• Molecular & Cellular Toxicology
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• v.5 no.3
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• pp.193-197
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• 2009

Suppressors of cytokine signaling (SOCS) proteins were originally identified as negative feedback regulators of cytokine signaling and include the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathways. Recent studies have shown that SOCS proteins negatively regulate the receptor tyrosine kinase (RTK) pathway including the insulin receptor (IR), EGFR, and KIT signaling pathways. In addition, SOCS1 and SOCS3 have been reported to have anti-tumor effects in human hepatocellular carcinoma (HCC). However, it is uncertain whether other members of the SOCS family are associated with tumor development and progression. In this study, to investigate whether SOCS6 is aberrantly regulated in HCC, we examined the expression level of SOCS6 in HCC by Western blot analysis and immunohistochemical staining. The results showed that SOCS6 was down-regulated in all examined HCCs compared to the corresponding normal tissues. In addition, expression of SOCS6 was observed in the cytoplasm of most normal and precancerous tissue, but not in the HCCs by immunohistochemical staining. This is first report to demonstrate that SOCS6 is aberrantly regulated in HCC. These findings suggest that underexpression of SOCS6 is involved in hepatocarcinogenesis, and SOCS6 may play a role, as a tumor suppressor, in HCC development and progression.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.12
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• pp.5069-5073
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• 2015

The single nucleotide polymorphism (SNP) rs1053004 in Signal transducer and activator of transcription 3 (STAT3) was recently reported to be associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) in a Chinese cohort. This study was aimed at investigating whether the SNP might also contribute to HCC susceptibility in the Thai population. Study subjects were enrolled and divided into 3 groups including CHB-related HCC (n=211), CHB without HCC (n=233) and healthy controls (n=206). The SNP was genotyped using allelic discrimination assays based on TaqMan real-time PCR. Data analysis revealed that the distribution of different genotypes was in Hardy-Weinberg equilibrium (P>0.05). The frequencies of allele T (major allele) in HCC patients, CHB patients and healthy controls were 51.4%, 58.6% and 61.4%, respectively, whereas the frequencies of C allele (minor allele) were 48.6%, 41.4% and 38.6%. The C allele frequency was higher in HCC when compared with CHB patients (odds ratio (OR)=1.34, 95% confidence interval (CI)=1.02-1.74, P=0.032). The genotype of SNP rs1053004 (CC versus TT+TC) was significantly associated with an increased risk when compared with CHB patients (OR=1.83, 95% CI=1.13-2.99, P=0.015). In addition, we observed a similar trend of association when comparing HCC patients with healthy controls (OR=1.77, 95% CI=1.07-2.93, P=0.025) and all controls (OR=1.81, 95% CI=1.19-2.74, P=0.005). These findings suggest that the SNP rs1053004 in STAT3 might contribute to HCC susceptibility and could be used as a genetic marker for HCC in the Thai population.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.13
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• pp.5541-5547
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• 2015

Background: The role of surgical resection for patients with single large (${\geq}5cm$) and/or multinodular (${\geq}2$) hepatocellular carcinoma (HCC) is still controversial. This systematic review was performed to evaluate the safety and efficacy of resection for patients with single large and/or multinodular HCC. Materials and Methods: Databases (the PubMed, Web of Science, Embase, and Cochrane databases) were systematically searched to identify relevant studies exploring the safety and efficacy of resection for single large and/or multinodular HCC, published between January 2000 and December 2014. Perioperative morbidity and mortality, overall survival, and disease-free survival of the resection group were calculated. In addition, these outcome variables were also calculated for the control group in the included studies. Results: One randomized controlled trial and 42 nonrandomized studies involving 9,580 patients were eligible for analysis. Eight (1,594 patients) of the 43 studies also reported the outcomes of transarterial chemoembolization (TACE). Although 51.4% of patients featured cirrhosis, 90.7% of them demonstrated Child-Pugh A liver function in the resection group. The median rates of morbidity (24.5%) and mortality (2.5%) after resection were significantly higher than that of TACE (11.0%, P<0.001; 1.9%, P<0.001). However, patients who underwent resection had significantly higher median one-, three-, and five-year overall survival (76.1%, 51.7%, and 37.4%) than those who underwent TACE (68.3%, 31.5%, and 17.5%, all P<0.001). The median 1-, 3-, and 5-year DFS rates after resection were 58.3%, 34.6%, and 24.0%, respectively. Conclusions: Although tumor recurrence after resection for patients with single large and/ or multinodular HCC continues to be a major problem, resection should be considered as a strategy to achieve long-term survival.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.2979-2986
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• 2014

