mechanistically connected to chromosome instability and transcriptional silencing, respectively, (3-5) the causes of aberrant genomic methylation patterns are currently unknown. DNA methylation is catalyzed by a family of three DNA methyltransferases: Dnmt1, Dnmt3a, and Dnmt3b.(6-8) Although the three Dnmt partially cooperate to establish and maintain genomic methylation patterns, they also have distinctive functions. Dnmt1 has a preference for hemimethylated DNA, and indeed a hypomorphic allele of Dnmt1 has been shown to cause global DNA hypomethylation. Thus, Dnmt1 is considered to be the major maintenance methyltransferase. Using Dnmt1 hypomorphic alleles as a model for global DNA hypomethylation, previous studies have revealed that global DNA hypomethylation inhibits tumorigenesis in the intestine, (5) whereas it induces or promotes T-cell lymphomas, (9) liver cancers,and fibrosarcomas.These results indicate that the forced reduction of genomic methylation levels leads to opposing effects on tumorigenesis depending on the cell type. Considering the fact that DNA hypomethylating agents have been used for cancer therapy in a subset of cancer, (1) it is important to clarify the effect of global DNA hypomethylation on the risk for tumor development in various organs.The potent carcinogenicity of 4-nitroquinoline 1-oxide (4NQO) depends on the formation of DNA adducts, in addition to the exertion of oxidative stress in target cells. (11,12) 4NQO has been shown to produce squamous neoplasms preferentially in the tongue and a small number of tumors arise in the esophagus in rodents exposed...
A number of possible preventive agents for cancers in different organs have been reported, however, little information is available regarding the effective agents for the development of gastric cancers. The rice components are known to be effective for the prevention of the development of cancers. Our group has demonstrated that fermented brown rice by Aspergillus Orzae (FBRA) has chemopreventive potentials in several organs. In this study, we investigated the modifying effects of FBRA exposed during the initiation or post-initiation phase of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in rats. Five-weekold male ACI rats were divided into 7 groups. Groups 1-5 were given oral administration of MNNG (100 mg/l in distilled water) for 24 weeks starting at 6 weeks of age. Groups 2 and 3 were fed a diet containing 5 and 10% FBRA during the initiation phase, respectively, whereas groups 4 and 5 were fed these diets during the post-initiation phase. Group 6 was given a diet containing 10% FBRA throughout the experiment. Group 7 was kept on the basal diet alone and served as an untreated control. Rats were sacrificed at 52 weeks after the start, and the epithelium of the stomach was investigated in detail. Incidence and multiplicity of gastric proliferative lesions of group 1 (MNNG alone) were 61% and 1.67±1.57/ rat, respectively. Those of group 5 (25%, 0.35±0.67) which were given FBRA at a dose of 10% during the post-initiation phase were significantly less than those of group 1. Furthermore, the same group expressed a significantly decreased Ki67-labeling index in the non-lesional gastric epithelium when compared to that of group 1. These results indicate that FBRA inhibits MNNG-induced development of gastric tumors by administration during the post-initiation phase in rats. FBRA is regarded as a promising dietary agent for the prevention of human gastric cancer.
Hyposalivation may be a significant and common etiology for the three oral complaints, although the considerable prevalence of complaints without hyposalivation suggests other etiologies, including those related to the OSC.
Abstract. Recent studies have shown that promoter hypermethylation of tumor suppressor genes is an important factor in carcinogenesis of several human organs. The purpose of this study was to examine the methylation status of CHFR, a novel cell cycle regulatory gene, in both primary oral cancer tumors and the adjacent normal mucosa, and to clarify the relation between the methylation status and expression of the CHFR-related chromosomal passenger protein Aurora-A. The methylation status of the CHFR gene was examined by the methylation-specific PCR (MSP) in 49 primary oral squamous cell carcinomas (OSCC) and 6 OSCC cell lines. In 13 cases, the adjacent normal oral mucosal tissues were also examined. Normal oral mucosa from 18 healthy volunteers was used as the control. The mRNA level of Aurora-A and CHFR in OSCC cell lines was investigated by real-time RT PCR and the protein expression of Aurora-A in certain tumor samples was confirmed by immunohistochemistry. Aberrant promoter methylation of the CHFR gene was detected in 34.7% (17 of 49) of OSCC cases. As for the 13 OSCC cases with paired cancerous and adjacent normal tissues, promoter hypermethylation of the CHFR gene was detected in 46.1% (6 of 13) of the cancerous tissues. In contrast, promoter hypermethylation of the CHFR gene was recognized in only 7.7% (1 of 13) of the surrounding normal mucosa.
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