• Journal of Nutrition and Health
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• v.31 no.6
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• pp.1014-1023
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• 1998

The influences of fish oil and different levels of vitamin I supplement on hepatocellular chemical carcinogenesis have been studied. Male Sprague-Dawley rats received diethylnitrosamine (DEN)(200mg/kg body weight) and were subjected to two-thirds partial hepatectomy to induce murine chemical hepatocarcinogenic procedure. Placental glutathione S-transferase(GST-P) positive foci area, antioxidant enzymes(Cu/Zn-superoxide dismutase(SOD), catalase, glutathione reductase (GR), total- glutathione peroxidase (TGPx), glutathione S -transferase (GST)), glucose 6-phosphatase (G6Pase) activities, and lipid peroxidation of microsomes(thiobarbituric acid reactive substances (TBARS)) were measured. Experimental animals were fed 15% corn or fish oil with 0, 40, 1,000, 10,000IU vitamin E /kg diet for 8 weeks. Vitamin E supplements decreased the area of GST-P positive foci in both groups. The higher the vitamin E levels, the smaller the area of GST-P positive foci were noticed. Compared to 0 IU vitamin E, 40 IU in corn oil and 1,000 IU in fish oil groups were effective in decreasing G57-P positive foci area. Fish oil groups tended to have smaller area of GST-P positive foci. fish oil groups showed lower body weight, lower activities of Cu/Zn-SOD and TGPx, higher TBARS contents, higher activities of GST, catalase, G6Pase, GR and higher liver/body ratio than corn oil groups. As the level of vitamin I increased, GST-P positive foci count, catalase activities, and TBARS tended to decrease. G6Pase activities tended to increase in both groups. At higher vitamin E levels, GST activities tended to decrease in fish oil groups. These results suggest that vitamin I has suppressive offects on hepatocellular chemical carcinogenesis probably through antioxidant eH:cts decreasing TBARS contents, $H_2O$$_2$, and organic peroxides. fish oil tended to have greated suppressive offects than corn oil on hepatocellular carcinogenesis. (Korean J Nutrition 31(6) : 1014-1023, 1998)

• Toxicological Research
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• v.13 no.4
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• pp.409-415
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• 1997

The influences of dietary supplement of citron tea on the hepatocellular chemical carcinogenesis have been studied by examining placental glutathione S-transferase(GST-P) positive foci area in a liver tissue, contents of total cytochrome P450, thiobarbituric acid reactive substances(TBARS) and glucose 6-phosphatase(G6Pase) in hepatic microsome and glutathione S-transferase(GST) activity. Weaning Sprague-Dawley male rats were fed AIN76 diet with or without citron tea supplement. Rats of CTR and CTR+ groups were fed diet without citron tea supplement while CDI and CDI+ groups were fed diet with citron tea supplement for the entire experimental period(13 weeks). Rats of CDP and CDP+ groups were fed diet without citron tea supplement for the first 7 weeks and swiched to citron tea containing diet for the last 6 weeks of experimental period. CTR+, CDI+ and CDP+ groups were carcinogen treated group. Diethylnitrosamine(DEN) was used as a carcinogen initiator and injected to the rats of carcinogen treated groups as a single dose of 200 mg/kg body weight intraperitoneally after 4 weeks of feeding. 2-Acethylaminofiuorene(AAF) was used as a carcinogen promoter and supplied in the diets of carcinogen treated rats as 0.02% content for the last 6 weeks starting from 2 weeks after DEN injection. Rats were sacrificed after 13 weeks of feeding. Liver/body weight ratio and GST activities were increased by carcinogen treatment. However, they were not changed by citron tea supplement. Total cytochrome P450 contents were not changed by carcinogen treatment or citron tea supplement. TBARS contents of carcinogen treated rats showed tendency to decrease by citron tea supplement. G6Pase activity decreased by carcinogen treatment and citron tea supplement. The area of GST-P positive foci detected in carcinogen treated rats were decreased by citron tea supplement and not affected by the timing and the duration of citron tea supplement. These results suggest that citron tea has suppressive effects on hepatocellular chemical carcinogenesis probably through antioxidant compounds by decreasing TBARS contents.

