• Asian Pacific Journal of Cancer Prevention
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• 제16권5호
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• pp.1821-1825
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• 2015

Background: Associations between the NQO1 C609T polymorphism and hepatocellular carcinoma (HCC) risk are a subject of debate. We therefore performed the present meta-analysis to evaluate links with HCC susceptibility. Materials and Methods: Several major databases (PubMed, EBSCO), the Chinese national knowledge infrastructure (CNKI) and the Wanfang database were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of associations. Results: A total of 4 studies including 1,325 patients and 1,367 controls were identified. There was a significant association between NQO1 C609T polymorphism and HCC for all genetic models (allelic model: OR=1.45, 95%CI=1.23-1.72, p<0.01; additive model: OR=1.96, 95%CI=1.57-2.43, p<0.01; dominant model: OR=1.62, 95%CI=1.38-1.91, p<0.01; and recessive model: OR=1.53, 95%CI=1.26-1.84, p<0.01). On subgroup analysis, similarly results were identified in Asians. For Asians, the combined ORs and 95% CIs were (allelic model: OR=1.50, 95%CI=1.24-1.82, p<0.01; additive model: OR=2.11, 95%CI=1.48-3.01, p<0.01; dominant model: OR=1.69, 95%CI=1.42-2.02, p<0.01; and recessive model: OR=1.59, 95%CI=1.16-2.19, p<0.01). Conclusions: The current meta-analysis suggested that the NQO1 C609T polymorphism could be a risk factor for developing HCC, particularly in the Chinese population.

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.3009-3014
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• 2015

The epidermal growth factor (EGF) may play a pathological role in hepatocellular carcinoma (HCC). However, the conclusions of published reports on the relationship between the EGF $61^*A/G$ polymorphism and HCC risk remain controversial. To derive a more precise estimation we performed a meta-analysis based on 14 studies that together included 2,506 cases and 4,386 controls. PubMed, EMBASE, Web of Knowledge and the Chinese National Knowledge Infrastructure (CNKI) databases were used to retrieve articles up to August 1, 2014. The crude odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated to evaluate the association. Meta-analysis results showed a significant association between the EGF $61^*A/G$ polymorphism and HCC risk in all four genetic models (allele model: OR=1.25, 95%CI=1.12-1.40; dominant model: OR=1.32, 95%CI=1.14-1.54; recessive model: OR=1.33, 95%CI=1.12-1.58; ho-mozygous model: OR=1.59, 95%CI=1.33-1.90). Moreover, significant associations were observed when stratified by ethnicity, source of controls, etiology and genotype methods. Thus, this meta-analysis suggests that the G-allele of the EGF $61^*A/G$ polymorphism is associated with an increased risk of HCC, especially in Asians and Caucasians, without influence from the source of controls or etiological diversity. Further studies with larger population sizes are needed to confirm these results.

• Asian Pacific Journal of Cancer Prevention
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• 제15권4호
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• pp.1649-1654
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• 2014

Background: Clinically significant portal hypertension (PHT) is considered as a contraindication for hepatectomy according to the guidelines of the European Association for Study of Liver and the American Association for Study of Liver Diseases. However, this issue remains controversial. Here we performed a metaanalysis to evaluate the impact of PHT on the results of hepatectomy for hepatocellular carcinoma (HCC). Methods: Cohort studies evaluating the impact of clinically significant PHT, defined as oesophageal varices and/or splenomegaly associated with thrombocytopenia, on the results of hepatectomy for HCC were identified using a predefined search strategy. Summary risk ratios (RRs) and 95% confidence intervals (95% CIs) for PHT and outcomes after hepatectomy for HCC were calculated. Results: Seven cohort studies which including 574 cases with PHT and 1,354 cases without PHT were considered eligible for inclusion. The meta-analysis showed that, in all patients, pooled RRs of post-operative liver failure, post-operative ascites, peri-operative blood transfusion, operative mortality, 3- and 5-year overall survival associated with PHT were 2.23 (95% CI: 1.48-3.34, P=0.0001), 1.77 (95% CI: 1.19-2.64, P=0.005), 1.23 (95% CI: 1.03-1.49, P=0.03), 2.58 (95% CI: 1.12-5.96, P=0.03), 0.82 (95% CI: 0.75-0.88, P<0.00001) and 0.76 (95% CI: 0.69-0.85, P<0.00001), respectively. In subgroup analysis, similar results were found in Child-Pugh class A patients. Conclusion: This meta-analysis suggests that presence of oesophageal varices and/or splenomegaly associated with thrombocytopenia is associated with higher rates of post-operative complications and poor long-term survival after hepatectomy for HCC.

