Levels In Hepatocellular Carcinoma Research Articles

Rapid evolution of expression levels in hepatocellular carcinoma

One interesting and important question when comparing and analysing human evolution and cancer evolution is whether cancer susceptibility is related to human evolution. Since cancer is an evolution on a small time and space scale, we compared and analysed liver gene expression data among orangutan, chimpanzee, human, nontumour tissue, and primary cancer using linear mixed model, analysis of variance (ANOVA), gene ontology (GO), and human evolution based cancer gene expression analysis. Our results revealed not only rapid evolution of expression levels in hepatocellular carcinoma (HCC) relative to the gene expression evolution rate of human, but also the correlation between human specific gene expression and cancer specific gene expression. Further gene ontology analysis also suggested statistical relationship between gene function and expression pattern might help understanding the relationship between human evolution and cancer development.

The prognostic value of myeloid derived suppressor cell level in hepatocellular carcinoma: Asystematic review and meta-analysis.

Background and aimsMany studies have investigated the association between the level of myeloid derived suppressor cells (MDSCs) and clinical features and prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. This systematic review and meta-analysis was conducted to summarize all available data and estimate the relationship.MethodsA comprehensive literature review was carried out using Medline, Embase and Web of Science database through December 2018 to identify relevant studies. The standardized mean difference (SMD) and the hazard ratio (HR) with 95% confidence interval (CI) were utilized for evaluating continuous outcomes and survival analysis, respectively. All statistical analyses were performed by STATA 14.0 software.ResultsA total of 13 studies with 1002 HCC patients were included in the meta-analysis. Overall, the proportion of MDSCs in HCC patients was higher than that in healthy controls (SMD = 4.49, 95% CI = 2.53–6.46, P<0.001), and patients with chronic liver disease (SMD = 3.41, 95% CI = 1.58–5.24, P<0.001). Subgroup analysis based on the phenotypes of MDSCs and geographical areas showed similar results. However, the frequency of MDSCs was not affected by the treatment with conventional approaches for HCC (SMD = -0.25, 95% CI = -0.57–0.06, P = 0.119). Moreover, increased MDSCs level was significantly associated with poorer overall survival (HR = 2.36, 95% CI = 1.70–3.29, P<0.001) and recurrence-free survival (HR = 2.72, 95% CI = 1.70–4.35, P<0.001), but not significantly correlated with any clinicopathological parameters.ConclusionThe results of this systematic review suggest that elevated MDSCs level appears to be associated with an increased risk for disease progression and poor prognosis for HCC.

The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity

SummaryUbiquitin and ubiquitin-like chains are finely balanced by conjugating and de-conjugating enzymes. Alterations in this balance trigger the response to stress conditions and are often observed in pathologies. How such changes are detected is not well understood. We identify the HSP70 chaperone as a sensor of changes in the balance between mono- and poly-NEDDylation. Upon DNA damage, the induction of the de-NEDDylating enzyme NEDP1 restricts the formation of NEDD8 chains, mainly through lysines K11/K48. This promotes APAF1 oligomerization and apoptosis induction, a step that requires the HSP70 ATPase activity. HSP70 binds to NEDD8, and, in vitro, the conversion of NEDD8 chains into mono-NEDD8 stimulates HSP70 ATPase activity. This effect is independent of NEDD8 conjugation onto substrates. The study indicates that the NEDD8 cycle is a regulatory module of HSP70 function. These findings may be important in tumorigenesis, as we find decreased NEDP1 levels in hepatocellular carcinoma with concomitant accumulation of NEDD8 conjugates.

