The patterns of expression of glutathione S-transferases A1 and A2 in human liver (hGSTA1 and hGSTA2, respectively) are highly variable, notably in the ratio of hGSTA1/hGSTA2. We investigated if this variation had a genetic basis by sequencing the proximal promoters (-721 to -1 nucleotides) of hGSTA1 and hGSTA2, using 55 samples of human liver that exemplified the variability of hGSTA1 and hGSTA2 expression. Variants were found in the hGSTA1 gene: -631T or G, -567T, -69C, -52G, designated as hGSTA1*A; and -631G, -567G, -69T, -52A, designated as hGSTA1*B. Genotyping for the substitution -69C > T by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), showed that the polymorphism was widespread in Caucasians, African-Americans and Hispanics, and that it appeared to conform to allelic variation. Constructs consisting of the proximal promoters of hGSTA1*A, hGSTA1*B or hGSTA2, with luciferase as a reporter gene, showed differential expression when transfected into HepG2 cells: hGSTA1*A approximately hGSTA2 > hGSTA1*B. Similarly, mean levels of hGSTA1 protein expression in liver cytosols decreased significantly according to genotype: hGSTA1*A > hGSTA1-heterozygous > hGSTA1*B. Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype. Consequently, the ratio of GSTA1/GSTA2 was highly hGSTA1 allele-specific. Because the polymorphism in hGSTA1 correlates with hGSTA1 and hGSTA2 expression in liver, and hGSTA1-1 and hGSTA2-2 exhibit differential catalysis of the detoxification of carcinogen metabolites and chemotherapeutics, the polymorphism is expected to be of significance for individual risk of cancer or individual response to chemotherapeutic agents.
To determine the most optimal treatment of cancer patients, it is fundamental to classify human carcinomas according to their primary anatomical site of origin. As for some patients, it is difficult to identify cancers occurring at obscure location and overlapping adjacent sites. The aim of this study is to partition the primary site of 486 patients in cancers of the digestive system by the expression pattern of the mucins and cytokeratins typifying each site. The expressions of MUC1, MUC2, MUC5AC, MUC6, CK7, CK8, CK13, CK14, CK18, CK19 and CK20 were evaluated immunohistochemically in 426 adenocarcinomas and 60 hepatocellular carcinomas using the tissue-array method. The finding of MUC series showed their characteristics in case of MUC2 in the appendix cancer and MUC1 and 5AC in pancreas cancer. As for CKs 7, 13, and 19, and 20 had a feature in cancers of common bile duct, liver, and appendix, respectively. We classified cancers in 11 sites by characteristic expression of antibodies. The sensitivity, specificity, positive predictive value, and diagnostic efficacy of significant antibodies were calculated with deducing the dichotomous tree made by SPSS 10.0. Six of 11 antibodies, CK 7, CK13, CK19, CK20, MUC1, and MUC5AC distinguished 6 groups from 11 sites. We also executed the clustering of cancers to investigate total relationship among cancers. They fell into three categories, which corresponded to embryologic origin. Unlike other sites, the small intestine and colorectum cancers expressed significantly different patterns to their sublocations. Mucins and CKs showed expression patterns to classify the primary sites of digestive cancers and may be helpful in predicting the primary sites of digestive cancers.
Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate cancer. The discussion highlights key findings from previous studies, which reported the role of miRNAs in risk and progression of prostate cancer, providing an understanding of the influence of miRNA on prostate cancer. Our review indicates that somewhat consistent results exist between these studies and reports on several prostate cancer related miRNAs. Present promising candidates are miR-1, −21, 106b, 141, −145, −205, −221, and −375, which are the most frequently studied and seem to be the most promising for diagnosis and prognosis for prostate cancer. Nevertheless, the findings from previous studies suggest miRNAs may play an important role in the risk and progression of prostate cancer as promising biomarkers.
The incidence of breast cancer in Korea has been increasing for the last two decades (1983-2005), and now, breast cancer is ranked the leading cause of cancer in Korean women. Along with other endocrine disrupting chemicals (EDCs), bisphenol A (BPA) has been suspected as a potential risk factor for breast cancer. We studied potential associations between BPA exposure and breast cancer risks in Korean women by performing biomonitoring of BPA among breast cancer patients and controls (N = 167). Blood samples were collected between 1994 and 1997 and kept over 10 years in a freezer under well controlled conditions. The blood BPA levels determined by HPLC/FD, ranged between LOD (0.012 microg/L) and 13.87 microg/L (mean +/- SD, 1.69 +/- 2.57 microg/L; median, 0.043 microg/L). In age-matched subjects (N = 152), there were some associations between BPA levels and risks of breast cancer, such as age at first birth and null parity. However, there were no significant differences in blood BPA levels between the cases and the controls (P = 0.42). Considering interactions between BPA exposure and risks of breast cancer, we suggest further enlarged biomonitoring studies of BPA to provide effective prevention against breast cancer.
