• Title, Summary, Keyword: Hepatocellular Carcinogenesis

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Serum Amyloid A is a Novel Prognostic Biomarker in Hepatocellular Carcinoma

  • Ni, Xiao-Chun;Yi, Yong;Fu, Yi-Peng;He, Hong-Wei;Cai, Xiao-Yan;Wang, Jia-Xing;Zhou, Jian;Fan, Jia;Qiu, Shuang-Jian
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.24
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    • pp.10713-10718
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    • 2015
  • Purpose: To investigate the prognostic value of serum amyloid A (SAA) in patients with hepatocellular carcinoma (HCC) undergoing surgery. Materials and Methods: Preoperative serum samples of 328 patients with HCC who underwent curative resection and of 47 patients with benign liver lesion were assayed. Serum levels of SAA were measured by enzyme-linked immunosorbent assay and its correlations with clinicopathological characteristics and survival were explored. Results: Levels of SAA were significantly higher in patients with HCC than those with benign liver lesion. There were strong correlations between preoperative serum SAA level and tumor size and more advanced BCLC stage. On univariate analysis, elevated SAA was associated with reduced disease-free survival and overall survival (p=0.001 and 0.03, respectively). Multivariate analyses showed that serum SAA level was an independent prognostic factor for overall survival (hazard ratio 2.80, p=0.01). Conclusions: High SAA serum level is a novel biomarker for the prognosis of HCC patients.

Prognostic Significance of Hes-1, a Downstream Target of Notch Signaling in Hepatocellular Carcinoma

  • Zou, Jing-Huai;Xue, Tong-Chun;Sun, Chun;Li, Yan;Liu, Bin-Bin;Sun, Rui-Xia;Chen, Jie;Ren, Zheng-Gang;Ye, Sheng-Long
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.9
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    • pp.3811-3816
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    • 2015
  • Background: Hairy and enhancer of split 1 (Hes-1) protein is a downstream target of Notch signaling and is a basic helix-loop-helix transcriptional repressor. However, definitive evidence for a role in hepatocellular carcinoma (HCC) cells has not been reported. Here, Hes-1 was revealed to an important component of the Notch signaling cascade in HCC cell lines possessing different potential for lung metastasis. Materials and Methods: RNAi mediated by plasmid constructs was used to analyze the role of Hes-1 in MHCC-97L HCC cells by assessing proliferation, apoptosis, cell migration and matrigel invasion following transfection. Hes-1 protein expression analysis in HCC tissue was also conducted by immunohistochemistry. Results: Our studies revealed that Hes-1 was decreased in HCC cell lines with higher lung metastasis potential at both the mRNA and protein levels. Down-regulation of the Hes-1 gene in MHCC-97L cells resulted in increased cell proliferation, reduced apoptosis and increased migration and invasion. Conclusions: Hes-1 has potential prognostic value in post-surgical HCC patients and may be an independent prognostic indicator for overall survival and tumor recurrence. These findings have important implications for understanding the mechanisms by which Hes-1 participates in tumor proliferation and invasion.

Suppressive Effects of Vitamin E on the Induction of Placental Glutathione S-transferase(GST-P) Positive foci and Antioxidant Enzyme Activity in Rat Hepatocarcinogenesis (비타민 E가 쥐간 세포의 암화과정에서 태반형 Glutathione S-transferase(GST-P) 양성 병소와 항산화요소계에 미치는 영향)

  • 최혜미
    • Journal of Nutrition and Health
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    • v.30 no.7
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    • pp.803-812
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    • 1997
  • The influences of dietary supplements of vitamin E on hepatocellular chemical carcinogenesis have been studied, Placental glutathione S-transferase(GST-P) positive foci area, antioxidant enzymes(superoxide dismutase(SOD), catalase, glutathione reductase, glutathione peroxidase, glutathione S-transferase(GST)), glucose 6-phosphatase(G6Pase) activities, and lipid peroxidation of mecrosomes(thiobarbituric acid reactive substances(TBARS) contents) were investigated. For is purpose , we used the murine chemical hepatocardinogenic procedure induced by modified Ito model, which consists of 200mg/kg body weight diethylinitrosamine (DEN) injection, 0.01% 2-acethlaminoflurene(2-AAF) feeding for 6 weeks, and partial hepatectomy on week 3. Weanling Sprague-Dawley male rats were fed pulverized Purina rat chow with 15, 000IU/kg diet vitamin E from initiation or promotion stages. We found that vitamin E supplement decreased the area of GST-P positive foci. Catalase, glutathione peroxidase, glutathione reductase. GST activities, and TBARS contents were decreased. On the other hand G6Pase activities were increased by vitamin E supplement. It seemed that vitamin E supplements helped endogenous defense systems against carcinogenesis by decreasing TBARS contents, $H_2O$$_2$ and organic peroxides. So, vitamin E seemed to protect cell from free radical damage in carcinogenesis. Anticarcinogenic effects of vitamin E were more effective at intiation that at promotion stage. These results suggest that vitamin E has suppressive effects on hepatocellular chemical carcinogenesis, probably through antioxidant effects against TBARS contents $H_2O$$_2$ and orgainc peroxides.