Prognostic role of serial alpha-fetoprotein levels in hepatocellular carcinoma treated with locoregional therapy

Background and aim: To evaluate early serial AFP changes in responders and non-responders to locoregional therapy and identify differences between significant AFP decliners and non-decliners post-treatment.Methods: Case records of hepatocellular carcinoma (HCC) patients having AFP ≥20 ng/ml and treated with locoregional therapy were examined retrospectively. Patients with complete details were included. Trends of serial AFP change (from baseline to post-treatment one month) in patients showing early tumor response (complete response (CR), partial response (PR), progressive disease (PD)) as assessed on multiphasic MRI/CT liver performed at one month following treatment. Receiver operating curves were drawn to estimate the best AFP reduction cut off for differentiating between responders (CR plus PR) from non-responders (PD). AFP decliners (those with AFP level reduction greater than 20% post-treatment) were identified and comparisons of their clinical parameters, tumor response and survival rate were made with AFP non-decliners.Results: HCC patients (n = 126) had mean age of 52.8 years, male:female ratio (4:1), Child’s A 94, BCLC stage A/B/C HCC 49/65/12, respectively. On 4–6 weeks’ MRI/CT, 46 patients developed CR, 55 PR and 25 PD. Reduction in median AFP level (83% in CR, 19% in PR) occurred in responders while 16% increase occurred in PD patients (non-responders). A 30% AFP reduction could differentiate responders from non-responders with 70% sensitivity and 68% specificity, AUROC 74% (CI 0.64–0.85). AFP decliners showed better survival and tumor response than non-decliners.Conclusions: Serial AFP change can predict tumor response to locoregional therapy in AFP producing HCC patients. AFP decliners have better survival and tumor response than AFP non-decliners.

Serum Serotonin as a Potential Diagnostic Marker for Hepatocellular Carcinoma.

To assess the potential role of serum serotonin level in hepatocellular carcinoma (HCC) diagnosis. A case-control study that involved 100 Egyptian adults. Subjects were divided into 4 groups: Group I: 21 patients with late-stage HCC on top of liver cirrhosis, Group II: 28 patients with early-stage HCC on top of liver cirrhosis, Group III: 26 patients with cirrhosis with no evidence of HCC, and Group IV: 25 healthy age- and sex-matched subjects were as a control group. Serum serotonin level was determined in all recruited subjects using high-performance liquid chromatography-fluorescent detection method. Alpha-fetoprotein had a statistically significant elevation in group I with a median of 1300 ng/L (195-2544 ng/L) compared to groups II and III (P ≤ 0.01). Regarding serum serotonin level, it had a statistically significant elevation in group II with a median of 275 ng/μL (204.7-400 ng/μL) compared to groups I, III, and IV with median of 33 ng/μL (30-50 ng/μL), 50 ng/μL (30-60 ng/μL), and 102 (85-150 ng/μL), respectively (P = 0.001). Receiver operating characteristic curve showed that serum serotonin at cutoff value of 108 ng/μL had a sensitivity of 100% and specificity of 92.3% in discriminating early-stage HCC from cirrhosis. Serum serotonin level is a rapid, sensitive, noninvasive diagnostic biomarker for the detection of early-stage HCC.

High nuclear NADPH oxidase 4 expression levels are correlated with cancer development and poor prognosis in hepatocellular carcinoma

NADPH oxidase (NOX) is a key source of reactive oxygen species (ROS). This study aimed to verify NOX2 and NOX4 expression levels in hepatocellular carcinoma (HCC). A total of 134 matched pairs of HCC cells and non-tumour hepatocytes from 134 patients were examined by immunohistochemical staining, and the association of NOX2 and NOX4 expression with clinicopathological parameters was analysed. Western blotting in four HCC cell lines and reverse transcription digital droplet polymerase chain reaction (RT-ddPCR) in 20 pairs of HCC and non-tumour tissue samples were also performed to detect NOX4. Cytoplasmic NOX2 and nuclear NOX4 expression levels were shown by immunohistochemistry to be higher in HCC cells than in non-tumour hepatocytes (p<0.001 each). The western blotting results for NOX4 in four HCC cell lines were consistent with the immunohistochemical results. Increased cytoplasmic expression of NOX2 and NOX4 in HCC cells was significantly correlated with liver cirrhosis (p<0.001 and p<0.031, respectively). However, decreased cytoplasmic expression of NOX2 and NOX4 was significantly correlated with advanced pathological TNM stage (p<0.029 and p<0.007, respectively). Multivariate analysis with clinicopathological parameters showed that high nuclear and low cytoplasmic NOX4 expression levels are correlated with short overall survival (p=0 .021). Our findings imply that cytoplasmic NOX2 and nuclear NOX4 expression is upregulated during HCC development. In particular, NOX4 translocation into the nucleus may affect the development and progression of HCC. NOX2 and NOX4 could be diagnostic markers and have therapeutic implications in HCC.

