• Journal of Cancer Prevention
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• v.23 no.4
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• pp.170-175
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• 2018

Background: Human hepatocellular carcinoma (HCC) is a common liver tumor and the main cause of cancer-related death. Tyrosine kinase inhibitors, such as imatinib and GNF5 which were developed to treat chronic myelogenous leukemia, regulate the progression of various cancers. The aim of this study was to confirm the anti-tumor activity of tyrosine kinase inhibitors through regulation of S-phase kinase-associated protein 2 (Skp2), an important oncogenic factor in various cancer cells, in human hepatocarcinoma SK-HEP1 cells. Methods: Cell viability and colony formation assays were conducted to evaluate the effects of imatinib, GNF5 and GNF2 on the growth of SK-HEP1 cells. Using immunoblot analysis, we assessed change of the activation of caspases, PARP, Akt, mitogen-activated protein kinases, and Skp2/p27/p21 pathway by imatinib and GNF5 in SK-HEP1 cells. Using sh-Skp2 HCC cells, the role of Skp2 in the effects of imatinib and GNF5 was evaluated. Results: Imatinib and GNF5 significantly inhibited the growth of SK-HEP1 cells. Treatment of imatinib and GNF5 decreased Skp2 expression and Akt phosphorylation, and increased the expression of p27, p21, and active-caspases in SK-HEP1 cells. In sh-Skp2 HCC cells, cell growth and the expression of Skp2 were inhibited by more than in the mock group treated with imatinib and GNF5. Conclusions: These results suggest that the anti-growth activity of tyrosine kinase inhibitors may be associated with the regulation of p27/p21 and caspases through Skp2 blockage in HCC cells.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4305-4309
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• 2012

Background: Previous studies on the association between the TP53 Arg72Pro polymorphism and hepatocellular carcinoma (HCC) risk obtained controversial findings. This study aimed to quantify the strength of the association by meta-analysis. Methods: We searched PubMed and Wangfang databases for published studies on the association between the TP53 Arg72Pro polymorphism and HCC risk, using the pooled odds ratio (OR) with its 95% confidence intervals (95% CI) for assessment. Results: 10 studies with a total of 2,026 cases and 2,733 controls were finally included into this meta-analysis. Overall, the TP53 Arg72Pro polymorphism was not associated with HCC risk (all P values greaterth HCC risk in Caucasians in three genetic models (For Pro versus Arg, OR = 1.20, 95%CI 1.03-1.41; For ProPro versus ArgArg, OR = 1.74, 95%CI 1.23-2.47; For ProPro versus ArgPro/ArgArg, OR = 1.85, 95%CI 1.33-2.57). However, there was no significant association between the TP53 Arg72Pro polymorphism and HCC risk in East Asians (all P values greater than 0.10). No evidence of publication bias was observed. Conclusion: Meta-analyses of available data suggest an obvious association between the TP53 Arg72Pro and HCC risk in Caucasians. However, the TP53 Arg72Pro polymorphism may have a race-specific effect on HCC risk and further studies are needed to elucidate this possible effect.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.10
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• pp.4303-4310
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• 2015

Rumex vesicarius is an edible herb distributed in Egypt and Saudi Arabia. The whole plant has significant value in folk medicine and it has been used to alleviate several diseases. Hepatocellular carcinoma (HCC), the major primary malignant tumor of the liver, is one of the most life-threatening human cancers. The goal of the current study was to explore the potent role of Rumex vesicarius extract against HCC induced in rats. Thirty adult male albino rats were divided into 3 groups: (I): Healthy animals received orally 0.9 % normal saline and served as negative control group, (II): HCC group in which rats were orally administered N-nitrosodiethylamine NDEA, (III): HCC group treated orally with R. vesicarius extract in a dose of 400 mg/kg b.wt daily for two months. ALT and AST, ALP and ${\gamma}$-GT activities were estimated. CEA, AFP, AFU, GPC-3, Gp-73 and VEGF levels were quantified. Histopathological examination of liver tissue sections was also carried out. The results of the current study showed that the treatment of the HCC group with R. vesicarius extract reversed the significant increase in liver enzymes activity, CEA, AFP, AFU, glypican 3, golgi 73 and VEGF levels in serum as compared to HCC-untreated counterparts. In addition, the favorable impact of R. vesicarius treatment was evidenced by the marked improvement in the histopathological features of the liver of the treated group. In conclusion, the present experimental setting provided evidence for the significance of R. vesicarius as anticancer candidate with a promising anticancer potential against HCC. The powerful hepatoprotective properties, the potent antiangiogenic activity and the effective antiproliferative capacity are responsible for the anticancer effect of this plant.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.8
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• pp.4913-4918
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• 2013

