• Journal of Life Science
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• v.29 no.9
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• pp.1034-1046
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• 2019

The mitochondria is the major cellular organelle of energy metabolism for the supply of cellular energy; it also plays an important role in controlling calcium regulation, reactive oxygen species (ROS) production, and apoptosis. Mitochondrial dysfunction causes various diseases, such as neurodegenerative diseases, Lou Gehrig's disease, cardiovascular disease, mental disorders, diabetes, and cancer. Most of the diseases are age-related diseases. In this review, we focus on the roles of mitochondrial dysfunction in cancer. Mitochondrial dysfunction induces carcinogenesis and is found in many cancers. The factors that cause mitochondrial dysfunction differ depending on the types of carcinoma, and those factors could cause cancer malignancy, such as resistance to therapy and metastasis. Mitochondrial dysfunction is caused by a lack of mitochondria, an inability to provide key substances, or a dysfunction in the ATP synthesis machinery. The main factor associated with cancer malignancy is mtDNA depletion. Mitochondrial dysfunction would leads to malignancy through changes in molecular activity or expression, but it is not known in detail which changes lead to cancer malignancy. In order to explore the relationship between mitochondrial dysfunction and cancer malignancy in detail, mitochondria dysfunctional cell lines are constructed using chemical methods such as EtBr treatment or gene editing methods, including shRNA and CRISPR/Cas9. Those mitochondria dysfunctional cell lines are used in the study of various diseases caused by mitochondrial dysfunction, including cancer.

• Proceedings of the Korean Society of Food Science and Nutrition Conference
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• 2004.11a
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• pp.65-70
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• 2004

Modulation of biotransformation enzymes is one mechanism by which a diet high in fruits and vegetable may influence cancer risk. Inhibition of cytochrome P450s (CYP) and concomitant induction of conjugating enzymes are hypothesized to reduce the impact of carcinogens in humans. Thus, exposure to types and amounts of phytochemicals may influence disease risk. Like other xenobiotics, many classes of phytochemicals are rapodly conjugated with glutathione, glucuronide, and sulfate moieties and excreted in urine and bile. In humans, circulating phytochemical levels very widely among individuals even in response to controlled dietary interventions. Polymorphisms in biotransformation enzymes, such as the glutathione S-transferases (GST), UDP-glucuronosyltransferases (UGT), and sulfotransferases (SULT), may ocntribute to the variability in phytochemical clearance and efficacy; polymorphic enzymes with lower enzyme activity prolong the half-lives of phytochmicals in vivo. Isothiocyanates (ITC) in cruciferous vegetables are catalyzed by the four major human GSTs: however reaction velocities of the enzymes differ greatly. In some observational studies of cancer, polymorphisms in the GSTMI and GSTTI genes that result in complete lack of GSTM1-1 protein, respectively, confer greater protection from cruciferous vegetable in individuals with these genotypes. Similarly, we have shown in a controlled dietary trial that levels of GST-alpha-induced by ITC-are higher in GSTMI-null individuals exposed to cruciferous vegetablse. The selectivity of glucuronosyl conjugation of flavonoids is dependent both on flavonoid structure as well as on the UGI isozyme involved in its conjuagtion. The effects of UGI polymorphisms on flavonoid clearnace have not been examind; but polymorphisms affect glucuronidation of several drugs. Given the strong interest in the chemopreventive effects of flavonoids, systematic evaluation of these polymorphic UGTs and flavonoid pharmacokinetics are warranted. Overall, these studies suggest that for phytochemicals that are metabolized by, and affect activity of, biotransformation enzymes, interactions between genetic polymorphisms in the enzymes and intake of the compounds should be considered in studies of cancer risk. Genetic polymorphisms in biotransformation enzymes may account in prat for individual variation in metabolism of a wide range of phytochemicals and their ultimate impact on health.