N-Acetyltransferase 10 Enhances Doxorubicin Resistance in Human Hepatocellular Carcinoma Cell Lines by Promoting the Epithelial-to-Mesenchymal Transition.

Background N-Acetyltransferase 10 (NAT10) has been reported to be expressed at high levels in hepatocellular carcinoma (HCC); however, its role in chemoresistance is unclear. This study is aimed at investigating whether NAT10 regulates the epithelial-mesenchymal transition (EMT) and chemoresistance in HCC. Methods HCC cell lines (Huh-7, Bel-7402, SNU387, and SNU449) were treated with remodelin, an inhibitor of NAT10, or transfected with small inhibitory RNAs (siRNAs) targeting NAT10 or Twist. The EMT was induced by hypoxia. The CCK-8 assay was used to quantify cell viability, the EdU incorporation assay to assess cell proliferation. siRNA knockdown efficiency and epithelial/mesenchymal marker expression were assessed by western blotting. Results Knockdown of NAT10 using siRNA or inhibition of NAT10 using remodelin increased the sensitivity of HCC cell lines to doxorubicin; similar effects were observed in cells transfected with the Twist siRNA. Inhibition of NAT10 using remodelin also reversed the ability of doxorubicin to induce the EMT in HCC cells. Furthermore, inhibiting NAT10 reversed the hypoxia-induced EMT. Finally, we confirmed that combining doxorubicin with remodelin delayed tumor growth and reduced tumor cell proliferation in a mouse xenograft model of HCC. Conclusions NAT10 may contribute to chemoresistance in HCC by regulating the EMT. The mechanism by which NAT10 regulates the EMT and doxorubicin sensitivity in HCC cells merits further investigation.

Prognostic and clinicopathological significance of Gamma-Glutamyltransferase in patients with hepatocellular carcinoma: A PRISMA-compliant meta-analysis.

Background:Many studies explored the prognostic and clinicopathological significance of pretreatment serum Gamma-Glutamyltransferase (GGT) level in hepatocellular carcinoma (HCC). However, there are inconsistent results in the prognostic and clinicopathological significance of pretreatment serum GGT level in HCC. Thus, we conducted this meta-analysis to comprehensively assess the prognostic and clinicopathological significance of pretreatment serum GGT level in HCC patients.Methods:We systematically searched PubMed, EMBASE and Web of Science for relevant studies (up to June 14, 2018). The estimated hazard ratios (HRs) were used to assess the association between pretreatment serum GGT level and survival in HCC patients. The estimated odds ratios (ORs) were applied to evaluate the correlation between pretreatment serum GGT and clinicopathological features in HCC.Results:Our results showed that high pretreatment serum GGT level was significantly correlated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.54–1.87; P < .01) and disease-free survival/relapse-free survival (DFS/RFS) (HR = 1.56, 95% CI: 1.42–1.71; P < .01). Additionally, our results also revealed that there was a close correlation between GGT level and several clinicopathological features in HCC patients, including vascular invasion, tumor size, tumor number and Alpha-fetoprotein (AFP) level.Conclusions:This meta-analysis shows that high pretreatment serum GGT level is significantly correlated with poor survival and unfavorable clinicopathological features in HCC patients, suggesting that pretreatment serum GGT may be an economical and effective prognostic biomarker for HCC patients. However, more high-quality studies are still warranted to further validate our findings, considering there are several limitations in this meta-analysis.

Paradoxical effects of cellular senescence-inhibited gene involved in hepatocellular carcinoma migration and proliferation by ERK pathway and mesenchymal-like markers.