Background: Recently, peroxiredoxin3 (PRDX3) was identified as a novel molecular marker for the progression of hepatocellular carcinoma (HCC). However, its potential clinical application as a serum marker for the early diagnosis and prognosis of HCC has not been investigated. Methods: PRDX3, alpha-fetaprotein (AFP), and other biochemical parameters were measured in serum samples from 297 Chinese patients, including 96 with HCC, 98 with liver cirrhosis (LC), and 103 healthy controls (HCs). Correlations between serum PRDX3 expression and clinicopathological variables and the relationship between serum PRDX3 expression and prognosis were analyzed. Results: Serum PRDX3 was significantly higher in HCC patients than in the LC and HC groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 85.9% and 75.3%, respectively, at a cutoff of 153.26 ng/mL, and the area under the curve was 0.865. Moreover, serum PRDX3 expression was strongly associated with AFP level, tumor diameter, TNM stage, and portal vein invasion. Kaplan-Meier curve analysis revealed that HCC patients with high serum PRDX3 expression had a shorter median survival time than those with low PRDX3 expression. Moreover, serum PRDX3 expression was an independent risk factor for overall survival. The inverse correlation between serum PRDX3 and patient survival remained significant in patients with early-stage HCC and in those with normal serum AFP levels. Conclusions: Serum PRDX3 can be used as a noninvasive biomarker for the diagnosis and/or prognosis of HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3151-3156
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• 2014

Background: Sorafenib is a promising drug for advanced hepatocellular carcinoma (HCC); however, treatment may be discontinued for multiple reasons, such as progressive disease, adverse events, or the cost of treatment. The consequences of sorafenib discontinuation and continuation are uncertain. Materials and Methods: We retrospectively analyzed 88 HCC patients treated with sorafenib from July 2007 to January 2013. Overall survival (OS), post-disease progression overall survival (pOS), and time to disease progression (TTP) were compared for survival analysis. Cox proportional hazard regression was performed to assess the effect of important factors on OS in the overall patient population and on pOS in patients who continued sorafenib treatment. Results: Sorafenib was discontinued and continued in 24 and 64 patients, respectively. The median OS (355 vs 517 days respectively; p=0.015) and median post-PD OS (260 vs 317 days, respectively; p=0.020) were statistically different between the discontinuation and continuation groups. Neither the median time to first PD nor the time to second PD were significantly different between the 2 groups. In the discontinuation group, 3 of the 24 patients (12.5%) suffered disease outbreaks. In Cox proportional hazard regression analysis after correction for confounding factors, BCLC stage (p=0.002) and PD site (p=0.024) were significantly correlated with pOS in patients who continued sorafenib treatment. Conclusions: Sorafenib discontinuation may cause HCC flares or outbreaks. It is advisable to continue sorafenib treatment after first PD, particularly in patients with Barcelona Clinic Liver Cancer stage B disease or only intrahepatic PD.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.1961-1970
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• 2014

Pyruvate kinase isozyme type M2 (PKM2) was first found in hepatocellular carcinoma (HCC), and its expression has been thought to correlate with prognosis. A large number of studies have demonstrated that epithelial-mesenchymal transition (EMT) is a crucial event in hepatocellular carcinoma (HCC) and associated metastasis, resulting in enhanced malignancy of HCC. However, the roles of PKM2 in HCC EMT and metastasis remain largely unknown. The present study aimed to determine the effects of PKM2 in EGF-induced HCC EMT and elucidate the molecular mechanisms in vitro. Our results showed that EGF promoted EMT in HCC cell lines as evidenced by altered morphology, expression of EMT-associated markers, and enhanced invasion capacity. Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by the ERK pathway, regulated ${\beta}$-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines. These discoveries provide evidence of novel roles of PKM2 in the progression of HCC and potential therapeutic target for advanced cases.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.13
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• pp.5155-5160
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• 2014

Aim: To investigate the efficacy and safety of lobaplatin-transcatheter arterial chemoembolization (TACE) combined with radioactive $^{125}I$ seed implantation in treatment of primary hepatocellular carcinoma (HCC). Methods: 75 patients with primary HCC were enrolled in the study, among them 43 receiving lobaplatin-TACE (TACE group) and 32 lobaplatin-TACE combined with $^{125}I$ seed implantation (TACE+$^{125}I$ group). After treatment, the local remission rates and postoperative complications of two groups were compared using the Pearson Chi-square test. Overall survival in the two groups was calculated using Kaplan-Meier survival curves and the differences were tested using Log-rank test. Results: There were 7 cases of complete response (CR), 13 of partial response (PR), 6 of stable disease (SD) and 17 of progressive disease (PD) in the TACE group, with 13 cases of CR, 9 of PR, 5 of SD and 5 of PD in the TACE+$^{125}I$ group. The disease control rates of TACE and TACE+$^{125}I$ group were 60.5% (26/43) and 84.4% (27/32), respectively, with a significant difference between them (P < 0.05). The survival rates at 6, 12 and 18 months in the TACE group were 100.0%, 81.8% and 50.0%, respectively, and those in TACE+$^{125}I$ group were 100.0%, 93.8% and 65.6%. The mean survival times in the TACE and TACE+$^{125}I$ groups were 19.5 and 22.9 months, respectively. There was a significant difference in the overall survival rate between two groups (P < 0.05). No serious complications were encountered in either group. Conclusion: Lobaplatin-TACE combined with $^{125}I$ seed implantation is favorable and safe for treatment of primary HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5995-6000
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• 2013

