Acid Anhydride Hydrolases ; Carcinoma, Hepatocellular ; etiology ; genetics ; Humans ; Liver Neoplasms ; etiology ; genetics ; Mutation ; Neoplasm Proteins ; genetics ; RNA, Messenger ; analysis

Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.
Biomarkers, Tumor/genetics/metabolism ; Carcinoma, Hepatocellular/*etiology ; Hepacivirus/genetics/*pathogenicity ; Hepatitis C/complications/pathology/virology ; Humans ; Liver Neoplasms/*etiology ; Risk

BACKGROUNDHepatitis B virus infection is closely related to hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is overexpressed in HCC and considered to play a role in hepatic carcinogenesis. In this study, we analyzed the polymorphism of COX-2 promoter -899G/C in healthy controls, chronic hepatitis B (CHB) patients, liver cirrhosis patients, and hepatocellular carcinoma (HCC) patients, to investigate the relationship between COX-2 -899G/C polymorphism and the risk for hepatitis B-related liver cancer in a Chinese population from Gansu province.

METHODSPatients were divided into four groups: 300 patients with CHB, 300 patients with liver cirrhosis, 300 patients with HCC, and 300 healthy controls. The polymorphism of COX-2 -899G/C was detected by PCR-TaqMan probes. The results were analyzed by SPSS 17.0.

RESULTSThe COX-2 -899G/C genotypes were GG, GC, and CC. Frequencies in CHB were 87.00%, 12.67%, 0.33%; in liver cirrhosis were 85.33%, 14.00%, 0.67%; in HCC were 77.00%, 21.67%, 1.33%; and in healthy controls were 90.67%, 9.00%, 0.33%, respectively. COX-2 -899C carriers may have an increased risk for hepatitis B-related liver cancer. Compared with the frequency of GG genotype, there were significant differences in the frequency of GC genotype between HCC and healthy control groups (OR = 2.835, 95%CI: 1.751 - 4.589); HCC and CHB groups (OR = 1.933, 95%CI: 1.248 - 2.994); and HCC and liver cirrhosis groups (OR = 1.175, 95%CI: 1.119 - 2.628). Stratification analyses showed that COX-2 -899C allele carriers with a drinking history are more susceptible to develop HCC.

CONCLUSIONCOX-2 -899C genotype may increase the susceptibility of individuals to hepatitis B-related liver cancer in Gansu province, China.

Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; Carcinoma, Hepatocellular ; etiology ; genetics ; Cyclooxygenase 2 ; genetics ; Female ; Genetic Predisposition to Disease ; Hepatitis B ; etiology ; genetics ; Humans ; Liver Neoplasms ; etiology ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic ; genetics ; Promoter Regions, Genetic ; genetics

BACKGROUNDWe have used suppression subtractive hybridization to construct a subtracted cDNA library of hepatocellular carcinoma (HCC) and isolated a panel of differential expression sequence tag (ESTs). By using bioinformatics and rapid amplification of cDNA ends (RACE), we found a novel HCC-associated gene IDD01. To further investigate its function, a recombinant eukaryotic vector pEGFP/ORF was constructed and transfected into the HepG2 cell line.

METHODSThe open reading frame (ORF) of IDD01 was amplified by RT-PCR, digested with Bamh I and Hind III, and subcloned into the pEGFP-C1 vector. The ligation reaction was conducted with T4 DNA ligase, and the recombinant vector was named pEGFP/ORF. Untransfer control (control group), pEGFP-C1 (HepG2/C1 group) and pEGFP/ORF (HepG2/ORF group) transfer groups were designed. Gene transfer was conducted with lipofectamine. To obtain stable transfection in HepG2 cells, selection was initiated with 500 microg/ml G418. Cellular IDD01 mRNA levels were assayed by semi-quantitative RT-PCR. The MTT colorimetric method and flow cytometry were used to determine the cell proliferation. The tumorigenic potential of transformed cells was determined from their ability to grow as anchorage-independent colonies on soft agar. Transient transfections were performed to observe subcellular location of GFP-IDD01 fusion protein.

RESULTSA 778 bp specific band of ORF was obtained by RT-PCR, and the positive clone of recombinant plasmid pEGFP/ORF (5.5 Kb) was identified by restriction endonuclease cleavage and sequence. The brightness ratio of IDD01 mRNA was not obvious between control and pEGFP/C1 groups, whereas the ratio of pEGFP/ORF was higher than that in the other two groups. After culture for 24 - 72 hours, the A(490) values in pEGFP/ORF were higher than those in the other two groups (P < 0.01). On histograms of flow cytometry, the S phase ratio of HepG2/ORF cells was significantly higher than that of the control and HepG2/C1 groups. The HepG2/ORF cells were able to form more colonies in soft agar compared with other HepG2 cell lines (P < 0.01). GFP-IDD01 fusion protein predominantly localized in the plasma, whereas EGFP protein diffused all over the cell.