Objective: To assess the level of an inpatient population's awareness about hepatitis and primary liver cancer (PLC), the most common type of which is hepatocellular carcinoma (HCC), and then to initiate education of this group. Methods: A survey was conducted with 1300 participants within the inpatient unit in representative tertiary hospitals in the Chaoshan area of China. Structured questionnaires contained demographic data and statements about different aspects of liver cancer and hepatitis. The questionnaires were completed by trained medical practitioners after they had conducted the interviews. Results: One way ANOVA showed that the sample population lacked adequate knowledge about HCC and hepatitis. Stepwise multiple regression analysis demonstrated that the participant's level of education had the greatest impact on their total knowledge score when other variables remained constant. Conclusions: The study demonstrated: a general lack of awareness amongst the participants about the preventative strategies, and the management options available for people with primary liver cancer and hepatitis; education level was an important factor affecting knowledge levels. The demonstrated deficiencies in people's knowledge about hepatitis and HCC, and their lack of subsequent protective behaviours are likely to play an important role in HCC and hepatitis transmission or prevention.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.13
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• pp.5343-5348
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• 2015

Promoter hypermethylation of the runt-related transcription factor 3 (RUNX3) gene is associated with increased risk of hepatocellular carcinoma (HCC). Oxidative stress plays a vital role in both carcinogenesis and progression of HCC. However, whether oxidative stress and RUNX3 hypermethylation in HCC have a cause-and-effect relationship is not known. In this study, plasma protein carbonyl and total antioxidant capacity (TAC) in patients with hepatitis B virus (HBV)-associated HCC (n=60) and age-matched healthy subjects (n=80) was determined. RUNX3 methylation in peripheral blood mononuclear cells (PBMC) of subjects was measured by methylation-specific PCR. Effect of reactive oxygen species (ROS) on induction of RUNX3 hypermethylation in HCC cells was investigated. Plasma protein carbonyl content was significantly higher, whereas plasma TAC was significantly lower, in HCC patients than healthy controls. Based on logistic regression, increased plasma protein carbonyl and decreased plasma TAC were independently associated with increased risk for HCC. PBMC RUNX3 methylation in the patient group was significantly greater than in the healthy group. RUNX3 methylation in hydrogen peroxide ($H_2O_2$)-treated HepG2 cells was significantly higher than in untreated control cells. In conclusion, increase in oxidative stress in Thai patients with HBV-associated HCC was demonstrated. This oxidative increment was independently associated with an increased risk for HCC development. RUNX3 in PBMC was found to be hypermethylated in the HCC patients. In vitro, RUNX3 hypermethylation was experimentally induced by $H_2O_2$. Our findings suggest that oxidative stress is a cause of RUNX3 promoter hypermethylation in HCC cells.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.2865-2869
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• 2013