BackgroundCellular senescence-inhibited gene (CSIG) strongly prolongs the progression of replicative senescence. However, roles and mechanisms of CSIG in tumor progression have not been studied widely.MethodsRoles of CSIG in migration and proliferation of SMMC7721 and Huh7 cells were analyzed by transwell or cell viability assays, respectively. Tumorigenicity assays were used to study whether CSIG knockdown could affect SMMC7721 proliferation in vivo. Next, Western blotting and RT-PCR were preformed to evaluate the effects of CSIG on P-ERK cascade and epithelial mesenchymal transformation markers. Then, the location and expression of CSIG protein was detected by immunofluorescence and Western blotting, respectively. Finally, the Cancer Genome Atlas dataset was used to analyze CSIG mRNA levels in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues.ResultsIn this study, we found that CSIG overexpression promoted SMMC7721 cell migration, and CSIG knockdown suppressed tumorigenicity of SMMC7721 cells. In contrast to expectation, CSIG up-regulation could significantly inhibit Huh7 cell growth and migration. CSIG could promote P-ERK activation and levels of mesenchymal-like markers in SMMC7721 cells, whereas CSIG suppressed P-ERK activation and levels of mesenchymal-like markers in Huh7 cells. CSIG protein was located in nucleoli as well as nucleoplasm of SMMC7721 cells, whereas CSIG protein was mainly expressed in the nucleoli rather than nucleoplasm of Huh7 cells. Finally, due to individual differences, raised or down-regulated trends of CSIG in HCC as compared with adjacent non-tumor tissues are different among various patient populations.ConclusionIn summary, these results indicate that CSIG might play different roles in SMMC7721 and Huh7 cells through regulating P-ERK pathway and mesenchymal-like markers. The differential distribution of CSIG might be an important factor that causes its different functions in SMMC7721 and Huh7 cells. CSIG might play different roles in various patient populations.

Prx2 links ROS homeostasis to stemness of cancer stem cells

Cancer stem cells (CSC) with low levels of reactive oxygen species (ROS) are resistant to conventional chemotherapy or radiation therapy. Peroxiredoxin 2 (Prx2) is a redox regulatory protein that plays a key role in maintaining ROS homeostasis in the tumor microenvironment. However, despite the role of Prx2 in ROS-mediated signal transduction, the association of Prx2 with stemness via ROS in CSC has not been thoroughly investigated. In this study, we investigated the link between Prx2 and CSC stemness through regulation of ROS levels in hepatocellular carcinoma (HCC) cells. ROS induced CSC stemness reduction and downregulated stem cell markers in Huh7 and SK-HEP1 cells. Prx2 knockdown decreased CSC sphere formation and expression of stem cell makers with increasing intracellular ROS levels. This effect was reversed by the ROS scavengers NAC and GSH in Prx2 knockdown cells. Conversely, we found that Prx2 overexpression promotes CSC stemness and the peroxidase activity of Prx2 is essential for CSC stemness using peroxidase inactive mutant, Prx2C51/172S. More importantly, the hyperoxidation-resistant mutant (Prx2ΔYF), which has a constant ROS scavenging activity even at high concentrations of ROS, increased the CSC stemness and expression of stem cell markers more than Prx2WT under oxidative stress. Taken together, our findings demonstrate that Prx2 links ROS homeostasis to CSC stemness; Prx2 is a mediator between ROS homeostasis and CSC stemness.

A systematic review and meta-analysis of evaluation of serum interleukin 8 levels in hepatocellular carcinoma.

Aim of the studyTo estimate serum interleukin 8 (IL-8) level in patients with hepatocellular carcinoma (HCC) compared to controls and patients with chronic hepatitis (CH) and liver cirrhosis (LC).Material and methodsThree databases, i.e. PubMed, Web of Science, and Scopus, were searched up to November 2017 without language restriction. The mean difference (MD) and 95% confidence interval (CI) were used by a random-effects analysis in RevMan version 5.3, and sensitivity analysis was performed as the secondary analysis.ResultsOut of 239 studies found, 10 studies recruiting 659 HCC patients, 237 controls, 357 patients with LC, and 48 patients with CH were included and analyzed in the meta-analysis. The pooled MDs were 39.48 (95%CI: 152.31, 406.47, p < 0.00001), 21.32 (95% CI: –6.04, 48.68, p = 0.13), and 36.46 (95% CI: 21.77, 51.15, p < 0.00001) in the patients with HCC compared to the controls, the patients with LC and those with CH, respectively.ConclusionsAn elevated serum IL-8 level in the HCC patients compared to the three other groups showed an increased risk for this cytokine in HCC patients. Therefore, this interleukin can be used as a new biomarker replacing alpha-fetoprotein (AFP) or as a clinical assay for evaluation of the pathogenesis and probably the progression or development of HCC.