• Asian Pacific Journal of Cancer Prevention
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• 제14권5호
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• pp.3045-3050
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• 2013

Purpose: Hepatic resection is arguably the preferred treatment for huge hepatocellular carcinoma (H-HCC). Estimating the remnant liver volume is therefore essential. This study aimed to evaluate the feasibility of using computer-assisted volumetric analysis for this purpose. Methods: The study involved 40 patients with H-HCC. Laboratory examinations were conducted, and a contrast CT-scan revealed that 30 cases out of the participating 40 had single-lesion tumors. The remaining 10 had less than three satellite tumors. With the consensus of the team, two physicians conducted computer-assisted 3D segmentation of the liver, tumor, and vessels in each case. Volume was automatically computed from each segmented/labeled anatomical field. To estimate the resection volume, virtual lobectomy was applied to the main tumor. A margin greater than 1 cm was applied to the satellite tumors. Resectability was predicted by computing a ratio of functional liver resection (R) as (Vresected-Vtumor)/(Vtotal-Vtumor) x 100%, applying a threshold of 50% and 60% for cirrhotic and non-cirrhotic cases, respectively. This estimation was then compared with surgical findings. Results: Out of the 22 patients who had undergone hepatectomies, only one had an R that exceeded the threshold. Among the remaining 18 patients with non-resectable H-HCC, 12 had Rs that exceeded the specified ratio and the remaining 6 had Rs that were < 50%. Four of the patients who had Rs less than 50% underwent incomplete surgery due to operative findings of more extensive satellite tumors, vascular invasion, or metastasis. The other two cases did not undergo surgery because of the high risk involved in removing the tumor. Overall, the ratio of functional liver resection for estimating resectability correlated well with the other surgical findings. Conclusion: Efficient pre-operative resectability assessment of H-HCC using computer-assisted volumetric analysis is feasible.

• BMB Reports
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• 제57권2호
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• pp.98-103
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• 2024

The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7675-7679
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• 2013

Background: A missense mutation in exon 7 (R249S) of the p53 tumor suppressor gene is characteristic of aflatoxin B1 (AFB1) exposure. AFB1 is believed to have a synergistic effect on hepatitis virus B (HBV) carcinogenesis. However, results of studies comparing R249S prevalence among patients are conflicting. The aim of this study was to determine the prevalence of the R249S mutation in hepatocellular carcinoma (HCC) patients with or without positive HBsAg. Materials and Methods: Paraffin embedded liver tissues were obtained from 124 HCC patients who underwent liver resection and liver biopsy in King Chulalongkorn Memorial Hospital. Restriction fragment length polymorphism (RFLP) was utilized to detect the R249S mutation. Positive results were confirmed by direct sequencing. Results: Sixty four (52%) patients were positive for HBsAg and 18 (15%) were anti-HCV positive. 12 specimens tested positive by RFLP. Ten HCC patients (8.1%) were confirmed to be R249S positive by Sanger sequencing (AGG to AGT). Out of these 10, six were HBsAg positive, and out of the remaining 4, two were anti-HCV positive. The R249S prevalence among HCC patients with positive HBsAg was 9.4% compared to 6.7% for HBsAg negative samples. Patients with the R249S mutation were younger ($55{\pm}10$ vs $60{\pm}13$ year-old) and tended to have a more advanced Edmonson-Steiner grade of HCC, although differences did not reach statistical significance. Conclusions: Our study shows moderate prevalence of aflatoxin B1-related p53 mutation (R249S) in HCC with or without HBsAg. HBsAg positive status was not associated with R249S prevalence.