• The Journal of Internal Korean Medicine
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• v.32 no.3
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• pp.397-410
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• 2011

Objectives : This study was designed to investigate the effect of Injinsammul-tang (IJS) on hepatocellular carcinogenesis in rats. Methods : Sprague Dawley (SD) rats of control and treatment groups received intraperitoneal injection of 50 mg/kg/day diethylnitrosamine (DENA) weekly for 8 weeks. Experimental rats were classified into 3 groups; normal group (Nor), hepatic cancer induced control group (Con), and IJS extract 250 mg/kg administered group (IST) after being injected with DENA. Thereafter the changes of body weight, liver weight and weight of liver/100g body weight, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and superoxide dismutase (SOD) were measured. Gross anatomy and optical microscopy were also observed. Results : The body weight decreased in Con and IST compared with the Nor. The weight of liver and the weight of liver/100g body weight increased significantly in Con and IST compared with the Nor. The activities of AST, ALT, ALP, LDH increased in the Con compared with Nor, but decreased in IST compared with Con. The activities of SOD increased in the Con and IST compared with Nor. Upon naked eye and light microscopic examination, IJS improved the morphological and histopathological changes of liver caused by DENA-induced hepatic neoplasm. The number of hepatic p53 positive cells decreased in the IST compared with Con. Conclusions : Most of the results did not show a significant effect, but some of the results showed a significant effect. It can be estimated that IJS has some effects on hepatocellular carcinogenesis induced by DENA in rats, and further studies will be needed.

• Journal of Pharmacopuncture
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• v.12 no.3
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• pp.5-24
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• 2009

Injinho-tang(IJ) has been used for the treatment of hepatobiliary diseases. This study was performed to observe the effect of IJ extract on the hepatocellular carcinogenesis and hepatic cirrhosis induced by Diethylnitrosamine(DENA) and $CCl_4$ in Rats. Experimental groups were divided into two ; 8th and 12th week group, and subdivided into four; normal group(Nor), hepatocellular cancer and hepatic cirrhosis inducing control group(Con), and IJ extract 260mg/kg/day(IJA) or 520mg/kg/day(IJB) administered groups to Con. The results obtained are as follows: The body weight was decreased in the Con, IJA and IJB compared with the Nor from the 2nd week to the 12th week. The weight of liver and the weight of liver/100g body weight were decreased significantly in Con, IJA and IJB compared with the Nor. The activities of aspartate aminotransferase(AST) and alanine aminotransferase(ALT) were significantly increased in the Con compared with Nor, but decreased in the IJA and IJB compared with Con from the 8th week group. The activities of alkaline phosphatase(ALP), lactacte dehydrogenase (LDH) and alpha fetoprotein(AFP) were increased significantly in the Con compared with Nor, but decreased in the IJA and IJB compared with Con. The activities of superoxide dismutase(SOD) were decreased in the IJA and IJB compared with Con, but the activities of catalase were increased in the IJA and IJB compared with Con. According to the light and electron microscopical observation, IJA and IJB improved the morphological and histopathological changes of the liver injured by DENA and $CCl_4$. The number of hepatic p53 positive cells was decreased in the IJA and IJB compared with Con. These results suggest that administration of IJ extract suppress or retard DENA and $CCl_4$-induced hepatocelluar carcinogenesis and hepatic cirrhosis in rats.