Clinicopathological and Prognostic Value of Plasma CD24 Level in Hepatocellular Carcinoma

Purpose: CD24 is overexpressed in hepatocellular carcinoma (HCC) tumor tissues and in the highly metastatic HCC cell lines. However, plasma CD24 level in HCC patients and the correlation of plasma CD24 level with clinicopathological factors and prognosis of HCC patients still remain unclear. Materials and Methods: Enzyme-linked immunosorbent assay was used to detect plasma CD24 level in 86 HCC patients, 35 healthy subjects, 26 patients with liver cirrhosis and 23 patients with chronic hepatitis. The relationship between plasma CD24 level with clinicopathological characteristics in HCC patients was assessed using the Mann–Whitney U test. Patient survival between groups was evaluated by the Kaplan-Meier method and the log-rank test, prognostic factors being analyzed by the Cox regression model. Results: Our present study demonstrated that plasma CD24 level in HCC patients was significantly higher than that in the controls. CD24 was significantly associated with tumor differentiation, but was not correlated with other clinicopathologic parameters including gender, age, tumor size, tumor number, capsulation status, HBsAg status, tumor node metastasis stage, ALT, AFP, and GGT level. CD24 might be a prognostic predictor for overall survival and recurrence-free survival. Conclusions: Plasma CD24 level was significantly higher in HCC patients than that in the controls. Plasma CD24 level was associated with tumor differentiation. The HCC patients with high plasma CD24 level had unfavorable prognosis. CD24 might be a prognostic biomarker for HCC in the future.

Microarray-based measurement of microRNA-449c-5p levels in hepatocellular carcinoma and bioinformatic analysis of potential signaling pathways

The clinical role and potential molecular mechanisms of microRNA-449c-5p (miR-449c-5p) in hepatocellular carcinoma (HCC) tissues remains unclear. Combining multiple bioinformatic tools, we studied the miR-449c-5p expression levels in HCC tissues and explored possible target genes and related signaling pathways. First, miR-449c-5p expression data from microarrays provided by publicly available sources were mined and analyzed using various meta-analysis methods. Next, genes that were downregulated after miR-449c-5p mimic transfection into HCC cells were identified, and in silico methods were used to predict potential target genes. Several bioinformatic assessments were also performed to evaluate the possible signaling pathways of miR-449c-5p in HCC. Five microarrays were included in the current study, including GSE98269, GSE64632, GSE74618, GSE40744 and GSE57555. The standard mean difference was 0.44 (0.07–0.80), and the area under the curve was 0.68 (0.63–0.72), as assessed by meta-analyses, which consistently indicated the upregulation of miR-449c-5p in HCC tissues. A total of 2244 genes were downregulated after miR-449c-5p mimic transfection into an HCC cell line, while 5217 target genes were predicted by in silico methods. The overlap of these two gene pools led to a final group of 428 potential target genes of miR-449c-5p. These 428 potential target genes were primarily enriched in the homologous recombination pathway, which includes DNA Polymerase Delta 3 (POLD3). Data mining with Oncomine and the Human Protein Atlas showed a decreasing trend in POLD3 mRNA and protein levels in HCC tissue samples. This evidence suggests that miR-449c-5p could play an essential role in HCC through various pathways and that POLD3 could be a potential miR-449c-5p target. However, these in silico findings should be validated with further experiments.