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Low Counts of γδ T Cells in Peritumoral Liver Tissue are Related to More Frequent Recurrence in Patients with Hepatocellular Carcinoma after Curative Resection

  • Cai, Xiao-Yan;Wang, Jia-Xing;Yi, Yong;He, Hong-Wei;Ni, Xiao-Chun;Zhou, Jian;Cheng, Yun-Feng;Jin, Jian-Jun;Fan, Jia;Qiu, Shuang-Jian
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.2
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    • pp.775-780
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    • 2014
  • Objectives: TCR-gamma-delta+T cells (${\gamma}{\delta}$ T cells) are non-conventional T lymphocytes that can recognize and eradicate tumor cells. Our previous studies showed that infiltration and function of ${\gamma}{\delta}$ T cells were substantially attenuated in hepatocellular carcinoma (HCC). However, their prognostic value was not clarified. Methods: The association between ${\gamma}{\delta}$ T cells and the clinical outcomes was determined by immunohistochemistry (IHC) in a HCC patient cohort (n = 342). Results:Immunohistochemistry showed decreased infiltration of ${\gamma}{\delta}$ T cells in tumoral tissues compared with paired peritumoral tissues. The counts of ${\gamma}{\delta}$ T cells in peritumoral tissues were negatively correlated with tumor size (P = 0.005). Survival analysis showed that the levels of peritumoral ${\gamma}{\delta}$T cells were related to both time to recurrence (TTR) and overall survival (OS) (P = 0.010 and P = 0.036, respectively) in univariate analysis, and related to TTR in multivariate analysis (P = 0.014, H.R. [95% CI] = 0.682 [0.502-0.927]). Furthermore, the level of peritumoral ${\gamma}{\delta}$ T cells showed independent prognostic value for TTR in Barcelona Clinic Liver Cancer (BCLC) stage A patients (P = 0.038, H.R. [95% CI] = 0.727 [0.537-0.984]). However, tumoral ${\gamma}{\delta}$ T cells did not show independent prognostic value for either TTR or OS in HCC patients. Conclusions: Low counts of ${\gamma}{\delta}$ T cells in peritumoral liver tissue are related to a higher incidence of recurrence in HCC and can predict postoperative recurrence, especially in those with early-stage HCC.

Altered Distribution and Expression Pattern of E-cadherin in Hepatocellular Carcinomas: Correlations with Prognosis and Clinical Features

  • Jiang, Xue-Mei;Zhang, Ju-Bo;Xiong, Ju;Huang, Xiao-Xi;Ren, Zheng-Gang
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.12
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    • pp.6455-6461
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    • 2012
  • Objective: E-cadherin has been identified as a tumor suppressor in many types of carcinoma. However, some studies recently suggested that the role and expression of E-cadherin might be more complex and diverse. In the present study, we evaluated the prognostic value of E-cadherin expression with reference to levels in membranes and cytoplasm, and the membrane/cytoplasm ratio, in hepatocellular carcinomas (HCCs) after curative hepatectomy. Methods: The expression of E-cadherin was assessed by immunohistochemistry in HCC tissue microarrays from 125 patients, and its prognostic values and other clinicopathlogical data were retrospectively analyzed. Patients were followed for a median period of 43.7 months (range 1 to 126 months). Results: Univariate analysis demonstrated that a high membrane/cytoplasm (M/C) ratio of E-cadherin expression was associated with poor overall survival (OS) (P =0.001) and shorter time to recurrence (TTR) (P=0.038), as well as tumor size, intrahepatic metastasis, and TNM stage. In contrast, neither membrane nor cytoplasmic expression of E-cadherin was related with OS and TTR. Furthermore, multivariate analysis confirmed the M/C ratio to be an independent predictor of OS (P=0.031). ${\chi}^2$ tests additionally showed that the M/C ratio of E-cadherin expression was related with early stage recurrence (P=0.012), rather than later stage recurrence. Conclusion: The M/C ratio of E-cadherin expression is a strong predictor of postoperative survival and is associated with early stage recurrence in patients with HCC.

Alteration of X-linked Inhibitors of Apoptosis (XIAP) Expression in Rat Model with DEN-induced Hepatocellular Carcinogenesis

  • Chang, Jae-Jin;Jeon, Su-Yeon;Song, Ji-Ye;Kim, Jin-Hee;Li, Lan;Park, Dae-Hun;Lee, Yun-Lyul;Park, Jeong-Joo;Woo, Dong-Wook;Kim, Gi-Jin;Lee, Min-Jae
    • 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.

Dehydroepiandrosterone supplement increases malate dehydrogenase activity and decreases NADPH-dependent antioxidant enzyme activity in rat hepatocellular carcinogenesis

  • Kim, Jee-Won;Kim, Sook-Hee;Choi, Hay-Mie
    • Nutrition Research and Practice
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    • v.2 no.2
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    • pp.80-84
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    • 2008
  • Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ${\sim}5$ fold and glucose 6-phosphate dehydrogenase activities were decreased by ${\sim}25%$ compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased siguificantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to fimction in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.

