• BMB Reports
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• v.38 no.5
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• pp.563-570
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• 2005

Tamoxifen citrate (TAM), is widely used for treatment of breast cancer. It showed a degree of hepatic carcinogenesis. The purpose of this study was to elucidate the antioxidant capacity of green tea (Camellia sinensis) extract (GTE) against TAM-induced liver injury. A model of liver injury in female rats was done by intraperitoneal injection of TAM in a dose of $45\;mg\;Kg^{-1}\;day^{-1}$, i.p. for 7 successive days. GTE in the concentration of 1.5%, was orally administered 4 days prior and 14 days after TAM-intoxication as a sole source of drinking water. The antioxidant flavonoid; epicatechin (a component of green tea) was not detectable in liver and blood of rats in either normal control or TAM-intoxicated group, however, TAM intoxication resulted in a significant decrease of its level in liver homogenate of tamoxifen-intoxicated rats. The model of TAM-intoxication elicited significant declines in the antioxidant enzymes (glutathione-S-transferase,glutathione peroxidase, superoxide dismutase and catalase) and reduced glutathione concomitant with significant elevations transaminase) levels. The oral administration of 1.5% GTE to TAM-intoxicated rats, produced significant increments in the antioxidant enzymes and reduced glutathione concomitant with significant decrements in TBARS and liver transaminases levels. The data obtained from this study speculated that 1.5% GTE has the capacity to scavenge free radical and can protect against oxidative stress induced by TAM intoxication. Supplementation of GTE could be useful in alleviating tamoxifen-induced liver injury in rats.

• Journal of Genetic Medicine
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• v.10 no.2
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• pp.124-127
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• 2013

Among cause of carcinogenesis, heredity is believed to take about 10 percent in ovarian cancer. BRCA1 or BRCA2 account for largest portion of Hereditary Breast and Ovary Cancer (HBOC). Frequency of BRCA1/2 germ line mutations varies according to region and ethnicity from 1.1-39.7 percent. The identification of ovarian cancers with a BRCA mutation is will be more and important due to the possibility to offer a genetic counseling and also due to potential beneficial treatment effects with a poly-ADP-ribose polymerase inhibitor in some individuals. We report the case of a 41 year old woman with a stage Ic mucinous ovarian adenocarcinoma and carrier daughter found on family genetic counseling. We indentified other family members with a history of breast cancer of 1st degree and pancreatic cancer of 2nd degree relative. After a screening with immunohistochemistry, the absence of nuclear expression for BRCA1 and BRCA2 was revealed. The gene sequencing confirmed heterozygous mutations of BRCA2 gene. The daughter of the case subject consented for a test. This test was shown the daughter is positive for BRCA2 mutation. Regular surveillance, chemoprophylaxis with oral contraceptive and prophylactic surgery after childbearing were offered to her.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.23 no.4
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• pp.306-323
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• 2001