Decreased CRHBP expression is predictive of poor prognosis in patients with hepatocellular carcinoma

Corticotropin releasing hormone binding protein (CRHBP) mediates the reaction between corticotropin releasing hormone (CRH) and corticotropin releasing hormone receptors (CRHRs). It is expressed in a number of organs, and the expression of CRHBP is associated with tumorigenesis and cancer progression. The aim of the present study was to investigate CRHBP expression levels in hepatocellular carcinoma (HCC) and its association with patient clinicopathological characteristics as well as prognosis. The expression of CRHBP was examined by immunohistochemistry in 169 HCC tissues and 151 adjacent non-tumorous tissues. The results were validated by western blotting using patient tissues and liver cancer cell lines. The association of CRHBP expression with clinicopathological patient characteristics and survival rate was analyzed statistically. Expression of CRHBP was detected in 142/151 (94.0%) non-tumorous liver tissues, and 84/169 (49.7%) HCC tissues (P<0.001). The expression of CRHBP was negatively associated with tumor size (P=0.013), Edmondson Grade (P=0.002), hepatitis B virus antigen (P=0.020), and α-fetoprotein levels (P=0.014). Patients exhibiting low CRHBP expression were associated with shorter survival time compared with those exhibiting high CRHBP expression (P=0.012). The results of western blotting analysis suggest that reduced CRHBP expression is frequently observable in patients with HCC. Low CRHBP expression in HCC tissues may be a predictor of clinical prognosis and a potential therapeutic target for HCC.

Alterations of glutamine and glutamate levels in patients and rats with hepatocellular carcinoma

The alteration of glutamine (Gln) and glutamate (Glu) levels in hepatocellular carcinoma (HCC) has yet to be thoroughly investigated. In this study, 28 HCC patients and 33 healthy people were enrolled. HCC in rats were induced by diethylnitrosamine. Human and rat sera and the extract of rat liver tissues were derivatized with phenylisothiocyanate (PITC) and then separated by an ACQUITY BEH C18 column with 0.1% formic acid and methanol as mobile phase. The UPLC-UV method showed high specificity. Gln and Glu concentrations ranging within 15.6–500 µg/mL showed good linear relationship with the peak area. The average recoveries were 85%–115%. Compared with those in the healthy group, Gln levels in the sera of HCC patients and HCC rats significantly (p < 0.05) decreased, whereas Glu levels increased. In HCC rats, Gln levels in the serum decreased by 36.3%, whereas Gln levels in the liver increased by 33.4%, with no statistical difference in the Gln/Glu ratio. Our results indicated that changes in Gln transporter activity may be closely related to the occurrence and development of HCC, which contributes to the HCC prevention and therapy and thus warrant further study.

Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy

PurposeTo investigate the clinical implications of the soluble programmed cell death-ligand 1 (sPD-L1) level in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT). Materials/methodsHCC patients treated with RT between June 2011 and March 2015 were prospectively recruited and sPD-L1 levels were measured using an enzyme-linked immunosorbent assay. Blood samples were obtained at the RT start, RT end, and 1-month follow-up. The associations of the sPD-L1 level with the clinical features and outcomes were analyzed. ResultsFifty-three patients with HCC were included. Thirty-four patients received conventional fractionated RT with hepatic arterial infusional chemotherapy, while 19 patients received stereotactic body radiotherapy (SBRT). The initial sPD-L1 level was significantly associated with stage, tumor size, portal vein tumor thrombosis, and venous invasion. The overall-survival was significantly poorer in patients with a higher level of initial sPD-L1 (≥1.315 pg/mL). A higher level of sPD-L1 at 1 month (≥12.9 pg/mL) was significantly related to early lung metastasis. The sPD-L1 level was significantly increased after RT and the change pattern of sPD-L1 was different between two RT schemes. ConclusionsThe level of sPD-L1 was associated with tumor aggressiveness and outcomes, suggesting its role as a possible predictive biomarker. The increases in sPD-L1 after RT suggests that combined treatment with RT and immune checkpoint inhibitors may be a promising therapeutic strategy in HCC.

Evaluation of serum interleukin-6 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis.