• Toxicological Research
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• v.17
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• pp.139-144
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• 2001

Chewing betel quid is associated with an increased risk of oral cancer. The betel quid chewed in Taiwan includes the inflorescence of Piper betle, which contains high concentrations of safrole (15 mg/fresh weight). Piper betle leaf is also used in betel quid; however, the concentration of safrole in betel leaf has not been documented. Chewing betel quid may contribute to safrole exposure in man (420 mm in saliva). Using $a^{32}$P-postlabeling method, we have recently demonstrated the presence of stable safrole-like DNA adducts in human oral tissues following betel quid chewing. Safrole is a rodent hepatocar-cinogen, and the real nature of safrole-DNA adducts in human tissues beside oral has not been elucidated. In this paper, we tested the safrole DNA adducts forming potential in human hepatic and oral derived cells by the ${32}^P$-postlabeling technique. The results suggest that oral cancer derived cell OC-2 alone is not able to form safrole-DNA adduct. However, safrole DNA adducts can be detected following I'-hydroxysafrole, a proximate safrole metabolite, treatment. In addition, pretreament of cytochrome P450 inducers also enhanced the formation of previously undetectable safrole DNA adducts. This finding couples with our previous results suggest that oral may serve as a target tissue for safrole, and safrole may be involved in oral carcinogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.5069-5074
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• 2012

Objectives: The purpose of this study was to determine the relationship between methylation status of the Dact1 gene and MTHFR a1298c polymorphic forms in transitional cell carcinoma tissues in a Chinese population. Methods: Polymorphisms of folate metabolism enzyme gene MTHFR were assessed by restrictive fragment length polymorphism (RFLP) methods and PCR-based DNA methylation analysis was used to determine the CpG island methylation status of the Dact1 gene. Associations between the methylation status of the Dact1 gene and clinical characteristics, as well as MTHFR a1298c polymorphisms, were analyzed. Results: aberrant methylation of the Dact1 gene was found in 68.3% of cancer tissues and 12.4% of normal tissues,. The methylation rate of the Dact1 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs. 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables, variant allele of MTHFR a1298c was found to be associated with methylation of the Dact1 gene. Compared with wild type CC, the odds ratio was 4.33 (95% CI: 1.06-10.59) for AC and 4.95 (95% CI: 1.18-12.74) for AA. The N stage in TNM staging and the occurrence of lymph node metastasis were associated with an MTHFR 1298 AA+AC genotype (P<0.05). Conclusion: MTHFR 1298 AC and AA genotypes might help maintain a normal methylation status of the Dact1 gene, aberrant CpG island methylation of which is closely related to the genesis and progression of transitional cell carcinoma.

• Journal of Life Science
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• v.24 no.1
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• pp.98-103
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• 2014

NAD(P)H quinone oxidoreductase 1 (NQO1) is a flavoprotein that catalyzes the two electron reduction of diverse substrates, including quinones. It uses NADH or NADPH as a cofactor for enzymatic machinery. In the metabolism of quinones, NQO1 has two conflicting functions because of the different stability of converted hydroquinones. The stable form of hydroquinone is excreted from cells by conjugation with glutathione or glucuronic acid. The unstable form of hydroquinone induces cell death by induction of oxidative stress and DNA damage. Certain quinones known as bio-reductive agents have a cytotoxic function following reduction by NQO1. Bio-reductive agents, such as ${\beta}$-lapachone or mitomycin C, induce the depletion of NAD(P)H and the generation of oxidative stress in an NQO1-dependent manner. NQO1 is highly expressed in several cancer tissues. Therefore, NQO1 is a good therapeutic target for cancer treatment with bio-reductive agents.

• Journal of the Korean Society of Food Science and Nutrition
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• v.21 no.6
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• pp.648-654
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• 1992

Purpose of this study was to investigate intake pattern of sodium in the family members of normal and stomach cancer patients, excluding patients themselves. Every food samples that they consumed for 3 days, drinking water, hot pepper paste, soybean paste and soy sauce from the each family were collected for Na analysis. Three days of morning urine from the each subjects was collected for determination of urinary Na excretion. Sodium contents of hot pepper paste, pickles, soups and meats in stomach cancer families were significantly higher than those in normal families. However, urinary sodium excretion between the two groups was not different. This suggests that sodium metabolism in human may be altered with a long-term intake of sodium=rich foods.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.28 no.5
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• pp.364-371
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• 2002