• Journal of Pharmacopuncture
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• v.13 no.2
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• pp.13-31
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• 2010

Objective : Bujeonghangam-tang(BH) has been used for cure of tumor as a traditional medicine. This study was carried out to clarify the effect of BH extract on hepatocellular carcinogenesis and hepatic cirrhosis induced by Diethylnitrosamine(DENA) and $CCl_4$ in Rats. Method : Experimental groups were divided into two, 8th and 12th week groups, and subdivided into four; normal group(Nor), cirrhosis and hepatic cancer inducing control group(Con), and BH extract 320 mg/kg/day(BHA) or 640 mg/kg/day(BHB) administered groups to Con. Results: In the 8th week group: The body weight decreased significantly in Con compared with the Nor. The activities of transaminase, alkaline phosphatase(ALP), and lactacte dehydrogenase(LDH) were significantly increased(p<0.05) in the Con compared with Nor, but decreased in the BHA and BHB compared with Con. Alpha fetoprotein(AFP) were the most increased in the Con compared to BHA and BHB. The results of light microscopical observation, a number of hepatocytes were damaged in the Con compared with Nor and BH extract administerd groups. The number of hepatic p53 positive cells was reduced in the BH extract administered groups. According to the electron microscopical observation, hepatocarcinoma cells were observed distinctly in the Con compared with BH extract administered groups. In the 12 weeks group: The results of body were similar to 8th week groups. The activities of transaminase and ALT were significantly increased(p<0.05) in the Con compared with Nor. LDH was significantly(p<0.05) increased in the Con compared with Nor but significantly (p<0.05) decreased in the BHB. Alpha fetoprotein(AFP) were the most increased in the Con among ex perimental groups. The activities of superoxide dismutase(SOD) were significantly (p<0.05) increased in the Con, but the activities of catalase were not increased(p<0.05) compared with Nor. The number of hepatic p53 positive cells was increased in the Con. The results of electron microscopical observation were similar to 8th week groups. Conclusion : These results suggest that ad ministration of BH extract suppress or retard DENA and $CCl_4$-induced hepatocellular carcinogenesis and hepatic cirrhosis in rats.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4363-4368
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• 2012

The epidermal differentiation complex (EDC) contains a large number of gene products which are crucial for the maturation of the human epidermis and can contribute to skin diseases, even carcinogenesis. It is generally accepted that activation of oncogenes and/or inactivation of tumor suppressor genes play pivotal roles in the process of carcinogenesis. Here, NICE-3, a novel EDC gene, was found to be up-regulated in human hepatocellular carcinoma (HCC) by quantitative real-time RT-PCR. Furthermore, overexpression of exogenous NICE-3 by recombinant plasmids could significantly promote cell proliferation, colony formation and soft agar colony formation in Focus and WRL-68 HCC cell lines. Reversely, NICE-3 silencing by RNA interference could markedly inhibit these malignant phenotypes in YY-8103 and MHCC-97H cells. Moreover, cell cycle analysis of MHCC-97H transfected with siRNA by flow cytometry showed that NICE-3 knockdown may inhibit cell growth via arrest in G0/G1 phase and hindering entry of cells into S phase. All data of our findings indicate that NICE-3 may contribute to human hepatocellular carcinoma by promoting cell proliferation.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.915-921
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• 2013

Background: Hepatocellular carcinoma is one of the leading causes of mortalities worldwide. The search for new therapeutic targets is of utmost importance for improved treatment. Altered expression of HDAC1 in hepatocellular carcinoma (HCC) and its requirement for liver formation in zebrafish, suggest that it may regulate key events in liver carcinogenesis and organogenesis. However, molecular mechanisms of HDAC1 action in liver carcinogenesis are largely unknown. The present study was conducted to identify HDAC1 interacting proteins in HepG2 cells using modified SH-double-affinity purification coupled with liquid mass spectrophotemetery. Materials and Methods: HepG2 cells were transfected with a construct containing HDAC1 with a C-terminal strepIII-HA tag as bait. Bait proteins were confirmed to be expressed in HepG2 cells by western blotting and purified by double affinity columns and protein complexes for analysis on a Thermo LTQ Orbitrap XL using a C18 nano flow ESI liquid chromatography system. Results: There were 27 proteins which showed novel interactions with HDAC1 identified only in this study, while 14 were among the established interactors. Various subunits of T complex proteins (TCP1) and prefoldin proteins (PFDN) were identified as interacting partners that showed high affinity with HDAC1 in HepG2 cells. Conclusions: The double affinity purification method adopted in this study was very successful in terms of specificity and reproducibility. The novel HDAC1 complex identified in this study could be better therapeutic target for treatment of hepatocellular carcinoma.