Background: Nausea and vomiting after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) are common in clinical practice, but few studies have reported the incidence and risk factors of such events. Objective: The purpose of this study was to analyze the incidence and risk factors of nausea and vomiting after TACE for HCC. Methods: This study was a single-center retrospective analysis of a prospectively maintained database. Between May 2010 and October 2012, 150 patients with HCC were analyzed for incidence and preprocedural risk factors. Results: The incidence of postembolization nausea and vomiting was 38.8% and 20.9%, respectively, in patients with HCC. Patients who developed nausea had lower levels (<100 IU/L) of serum alkaline phosphatase (ALP) compared to those without nausea ($123.04{\pm}69.38$ vs. $167.41{\pm}138.95$, respectively, p=0.044). Female gender correlated to a higher incidence of nausea as well (p=0.024). Patients who developed vomiting, compared to those who did not, also had lower levels (<100 IU/L) of serum ALP ($112.52{\pm}62.63$ vs. $160.10{\pm}127.80$, respectively, p=0.010), and serum alanine transferase (ALT) ($35.61{\pm}22.87$ vs. $4.97{\pm}29.62$, respectively, p=0.045). There were no statistical significances in the incidences of nausea and vomiting between male patients over 50 years old and female patients who have entered menopause (p=0.051 and p=0.409, respectively). Multivariate analysis by logistic regression analysis demonstrated that female gender and ALP>100 IU/L were the most independent predictive factors of postembolization nausea (odds ratio (OR): 3.271, 95% CI: 1.176-9.103, p=0.023 and OR: 0.447, 95% CI: 0.216-0.927, p=0.030, respectively). ALP>100 IU/L was also the most independent predictive risk factor of postembolization vomiting (OR: 0.389, 95% CI: 0.159-0.952, p=0.039). Conclusions: Postembolizaiton nausea and vomiting are common in patients with HCC. Recognition of the risk factors presented above before TACE is important for early detection and proper management of postembolization nausea and vomiting. Nevertheless, future studies are required.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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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.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.sup3
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• pp.219-224
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• 2016

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver making up more than 80 percent of cases. It is known to be the sixth most prevalent cancer and the third most frequent cause of cancer related death worldwide. Epigenetic regulation constitutes an important mechanism by which dietary components can selectively activate or inactivate target gene expression. The miR-34 family members including mir-34a, mir-34b and mir-34c are tumor suppressor micro RNAs, which are expressed in the majority of normal tissues. Several studies have indicated silencing of miR-34 expression via DNA methylation in multiple types of cancers. Bioactive nutrients like curcumin (Cur) have excellent anticarcinogenic activity and minimal toxic manifestations in biological systems. This compound has recently been determined to induce epigenetic changes. However, Cur is lipophilic and has a poor systemic bioavailability and poor absorption. Its bioavailability is increased through employing dendrosome nanoparticles. The aim of the current study was to investigate the effect of dendrosomal nanocurcumin (DNC) on expression of mir-34 family members in two HCC cell lines, HepG2 and Huh7. We performed the MTT assay to evaluate DNC and dendrosome effects on cell viability. The ability of DNC to alter expression of the mir-34 family and DNA methyltransferases (DNMT1, DNMT3A and 3B) was evaluated using semi-quantitative and quantitative PCR. We observed the entrance of DNC into HepG2 and Huh7 cells. Gene expression assays indicated that DNC treatment upregulated mir34a, mir34b and mir34c expression (P<0.05) as well as downregulated DNMT1, DNMT3A and DNMT3B expression (P<0.05) in both HepG2 and Huh7 cell lines. DNC also reduced viability of Huh7 and HepG2 cells through restoration of miR-34s expression. We showed that DNC could awaken the epigenetically silenced miR-34 family by downregulation of DNMTs. Our findings suggest that DNC has potential in epigenetic therapy of HCC.