Many chemical compopunds are converted into reactive electrophilic metabolites by the oxidative(Phase I) enzymes, which are mainly cytochrome P-450 enzyme(CYPs). Phase II conjugating enzymes, such as glutathione S-transferase(GST), usually act as inactivation of enzymes. Genetic polymorphisms have been found to be associated with increased susceptibility to cancer of the lung, bladder, breast and colorectal. Many of the polymorphic genes of carcinogen metabolism show considerably different type of cancer among different ethnic groups as well as individuals within the same group. The aim of this study is (1) to establish the frequencies of genetic polymorphisms of GSTM1 and CYP1A1 in Korean oral squamous cell carcinoma(SCC), (2) to associate oral SCC with the risk of these genetic polymorphisms. The genetic polymorphisms of the GSTM1 and the CYP1A1 genes among 50 Korean oral SCC were analyzed using polymerase chain reaction(PCR). The results suggest that the homozygote and the mutant type of CYP1A1 MspI polymorphisms may be associated with genetic susceptibility to oral SCC in Korean. A combination of the GSTM1 null type with the homozygote(m1/m1), and the mutant(m2/m2) type of CYP1A1 MspI polymorphisms showed a relatively high risk of oral SCC in Korean. In the smoking group, the GSTM1 wild genotype may be the high risk factor of oral SCC in Korean. These data coincide with the hypothesis which states that different susceptibility to cancer of genetic polymorphisms exist among different ethnic group and different types of human cancer.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.1 no.2
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• pp.137-144
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• 2015

Hypoxia is an important adverse prognostic factor for tumor progression and is a major cause of failure of radiation therapy. In case of short-term hypoxia, the metabolism can recover to normal, but if hypoxia persists, it causes irreversible cell damage and finally leads to death. So a hypoxia marker would be very useful in oncology. In particular, 2-nitroimidazole can be reduced to form a reactive chemical species, which can bind irreversibly to cell components in the absence of sufficient oxygen, thus, the development of radiolabeled nitroimidazole derivatives for the imaging of hypoxia remains an active field of research to improve cancer therapy result. 2-nitroimidazole based hypoxia marker, [$^{18}F$]FMISO holds promise for the evaluation of tumor hypoxia by Positron emission tomography (PET), at both global and local levels. In the present study, [$^{18}F$]FMISO was synthesized using an automatic synthesis module with high radiochemical purity (>99%) in 60 min. Immunohistochemical analysis using pimonidazole confirmed the presence of hypoxia in xenografted CT-26 tumor tissue. A biodistribution study in CT-26 xenografted mice showed that the increased tumor-to-muscle ratio and tumor-to-blood ratios from 10 to 120 min post-injection. In the PET study, [$^{18}F$]FMISO also showed increased tumor-to-muscle ratios from 10 to 120 min post-injection. In conclusion, this study demonstrates the feasibility and utility of [$^{18}F$]FMISO for imaging hypoxiain mouse colon cancer model using small animal PET.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10187-10192
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• 2015

Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3101-3109
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• 2015

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in amino acid synthesis and DNA function. Two common polymorphisms are reported, C677T and A1298C, that are implicated in a number of human diseases, including cancer. Objective: The association between MTHFR C677T and A1298C genotype and haplotype frequencies in risk for lung cancer (LC) was investigated in the Jordanian population. Materials and Methods: A total of 98 LC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 89 controls taken from the general population, employing the PCR-RFLP technique. Results: The frequency of the genotypes of MTHFR C677T among Jordanians was: CC, 59.6%, CT, 33%; and TT, 7.4% among LC cases and 49.4%, 40.2% and 10.3% among controls. No significant association was detected between genetic polymorphism at this site and LC. At MTHFR A12987C, the genotype distribution was AA, 29.5%; AC, 45.3%, and CC 25.3% among LC cases and 36.8%, 50.6% and 12.6% among controls. Carriers of the CC genotype were more likely to have LC (OR=2.5; 95%CI: 1.04-6; p=0.039) as compared to AA carriers. Smokers and males with the CC genotype were 9.9 and 6.7 times more likely to have LC, respectively ($OR_{smokers}=9.9$; 95%CI: 1.2-84.5, p=0.018; $OR_{men}=6.6$; 95%CI: 1.7-26.2, p=0.005). Haplotype analysis of MTHFR polymorphism at the two loci showed differential distribution of the CC haplotype (677C-1298C) between cases and controls. The CC haplotype was associated with an increased risk for lung cancer (OR=1.6; 95% CI: 1.03-2.4, p=0.037). Conclusions: The genetic polymorphism of MTHFR at 1298 and the CC haplotype (risk is apparently lower with the C allele at position 677) may modulate the risk for LC development among the Jordanian population. Risk associated with the 1298C allele is increased in smokers and in males. The results indicate that a critical gene involved in folate metabolism plays a modifying role in lung cancer risk, at least in the Jordanian population.