• Asian Pacific Journal of Cancer Prevention
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• 제14권10호
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• pp.5761-5767
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• 2013

The potential correlation of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism with hepatocellular carcinoma (HCC) susceptibility is ambiguous. Taking account of inconsistent results of previous meta-analyses and new emerging literatures, we conducted a meta-analysis covering 15 case-control datasets to evaluate the relationship. Relevant studies from Medline, Embase and CNKI were retrieved. A fixed-effect model or a random-effect model, depending on between-study heterogeneity, were applied to estimate the association between XRCC1 polymorphism Arg399Gln and HCC risk with the results presented as odds ratios (ORs) and 95% confidence intervals (95% CIs). In accordance with Hardy-Weinberg equilibrium, 15 studies with data for 6,556 individuals were enrolled in this systematic review. For overall HCC,thr XRCC1 polymorphism Arg399Gln was significantly associated with HCC susceptibility in a homozygote model as well as in a dominant model (G/G vs. A/A, OR=1.253, p=0.028; G/G+A/G vs. A/A, OR= 1.281, p=0.047, respectively), but not in a heterozygote model (A/G vs. A/A, OR=1.271, p=0.066) or a recessive model (G/G vs. A/G + A/A, OR= 1.049, p=0.542). Similar results were also observed on stratification analysis by ethnicity (A/G vs. A/A, OR=1.357, p=0.025; G/G vs. A/A, OR=1.310, p=0.011; G/G+A/G vs. A/A, OR= 1.371, p=0.013). However, no potential contribution of XRCC1 Arg399Gln polymorphism to HCC susceptibility in HBV/HCV subgroups was identified. No publication bias was found in this study. In conclusion, the XRCC1 Arg399Gln polymorphism contributes to HCC susceptibility. Due to the lack of studies in Western countries, further large-sample and rigorous studies are needed to validate the findings.

• The Korean Journal of Physiology and Pharmacology
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• 제7권1호
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• pp.29-31
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• 2003

It is well known that different expression of Apo-1/Fas (CD95) plays important roles in various tumors and hepatocellular carcinoma (HCC) pathogenesis. Apo-1/Fas mediated apoptosis is one of the important pathways of apoptosis and is known to mediate apoptotic cell death by fas ligand (FasL). To examine the possible relationship between Apo-1/Fas gene polymorphism and HCC susceptibility, MvaI restriction fragment length polymorphism (RFLP) of Apo-1/Fas gene was examined in 94 Korean HCC patients and 240 control subjects. No statistically significant difference in the genotypic distribution and allelic frequencies was found between the control and the HCC. It is, therefore, concluded that Apo-1/Fas gene polymorphism is not associated with HCC susceptibility. Further studies are needed in order to clarify the relationships between genotypes of Apo-1/Fas gene and HCC pathogenesis.

• BMB Reports
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• 제55권11호
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• pp.547-552
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• 2022

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

• Asian Pacific Journal of Cancer Prevention
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• 제14권5호
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• pp.3275-3279
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• 2013

Background: Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) plays a very important role in the development and progression of cancer. Many epidemiological studies have evaluated associations between the TNF-${\alpha}$ 238 G/A polymorphism and hepatocellular carcinoma (HCC) risk, but the published data are inconclusive. Therefore, we performed the present meta-analysis. Methods: Electronic searches of several databases were conducted for all publications on the association between TNF-${\alpha}$ 238 G/A polymorphism and HCC through July 2012. Asummary odds ratio (OR) with its 95% confidence interval (CI) were calculated to evaluate the strength of this association. Results: Eleven case-control studies with a total of 1,572 HCC cases and 1,875 controls were finally included in this meta-analysis. Overall, the TNF-${\alpha}$ 238 G/A polymorphism was significantly associated with increased risk of hepatocellular carcinoma in three genetic comparison models (For A versus G: OR 1.32, 95%CI 1.04-1.69, P = 0.02, $I_2$ = 40%; for AG versus GG: OR 1.32, 95%CI 1.02-1.71, P = 0.03, $I_2$ = 40%; for AA/AG versus GG: OR 1.33, 95%CI 1.03-1.72, P = 0.03, $I_2$ = 41%) when all studies were pooled. Subgroup analysis by ethnicity further showed that there was a significant association between the TNF-${\alpha}$ 238 G/A polymorphism and risk of HCC in Asians under three genetic comparison models (For A versus G: OR 1.30, 95%CI 1.00-1.68, P = 0.05, $I_2$ = 45% for AA/AG versus GG: OR 1.31, 95%CI 1.00-1.71, P = 0.05, $I_2$ = 46%). Conclusions: This meta-analysis provided convincing evidence that the TNF-${\alpha}$ 238 G/A polymorphism is associated with increased susceptibility to HCC. However, more well-designed studies with large sample size are needed to validate this association in Caucasians.