• Journal of Yeungnam Medical Science
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• v.13 no.1
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• pp.146-151
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• 1996

Majority of hepatocellular carcinoma is evolved from a well differentiated cancerous condition such as hyperplastic lesions eg. adenomatous hyperplasia in cirrhotic liver or de no vo carcinogenesis and prolifenation along with dedifferentiation. Adenomatous hyperplasia is may be seen in severe acute hepatic injury, like submassive hepatic necrosis, or in chronic liver diseases, particularly liver cirrhosis and it has recently attracted much interest from both clinicians and pathologists because it is regarded as a precursor lesion of hepatocellular carcinoma. Hepatic adenomatous hyperplasia resembling focal nodular hyperplasia might have developed from localized vascular changes associated with chronic liver disease, pre-existing arterial malformation and early stage of angiogenesis in hepatocarcinogenesis. We present a patient who developed hepatocellular carcinoma after hepatic artery ligation.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3627-3630
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• 2012

The epithelial cell adhesion molecule (EpCAM) is a pan-epithelial differentiation antigen that is expressed on almost all carcinomas. However, a role in rat liver carcinogenesis has never been reported previously. Thus, its expression was investigated herein in rat liver tumors induced by diethylnitrosamine (DEN). Twenty male 5-week-old F344 rats were used in this experiment. Mini-osmotic pumps containing doses of 47.5 mg of DEN were inserted into the abdominal cavity of each animal to initiate liver carcinogenesis. All animals were sacrificed at 26 weeks after DEN treatment. At necropsy, hepatic masses were processed for histopathological examination, which revealed forty-four hepatocellular adenomas (HCAs) and twenty hepatocellular carcinomas (HCC). Tumors were immunohistochemically analyzed for EpCAM, proliferating cell nuclear antigen (PCNA) and co-localization of the two. EpCAM expression was mainly detected in hepatic tumor cells, showing a cytoplasmic staining pattern. However, expression was also slightly observed in normally-appearing surrounding hepatic cells. PCNA expression was highly detected in tumor cells, showing nuclear staining. Double staining of EpCAM and PCNA in tumors showed many cells with co-localization. Taken together, EpCAM and PCNA expression were increased in DEN-induced tumors and many tumor cells showed co-expression. It is suggested that EpCAM may increase during DEN-induced tumors, possibly associated with cell proliferation.

• Molecular & Cellular Toxicology
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• v.4 no.4
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• pp.278-284
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• 2008

The X-linked inhibitor of apoptosis (XIAP) is a member of a novel family of inhibitors of apoptosis and has several BIR domains (BIR1, BIR2, and BIR3) and a carboxy-terminal RING zinc-finger. Since suppressionof apoptosis is fundamentally important for carcinogenesis and tumor growth, we investigated the expression and function of XIAP in DEN-induced carcinogenesis using rat model. Wistar rats were injected intraperitoneally with DEN at a dose of 50 mg/kg in twice a week for 12 weeks (Group II) and 16 weeks (Group III) followed by the recovery periods, respectively. The evaluation of DEN-induced carcinogenesis carried out the blood, RT-PCR, histopathological and western blot analysis. The level of blood chemistry including GOT/GPT, albumin, and total bilirubin were significantly exchanged comparing to control and Group I/Group II. The expression of albumin and collagen mRNA were significantly exchanged (P<0.05) in both groups. In addition, AFP mRNA expression decreased more after recovery periods than Group II. XIAP was expressed constitutively in normal rat liver as well as DEN-induced Groups I and Group II. In addition, XIAP expression increased more in Group I with 4 weeks recovery periods than Group I. However, XIAP expression shown to increase in Group lI, otherwise, it was decreased in Group II with 10 weeks repair periods. Taken together, these results suggest the alteration of XIAP expression could be involved in hepatocellular carcinogenesis.