Aim of the studyThis meta-analysis evaluated serum interleukin-6 (IL-6) levels in hepatocellular carcinoma (HCC) patients compared with healthy controls and hepatitis and cirrhotic patients.Material and methodsThe three databases PubMed, Scopus, and Web of Science were searched for assessment of IL-6 levels in HCC patients (without cirrhosis and hepatitis) compared with healthy controls (without HCC, cirrhosis and hepatitis) and the studies were selected based on inclusion and exclusion criteria. A random-effect meta-analysis was performed with RevMan 5.3 software, using mean difference (MD) and 95% confidence intervals (CIs).ResultsOut of 503 studies searched in databases, 18 studies were included in the meta-analysis. The pooled analysis with continuous data demonstrated that the IL-6 level in HCC patients was significantly higher than that in healthy controls (MD = 12.44; 95% CI: 9.02-15.85; p < 0.00001). Also, the pooled analysis demonstrated that the IL-6 levels in cirrhotic patients (MD = –6.98; 95% CI: –12.91-1.05; p < 0.02) and patients with hepatitis (MD = –8.43; 95% CI: –11.91-4.95; p < 0.00001) were significantly lower than the level in HCC patients, and the subgroup analyses had high heterogeneity.ConclusionsThe elevated IL-6 levels in HCC patients compared with hepatitis and cirrhosis patients and healthy controls may show a significant association of this cytokine with increased risk of HCC and its potential as a diagnostic marker for HCC in future diagnostic and therapeutic strategies.

Evaluation of serum interleukin-10 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis.

Aim of the studyThis meta-analysis aimed to evaluate serum IL-10 levels in HCC patients.Material and methodsThe three databases PubMed, Scopus and Web of Science were checked on July 2017 for assessment of IL-10 levels in hepatocellular carcinoma (HCC) patients compared with healthy controls in publications with an English abstract. A random-effect meta-analysis was performed using mean difference (MD) and 95% confidence intervals (CIs). Also, publication bias was evaluated through funnel plot analysis with the Begg’s and Egger’s tests.ResultsOut of 171 studies searched in the databases, nine studies were included in the meta-analysis. The pooled analysis with continuous data concluded that IL-10 level in the patients was significantly higher than the controls (MD = 6.96; 95% CI = 4.91-9.01; p < 0.00001), in the HCC patients was significantly higher than the cirrhotic patients (MD = 2.92; 95% CI = 0.72-5.12; p = 0.009), and was similar in the HCC patients compared with the patients with hepatitis (MD = 3.91; 95% CI = –4.25-12.07; p = 0.35).ConclusionThe increased IL-10 levels in the HCC patients compared with the cirrhotic patients and the healthy controls may show a significant role of this cytokine in the elevated risk of HCC, but the lack of significant difference in the levels between HCC and hepatitis makes it an unreliable tumor marker in the latter.

Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma.

It has been reported that the transcription factor activating enhancer-binding protein 4 (TFAP4) is upregulated and associated with an aggressive phenotype in several cancers. However, the precise mechanisms underlying the oncogenic role of TFAP4 remain largely unknown.Methods: TFAP4 expression levels in hepatocellular carcinoma (HCC) cells and tissues were detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of TFAP4 in the tumor-initiating cell (TIC)-like phenotype and the tumorigenic capability of HCC cells. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays were performed to determine the underlying mechanism of TFAP4-mediated HCC aggressiveness.Results: TFAP4 was markedly upregulated in human HCC, and was associated with significantly poorer overall and relapse-free survival in patients with HCC. Furthermore, we found that overexpression of TFAP4 significantly enhanced, whereas silencing TFAP4 inhibited, the tumor sphere formation ability and proportion of side-population cells in HCC cells in vitro, and ectopic TFAP4 enhanced the tumorigenicity of HCC cells in vivo. Mechanistically, we demonstrated that TFAP4 played an important role in activating Wnt/β-catenin signaling by directly binding to the promoters of DVL1 (dishevelled segment polarity protein 1) and LEF1 (lymphoid enhancer binding factor 1).Conclusions: Our results provide new insight into the mechanisms underlying hyperactivation of the Wnt/β-catenin pathway in HCC, as well the oncogenic ability of TFAP4 to enhance the tumor-forming ability of HCC cells.

Serum Glypican-3, Vascular Endothelial Growth Factor, and Interleukin-6 Levels in Hepatocellular Carcinoma

Serum Glypican-3, Vascular Endothelial Growth Factor, and Interleukin-6 Levels in Hepatocellular Carcinoma