종양발생에서 유전자 발현을 확인하고 profile 변화를 monitor하는 것은 병리학적 변화의 원인뿐 아니라 질병탐지와 진료의 새로운 목표를 확인하기 위한 새로운 기회를 제공해준다. cDNA microarray는 수천개의 유전자 발현을 동시에 연구할 수 있는 최신의 방법으로 피부, 유방, 간을 비롯한 다른 인체장기에서는 일부 이루어졌으나 array를 이용해 타액선 종양 연구에서는 전혀 이루어지지 않았다. 인간의 타액선 세포의 악성형질전환을 조절하는 분자적 상태를 연구하기 위해 본 연구는 약 2,000개의 유전자가 print된 cDNA microarray를 이용하여 인간 타액선 도관상피세포주(HSG)와 악하선에서 기원한 미분화 선암종(SGT)간에 비교연구를 하였다. Cy3와 Cy5 dye로 각각의 세포주에서 얻은 RNA와 reciprocal hybridize시키고 GenePix 4000 scanner로 스캔하고 GenePix Pro로 분석한 후 log2로 평균발현비율을 전환시켜 최소 2배이상의 발현을 보이는 유전자를 분석대상으로 하였다. 90%이상의 유전자가 비슷한 발현을 보였으며 2배이상의 발현을 보이는 경우 HSG가 SGT에 비해 72개 유전자가, SGT가 HSG에 비해 111개의 유전자 발현이 up-regulation되어 총 10%미만의 발현차이를 보였고 반복된 hybridization 으로부터 얻은 선택된 spot의 Pearson 상관계수는 -0.85이였다. HSG에서는 6번 p 염색체에서 과발현되는 유전자가 가장 많았고, SGT에서는 11번 q 염색체에서 가장 많았는데 HSG에서는 SGT에 비해 9, 13, 17, 18, 20, 21, 22염색체에서 과발현 되는 유전자 수가 많았고, SGT에서는 HSG에 비해 2, 7, 10, 15 염색체에서 유전자 발현 증가가 관찰되었다. HSG와 SGT간의 유전 발현을 기능별로 분석한 결과 몇 가지 주요 경로가 세포악성에 관련됨을 발견하였고, 타액선 도관상피세포에서 선암종을 구별하는데 기여하는 관련된 몇종의 과다 발현된 유전자를 찾았는데 전사인자, 성장인자 및 수용기, 세포골격 및 세포외기질 단백, 세포내 신호전달조절자 및 인자, 세포표면 항원등의 그룹으로 분류할 수 있었다. 따라서 이러한 microarray를 이용한 분자학적 표지자 연구가 악성 타액선 종양 발생과정에서 큰 도움을 줄 수 있을 뿐 아니라 유전자 조절에 의한 진단, 예후, 치료에서의 정확성을 개선시킬 수 있으리라 여겨진다.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.26 no.3
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• pp.245-253
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• 2000

The development and progression of oral cancer is associated with an accumulation of multiple genetic alterations through the multistep processes. Comparative genomic hybridization(CGH), newly developed cytogenetic and molecular biologic technique, has been widely accepted as a useful method to allow the detection of genetic imbalance in solid tumors and the screening for chromosome sites frequently affected by gains or losses in DNA copy number. The authors examined 19 primary oral squamous cell carcinomas using CGH to identify altered chromosome regions that might contain novel oncogenes and tumor suppressor genes. Interrelationship between these genetic aberrations detected and major oncogenes and tumor suppressor genes previously recognized in carcinogenesis of oral cancers was studied. 1. Changes in DNA copy number were detected in 14 of 19 oral cancers (78.9%, mean: 5.58, range: $3{\sim}13$). High level amplification was present in 4 cases at 9p23, $12p21.1{\sim}q13.1$, 3q and $8q24{\sim}24.3$. Fourteen cases(78.9%, mean: 3.00, range: $1{\sim}8$) showed gains of DNA copy number and 12 cases(70.5%, mean: 2.58, range: $1{\sim}9$) revealed losses of DNA copy number. 2. The most common gains were detected on 3q(52.6%), 5p(21.0%), 8q(21.0%), 9p(21.0%), and 11q(21.0%). The losses of DNA copy number were frequently occurred at 9p(36.8%), 17q(36.8%), 13q(26.3%), 4p(21.0%) and 9p(21.0%). 3. The minimal common regions of gains were repeatedly observed at $3q24{\sim}26.7$, $3q27{\sim}29$, $1q22{\sim}31$, $5p12{\sim}13.3$, $8q23{\sim}24$, and 11q13.1-13.3. The minimal common regions of losses were detected at $9q11{\sim}21.3$, 17p31, $13q22{\sim}34$, and 14p16. 4. In comparison of CGH results with tumor stages, the lower stage group showed more frequent gain at 3q, 5q, 9p, and 14q, whereas gains at 1q($1q22{\sim}31$) and 11q($11q13.1{\sim}13.3$) were mainly detected in higher stage group. The loss at $13q22{\sim}34$ was exclusively detected in higher stage. The results indicate that the most frequent genetic alterations in the development of oral cancers were gains at $3q24{\sim}26.3$, $1q22{\sim}31$, and $5p12{\sim}13.3$ and losses at $9q11{\sim}21.3$, 17p31, and 13q. It is suggested that genetic alterations manifested as gains at $3q24{\sim}26.3$, $3q27{\sim}29$, $5p12{\sim}13.3$ and 5p are associated with the early progression of oral cancer. Gains at $1q22{\sim}31$ and $11q13.1{\sim}13.3$ and loss at 13q22-34 could be involved in the late progression of oral cancers.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.22 no.2
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• pp.164-173
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• 2000