Endocrine disrupting chemicals (EDCs) have been emphasized due to their threats in fertility, intelligence, and survival. For the last decade, many researchers have investigated EDC-health outcome. However, EDC responses in human were not clearly clarified through experimental and epidemiological data. Therefore, considering particular status of EDC endpoints, we suggest that one of the best ways to prevent unknown health risks from EDCs is to perform exposure monitoring or to do surveillance for EDC release into the environment. For this purpose, this review considers exposure status of EDCs, and EDC-related health risks, focusing on the mainly highlighted EDCs, such as dioxins/PCBs, DDT/DDE, bisphenol A, phthalates, alkylphenols, and phytoestrogens. We also reviewed tobacco, a mixed source of EDC-related endocrine disorders.
This review is focused on current information of avoidable environmental pollution and occupational exposure as causes of cancer. Approximately 2% to 8% of all cancers are thought to be due to occupation. In addition, occupational and environmental cancers have their own characteristics, e.g., specific chemicals and cancers, multiple factors, multiple causation and interaction, or latency period. Concerning carcinogens, asbestos/silica/wood dust, soot/polycyclic aromatic hydrocarbons [benzo(a) pyrene], heavy metals (arsenic, chromium, nickel), aromatic amines (4-aminobiphenyl, benzidine), organic solvents (benzene or vinyl chloride), radiation/radon, or indoor pollutants (formaldehyde, tobacco smoking) are mentioned with their specific cancers, e.g., lung, skin, and bladder cancers, mesothelioma or leukemia, and exposure routes, rubber or pigment manufacturing, textile, painting, insulation, mining, and so on. In addition, nanoparticles, electromagnetic waves, and climate changes are suspected as future carcinogenic sources. Moreover, the aspects of environmental and occupational cancers are quite different between developing and developed countries. The recent follow-up of occupational cancers in Nordic countries shows a good example for developed countries. On the other hand, newly industrializing countries face an increased burden of occupational and environmental cancers. Developing countries are particularly suffering from preventable cancers in mining, agriculture, or industries without proper implication of safety regulations. Therefore, industrialized countries are expected to educate and provide support for developing countries. In addition, citizens can encounter new environmental and occupational carcinogen nominators such as nanomaterials, electromagnetic wave, and climate exchanges. As their carcinogenicity or involvement in carcinogenesis is not clearly unknown, proper consideration for them should be taken into account. For these purposes, new technologies with a balance of environment and gene are required. Currently, various approaches with advanced technologies--genomics, exposomics, etc.--have accelerated development of new biomarkers for biological monitoring of occupational and environmental carcinogens. These advanced approaches are promising to improve quality of life and to prevent occupational and environmental cancers.
Urinary naphthols, 1- and 2-naphthol, recently have been suggested as route-specific biomarkers for exposure to airborne polycyclic aromatic hydrocarbons. For the proper application of urinary naphthols as biomarkers, we studied effects of lifestyle on urinary naphthols levels in 119 Japanese male workers. After improving the detection limit of urinary naphthols up to 0.27 microg/L by high-resolution capillary gas chromatography/mass spectrometry/selected ion monitoring, urinary naphthols were detectable in approximately 90% of the subjects. Among detectable samples, the geometrical mean (GM) of urinary 1-naphthol concentration was 5.13 microg/L (geometrical standard deviation, GSD, 4.90), while the GM of urinary 2-naphthol concentration was 3.16 microg/L (GSD, 5.61). We observed that urinary 1- and 2-naphthol level were three- and sevenfold higher, respectively, among smokers than among nonsmokers (p < 0.01). The ratios of urinary 2-naphthol to 1-naphthol were significantly higher among smokers than nonsmokers (p < 0.05). The number of cigarettes smoked and urinary cotinine levels were also positively related to the concentration of urinary naphthols (p < 0.01), while other lifestyle factors, i.e., age and consumption of alcohol, greasy or salty food, sweets, fruits, vegetables, meat, or fish, were not. We also studied whether genetic polymorphisms of enzymes, which were involved in naphthalene metabolism, affected urinary naphthols levels. The cytochrome P450 (CYP) 1A1 exon 7 genetic polymorphism was not related to urinary naphthol levels. Among smokers, the subjects with c1/c2 or c2/c2 type of CYP2E1, which was determined by CYP2E1 RsaI polymorphism in 5'-flaking region, showed higher concentrations of urinary 2-naphthol than the subjects with c1/c1 type regardless of creatinine-correction (p < 0.05) and the subjects with glutathione S-transferase (GST) M1 deficient type showed higher concentrations of both urinary 1- and 2-naphthol than those with GSTM1 normal type but only without creatinine-correction (p < 0.05). Thus, when urinary naphthols are used as biomarkers, smoking and the genetic polymorphisms of CYP2E1 and GSTM1 should be considered.
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