Hepatitis B virus (HBV) infection can become chronic and if left untreated can progress to hepatocellular carcinoma (HCC).Thailand is endemic for HBV and HCC is one of the top five cancers, causing deaths among Thai HBV-infected males. A single nucleotide polymorphism (SNP) at the KIF1B gene locus, rs17401966, has been shown to be strongly associated with the development of HBV-related HCC. However, there are no Thai data on genotypic distribution and allele frequencies of rs17401966. Thai HBV patients seropositive for HBsAg (n=398) were therefore divided into two groups: a case group (chronic HBV with HCC; n=202) and a control group (HBV carriers without HCC; n=196). rs17401966 was amplified by polymerase chain reaction (PCR) and analyzed by direct nucleotide sequencing. The genotypic distribution of rs174019660 for homozygous major genotype (AA), heterozygous minor genotype (AG) and homozygous minor genotype (GG) in the case group was 49.5% (n=100), 40.1% (n=81) and 10.4% (n=21), respectively, and in controls was 49.5% (n=97), 42.3% (n=83) and 8.2% (n=16). Binary logistic regression showed that rs17401966 was not statistically associated with the risk of HCC development in Thai chronic HBV patients (p-value=0.998, OR=1.00 and 95% CI=0.68-1.48). In conclusion, the KIF1B gene SNP (rs174019660) investigated in this study showed no significant association with HBV-related HCC in Thai patients infected with HBV, indicating that there must be other mechanisms or pathways involved in the development of HCC.

• 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.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.1051-1056
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• 2015

Aberrant expression of genes in de novo lipogenesis (DNL) pathway were associated with various cancers, including hepatocellular carcinoma (HCC). Single nucleotide polymorphisms (SNPs) of DNL genes have been reported to be associated with prognosis of some malignancies. However, the effects of SNPs in DNL genes on overall survival of HCC patients receiving transarterial chemoembolization (TACE) treatment are still unknown. In present study, nine SNPs in three genes (ACLY, ACACA and FASN) in DNL pathway were genotyped using the Sequenom iPLEX genotyping system in a hospital-based cohort with 419 HCC patients treated with TACE, and their associations with HCC overall survival were evaluated by Cox proportional hazard regression analysis under three genetic models (additive, dominant and recessive). Although we did not find any significant results in total analysis (all p>0.05), our stratified data showed that SNP rs9912300 in ACLY gene was significantly associated with overall survival of HCC patients with lower AFP level and SNP rs11871275 in ACACA gene was significantly associated with overall survival of HCC patients with higher AFP level. We further identified the significant interactions between AFP level and SNP rs9912300 or rs11871275 in the joint analysis. Conclusively, our data suggest that genetic variations in genes of DNL pathway may be a potential biomarker for predicting clinical outcome of HCC patients treated with TACE.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.2033-2036
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• 2013

Many studies have suggested that the XRCC1 Arg280His gene polymorphism might be involved in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to assess the association between XRCC1 Arg280His and HCC susceptibility. Published literature from PubMed, EMBASE and CNKI Data was searched. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models when appropriate. Begg's test was used to measure publication bias. A total of 7 case-control studies covering 1,448 HCC cases and 1,544 controls were included. No significant variation in HCC risk was detected in any of the genetic models overall. In the stratified analysis, four studies with sample sizes over 300 produced similar results. The corresponding pooled ORs were not substantially altered after the exclusion of three studies deviating from Hardy-Weinberg equilibrium in the control group, which indicated reliability for our meta-analysis results.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6023-6026
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• 2012

The incidence of hepatocellular carcinoma (HCC) in Malaysia for the year 2001 was 2.8 per 100,000 people. The mortality rate is increasing. A retrospective cohort study measuring the survival of HCC patients who received treatment in Selayang Hospital was conducted from 1 January 2003 to 31 December 2006. The main objectives of the study were to measure the survival of the patients and to understand the influencing factors, especially ethnicity. The subjects were newly diagnosed cases of HCC by CT scan and histopathological assessment who underwent futher investigations and treatments in Hospital Selayang (inception cohort). The survival time was measured from the date of diagnosis until the subjects died, or failed to follow-up at the end of the study period (31 December 2007). A total of 299 patients were selected with 95 patients dying, the majority among Chinese (39.1%). Subgroup analysis according to ethnicity proved significantly that Chinese patients who had smaller tumor, less number of nodules, low AFP level, Child Pugh Class A and received surgical treatment had a better median survival rate compared to other ethnic groups. Malay (cHR: 1.3, 95%CI; 0.89-1.85) and Indian (cHR: 1.3, 95%CI; 0.74-2.26) patients had a poor survival compared to Chinese patients, but not in the final model. Therefore ethnicity may play a role in survival of HCC patients, but not as a main hazard prognostic factor.