The p16 protein is a cyclin dependent kinase inhibitor that inhibits cell cycle progression from $G_1$ phase to S phase in cell cycle. Many p16 gene mutations have been noted in many cancer-cell lines and in some primary cancers, and alterations of p16 gene function by DNA methylation have been noticed in various kinds of cancer tissues and cell-lines. There have been a large body of literature has accumulated indicating that abnormal patterns of DNA methylation (both hypomethylation and hypermethylation) occur in a wide variety of human neoplasma and that these aberrations of DNA methylation may play an important epigenetic role in the development and progression of neoplasia. DNA methylation is a part of the inheritable epigenetic system that influences expression or silencing of genes necessary for normal differentiation and proliferation. Gene activity may be silenced by methylation of up steream regulatory regions. Reactivation is associated with demethylation. Although evidence or a high incidence of p16 alterations in a variety of cell lines and primary tumors has been reported, that has been contested by other investigators. The precise mechanisms by which abnormal methylation might contribute to carcinogenesis are still not fully elucidated, but conceivably could involve the modulation of oncogene and other important regulatory gene expression, in addition to creating areas of genetic instability, thus predisposing to mutational events causing neoplasia. There have been many variable results of studies of head and neck squamous cell carcinoma(HNSCC). This investigation was studied on 13 primary HNSCC for p16 gene status by protein expression in immunohistochemistry, and DNA genetic/epigenetic analyzed to determine the incidence, the mechanisms, and the potential biological significance of its Inactivation. As methylation detection method of p16 gene, the methylation specific PCR(MSP) is sensitive and specific for methylation of any block of CpG sites in a CpG islands using bisulfite-modified DNA. The genomic DNA is modified by treatment with sodium bisulfate, which converts all unmethylated cytosines to uracil(thymidine). The primers designed for MSP were chosen for regions containing frequent cytosines (to distinguish unmodified from modified DNA), and CpG pairs near the 5' end of the primers (to provide maximal discrimination in the PCR between methylated and unmethylated DNA). The two strands of DNA are no longer complementary after bisulfite treatment, primers can be designed for either modified strand. In this study, 13 paraffin embedded block tissues were used, so the fragment of DNA to be amplified was intentionally small, to allow the assessment of methylation pattern in a limited region and to facilitate the application of this technique to samlples. In this 13 primary HNSCC tissues, there was no methylation of p16 promoter gene (detected by MSP and automatic sequencing). The p16 protein-specific immunohistochemical staining was performed on 13 paraffin embedded primary HNSCC tissue samples. Twelve cases among the 13 showed altered expression of p16 proteins (negative expression). In this study, The author suggested that low expression of p16 protein may play an important role in human HNSCC, and this study suggested that many kinds of genetic mechanisms including DNA methylation may play the role in carcinogenesis.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.32 no.3
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• pp.218-228
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• 2010