The Effect of the Keughachukeo-tang Extract on the Hepatocellular Carcinogenesis and Acute Liver Damage Induced by Diethylnitrosamine and CCl4 in Rats (膈下逐瘀湯이 Diethylnitrosamine과 CCl4로 유발된 흰쥐의 肝癌 形成과 肝損傷에 미치는 영향)

  • Heo, Rae-Kyong;Seung, Kee-Moon;Kim, So-Yeon;Je, Jun-tae;Kwon, So-yeon;Moon, Goo;Lee, Jong-Deok;Won, Jin-Hee
    • Journal of Pharmacopuncture
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    • v.12 no.4
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    • pp.63-76
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    • 2009
  • This study was performed to observe the effect of Keughachukeo-tang(KH) extract on the hepatocellular carcinogenesis and acute liver damage induced by Diethylnitrosamine(DENA) and $CCl_4$ in Rats. Experimental groups were divided into four; normal group(Nor), acute liver damage and hepatocellular cancer inducing control group(Con), KH extract 350㎎/㎏/day(KHA), and 700㎎/㎏/day(KHB) administered groups to Con. The results obtained are as follows: The body weight increased in KHA and KHB than Con from 7th week to the 8th week. The activities of Alanine aminotransferase(ALT) were the most increased in the Con among experimental group. The activities of aspartate aminotransferase(AST), alkaline phosphatase(ALP), and lactacte dehydrogenase(LDH) were significantly decreased(p$<$0.05) in the KHA and KHB compared with Con. Alpha fetoprotein(AFP) were the most increased in the Con among experimental groups. The activities of superoxide dismutase(SOD) were the most increased in the Con among experimental groups. The activities of catalase were significantly increased(p$<$0.05) in the KHA and KHB compared with Con. The results of light microscopical observation, a number of hepatocytes were damaged in the Con compared with Nor and KH extract administerd groups. The number of hepatic p53 positive cells was reduced in the KH extract administered groups compared with Con. These results suggest that administration of KH extract suppress or retard on the Hepatocellular Carcinogenesis and acute liver damage induced by DENA and $CCl_4$ in Rats.

The Effect of the Curcumae Longae Rhizoma (CLR) Extract on the Hepatocellular Carcinogenesis and Acute Liver Damage Induced by Diethylnitrosamine (DENA) and CCl4 in Rats (강황추출물이 Diethylnitrosamine과 CCl4로 유발된 흰쥐의 간암과 간 손상에 미치는 영향)

  • Jung, Tae-San;Choi, Chang-Won
    • Herbal Formula Science
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    • v.22 no.1
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    • pp.177-192
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    • 2014
  • Objective : In order to investigate the effect of Curcumae Longae Rhizoma(CLR) extract on the hepatocellular carcinogenesis and acute liver damage induced by diethylnitrosamine(DENA) and $CCl_4$ in rats. Methods : Experimental groups were subdivided into four; normal group (Nor), acute liver damage and hepatocellular cancer inducing control group (Con), and CLR extract 200mg/kg/day (CAA) or 400mg/kg/day (CAB) administered groups to Con. Thereafter the changes of the body weight, the liver weight and the weight of liver/100g body weight, total cholesterol, HDL cholesterol, triglyceride, the activities of AST, ALT, ALP, LDH, AFP, SOD, catalase were measured. And we observed by optical and electron microscopy. Result : 1. The body weight was decreased in Con compared with Nor for 5 weeks, but increased in Con compared with Nor from 6 week to 9 week. During experimental period of total 9 weeks, CAA and CAB were increased compared with Con. 2. The liver weight was increased significantly (p<0.05) in Con compared with Nor. The weight of liver/100g body weight was increased significantly (p<0.05) in Con compared with Nor and decreased significantly (p<0.05) in CAB compared with Con. 3. The level of total cholesterol was increased in Con and CAA compared with Nor, but there was not statistically significant. The level of triglyceride was decreased in Con compared with Nor. But increased in CAA and CAB compared with Con. The level of HDL-cholesterol was significantly increased (p<0.05) in CAA and CAB compared with Con. 4. The activities of AST, ALT were increased in Con compared with Nor, but decreased in CAA compared with Con, significantly decreased (p<0.05) in CAB compared with Con. 5. The activities of ALP, LDH were increased in Con compared with Nor, but decreased in CAA and CAB compared with Con. 6. The activities of AFP was increased significantly (p<0.05) in Con compared with Nor, but decreased significantly (p<0.05) in CAA and CAB compared with Con. 7. The activities of SOD were increased in Con, CAA and CAB compared with Nor, but decreased in CAA and CAB compared with Con. The activities of Catalase was more increased in CAA and CAB compared than Con. 8. The results of light microscopical observation, a number of hepatocytes were damaged in Con compared with Nor and CAB. 9. According to the electron microscopical observation, irregular nuclear membrane, condensed nucleoplasm was observed in Con, the experimental group was observed in the nucleus of the well-preserved and evenly developed nucleoplasm. Conclusions : These results suggest that administration of CLR extract suppress or retard on the hepatocellular carcinogenesis and acute liver damage induced by DENA and $CCl_4$ in rats.