Components of dental resin-based restorative materials are reported to leach from the filling materials even after polymerization. Hydroquinone (HQ) is one of the major monomers used in the dental resin and is known as a carcinogen. Thus, carcinogenic risk of HQ leaching from the dental resin becomes a public health concern. The present study attempted to examine the carcinogenic potentials of HQ on the human epithelial cell, which is the target cell origin of the most of oral cancers. Cytotoxicity of HQ was observed above 50${\mu}M$ as measured by LDH assay, indicating a relatively low toxicity of this substance in human epithelial cells. The parameters of neoplastic cellular transformation such as cell saturation density, soft agar colony formation and cell aggregation were analyzed to examine the carcinogenic potential of HQ. The study showed that 2-week exposure of HQ showed the tendency of increase in the saturation density and the significant enhancement of soft agar colony formation at the highest dose, 50 ${\mu}M$ only. It is suggested that HQ has a weak potential of carcinogenicity. When cells were treated with HQ and TPA, a well-known tumor promoter, the parameters of neoplastic cellular transformation was significantly increased. This result indicates that the potential risk of carcinogenicity from HQ is largely dependent upon the presence of promoter. Exposure of 50 ${\mu}M$ HQ increased the time-dependent apoptosis as measured by the ELISA kit. This concentration coincides with a dose of neoplastic transformation, indicating a possible link between apoptosis and HQ-induced cellular transformation. Hydroquinone generated Reactive Oxygen Species (ROS) which was evidenced by the treatment of antioxidants such as trolox and N-acetyl cysteine and the GSH depleting agent, BSO. Antioxidants blocked the generation of ROS and the GSH depleting agent, BSO dramatically increased the ROS production. Since HQ is known to increase ROS production thru activation of transcriptional factor such as c-Myb and Pim-1, it is speculated that ROS generation by HQ plays a role in the activation of oncogene, which may lead to neoplastic transformation. In addition, ROS is involved in the alteration of signal transduction, which regulates the apoptosis in many cellular systems. Thus, ROS-mediated apoptosis may be involved in the HQ-induced carcinogenic processes. Protein kinase C (PKC) is known to play pivotal roles in neoplastic transformation of cells and its high expression is often found in a variety of types of tumors including oral cancer. PKC translocation of PKC-${\alpha}$ was observed following HQ exposure. Altered signaling system may also play a role in the transformation process. Taken together, HQ leached from the dental resin does not pose a significant threat as a cancer causing agent, but its carcinogenic potential can be significantly elevated in the presence of promoter. The mechanism of HQ-induced carcinogenesis involved ROS generation, apoptosis and altered signaling pathway. The present study will provide a valuable data to estimate the potential risk of HQ as a carcinogen and understand mechanism of HQ-induced carcinogenesis in human epithelial cells.

• Journal of Ginseng Research
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• v.39 no.3
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• pp.230-237
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• 2015

Background: Colorectal cancer (CRC) is a leading cause of death worldwide. Chronic gut inflammation is recognized as a risk factor for tumor development, including CRC. American ginseng is a very commonly used ginseng species in the West. Methods: A genetically engineered $Apc^{Min/+}$ mouse model was used in this study. We analyzed the saponin composition of American ginseng used in this project, and evaluated its effects on the progression of high-fat-diet-enhanced CRC carcinogenesis. Results: After oral ginseng administration (10-20 mg/kg/d for up to 32 wk), experimental data showed that, compared with the untreated mice, ginseng very significantly reduced tumor initiation and progression in both the small intestine (including the proximal end, middle end, and distal end) and the colon (all p < 0.01). This tumor number reduction was more obvious in those mice treated with a low dose of ginseng. The tumor multiplicity data were supported by body weight changes and gut tissue histology examinations. In addition, quantitative real-time polymerase chain reaction analysis showed that compared with the untreated group, ginseng very significantly reduced the gene expression of inflammatory cytokines, including interleukin-$1{\alpha}$ (IL-$1{\alpha}$), IL-$1{\beta}$, IL-6, tumor necrosis factor-${\alpha}$, granulocyte-colony stimulating factor, and granulocyte-macrophage colony-stimulating factor in both the small intestine and the colon (all p < 0.01). Conclusion: Further studies are needed to link our observed effects to the actions of the gut microbiome in converting the parent ginsenosides to bioactive ginseng metabolites. Our data suggest that American ginseng may have potential value in CRC chemoprevention.

• 한국생물공학회:학술대회논문집
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• 2001.11a
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• pp.867-870
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• 2001

All-trans-retinoic acid (RA) plays essential roles in the regulation of differentiation and proliferation. It has been proved that RA is effective in the treatments of epithelial and hematologic malignancies. However, in spite of its pronounced effects, the clinical applications of RA are limited due to the retinoid acute resistance. Although RA induces complete remission in a high proportion of the patients of acute promyelocytic leukemia (APL), the cancer was relapsed in many patients after a brief remission in spite of a continued RA treatment. Patients who relapsed from remission that was initially induced by RA had clinically resistant to further RA treatment. That is, specific cytochrome P450 enzymes in the liver were induced by the continuous oral administration of RA, thereby accelerating the metabolism of RA. To overcome this problem, biodegradable microspheres were proposed by us, previously. And, several microsphere formulations for RA delivery have been prepared and studied on their effectiveness. Recently, poly(D,L-lactide) (PDLLA) microsphere formulation was optimized, And, from the animal studies by using a mouse and a rat, it have appeared to be effective on both the inhibition of tumor growth and chemoprevention of a carcinogenesis. In this study, subacute toxicities of the PDLLA microsphere formulation have been investigated as a preclinical test. For the test, the microspheres was injected subcutaneously into the back site of rats, and body weight change, clinical signs, hematological changes, blood biochemistry were evaluated. As a result, severe toxicities such as mortality were observed at the dose of 100mg RA/kg, and toxicities were not observed at the dose of 50mg RA/kg, which is the effective dose against carcinogenesis. Bone fracture, observed at several rats, might be inhibited by treating them with anti-inflammatory drugs.

• Journal of Microbiology
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• v.38 no.3
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• pp.169-175
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• 2000

Epidemiological and experimental studies provide evidences that diet and intestinal microflora play an important role in colon carcinogenesis. In recent years, it has been suggested that lactic acid bacteria (LAB) used to ferment dairy products have an inhibitory effect on the colon cancer. This study was designed to determine the effect of Bifidobacterium longum HY8001 (Bif) and Lactobacillus acidophilus HY2104(Lac) of Korean origin on azoxymethane (AOM)-induced colonic preneoplastic lesions such as aberrant crypt foci(ACF) formation and cecal pH. At five weeks of age, Spraque-Dawley rats were divided at random into four (AOM alone, Bif, ,Lac, and Bif+Lac) groups. Animals were weighed weekly and oral administration of LAB cultures were performed daily until the termination of the study. Two weeks later, all animals were given a subcutaneous injection of AOM dissolved in normal saline at a dose of 15 mg/kg of body weight once per week for 2 weeks. All rats were necropsied 7 weeks after the last AOM injection , and the ACF were visualize under light microscopy in the formalin-fixed, unsectioned methylene blue-stained colons. The total number of aberrant crypt in Bif, Lac, and Bif+Lac groups were significantly lower than that of the AOM alone group and the percentage of inhibitions weas 35.0, 45.6%, respectively. Significant inhibition (p<0.001) in the total number of ACF was also observed in LAB treated groups (Bif , Lac, and Bif+Lac group by 3003, 38.6, and 41.2%, respectively). Furthermore, cecal pH appeared to significantly decrease by LAB administration. The results of present study provide some evidences for potential colon tumor-inhibitory properties of lactic cultures and fermented dairy products.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7583-7586
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• 2013

Background: Suppressor of cytokine signaling (SOCS)-1 acts as a key regulator of many cytokine signaling pathways and its abnormal expression has been identified in several human malignancies, suggesting potential roles in carcinogenesis. The aim of this study was to investigate any association between the functional SOCS-1 -1478CA>del polymorphism and colorectal cancer (CC) as well as age at onset in a Turkish clinical sample. Materials and Methods: A total of 122 subjects were enrolled in this case-control study (70 CC cases and 52 controls). The SOCS-1 -1478CA>del polymorphism was genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: The odds ratio of the del allele for CC relative to the CA allele was not significantly different between the groups (OR=0.71, 95% CI=0.41-1.22, p=0.27). This result did not change after adjustment for age and sex on multivariable regression analysis (OR=0.84, 95% CI=0.59-1.34, p=0.53). When the SOCS-1 -1478CA>del polymorphism was analyzed among CC patients in relation to the age at disease onset, we found no significant differences between subjects with the del/del, CA/del, and CA/CA genotypes. Conclusions: The results of our study did not point towards a major role of the SOCS-1 -1478CA>del polymorphism in the pathogenesis of CC in Turkish subjects.