CONCLUSIONThe IDD01 gene is a positive effector in cell proliferation and contributes to the carcinogenesis and progression of HCC. This gene may serve as a potential target for pharmaceutical intervention of HCC.

Carcinoma, Hepatocellular ; etiology ; genetics ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Genes, Neoplasm ; physiology ; Humans ; Liver Neoplasms ; etiology ; genetics ; Open Reading Frames ; Plasmids

Hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis with rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although discovered > 40 years ago, little attention has been paid to this pathogen from both scientific and public communities. However, effectively combating hepatitis D requires advanced scientific knowledge and joint efforts from multi-stakeholders. In this review, we emphasized the recent advances in HDV virology, epidemiology, clinical feature, treatment, and prevention. We not only highlighted the remaining challenges but also the opportunities that can move the field forward.
Carcinoma, Hepatocellular/complications* ; Hepatitis B virus ; Hepatitis D/epidemiology* ; Hepatitis Delta Virus/genetics* ; Humans ; Liver Cirrhosis/etiology* ; Liver Neoplasms/complications*

OBJECTIVETo investigate the association of genetic polymorphisms in glutathione S-transferases(GST) M1 with hepatitis beta-related hepatocellular carcinoma (HCC).

METHODSGenomic DNA was isolated from peripheral blood of HBsAg carriers, including 91 cases of HCC, 58 liver cirrhosis(LC), 63 chronic hepatitis B(CHB), and 134 normal controls. GSTM1 genotypes were detected by multiplex PCR.

RESULTSThe null genotype of GSTM1 was significantly frequent in patients with HCC compared with controls (P<0.05), but there were no significant differences in frequency of GSTM1 null genotype among patients with liver cirrhosis, chronic hepatitis B and normal controls. Subjects carrying null genotypes of GSTM1 had higher risk of developing HCC compared with those carrying positive genotype (OR=1.81.95% CI=1.05 approximately equals 3.12).

CONCLUSIONThe GSTM1-null genotype may be associated with an increased risk of HCC, but not of CHB and LC.

Adult ; Carcinoma, Hepatocellular ; etiology ; genetics ; virology ; Female ; Genotype ; Glutathione Transferase ; genetics ; Hepatitis B, Chronic ; complications ; genetics ; Humans ; Liver Cirrhosis ; etiology ; genetics ; virology ; Liver Neoplasms ; etiology ; genetics ; virology ; Male ; Middle Aged ; Polymorphism, Genetic

Transforming growth factor-b1 (TGF-beta 1) can act as both a tumor suppressor and a stimulator of tumor progression. We have examined the relationship between polymorphisms of the TGF-beta 1 gene and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. A total of 1,237 Korean subjects were prospectively enrolled; 1,046 patients with chronic HBV infection and 191 healthy controls with no evidence of recent or remote HBV infection. The patients were divided into two groups: those without (n=809) and those with HCC (n=237). Single nucleotide polymorphisms (SNPs) of TGF-beta 1 were searched for and genotyped using the single base extension method. In Korean subjects, only two SNPs were found among the seven known polymorphisms of TGF-beta 1, at position -509 and in codon 10. The risk of HCC was significantly lower in patients with the T/T or C/T genotypes than in those with the C/C genotypes at position -509 (P<0.02), and also lower among those with the Pro/Pro or Leu/Pro genotypes than in those with the Leu/Leu genotypes in codon 10 (P<0.007). Haplotype analysis revealed that the possession of [-509C>T; L10P] conferred a decreased likelihood of HCC (OR=0.74; 95% CI, 0.59-0.93; P=0.008). In conclusion, the presence of the TGF-beta 1 -509C>T promoter or of the L10P polymorphism, and the combination of both [-509C>T; L10P] as a haplotype were strongly associated with a reduced risk of HCC in patients with chronic HBV infection.
Adult ; Aged ; Carcinoma, Hepatocellular/etiology/*genetics ; Female ; Hepatitis B/complications/*genetics ; Human ; Liver Neoplasms/etiology/*genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Transforming Growth Factor beta/*genetics ; Variation (Genetics)

Hepatitis B virus (HBV) infection is the major etiology of chronic liver disease worldwide and thus a global health problem, especially in Asia-Pacific region. The long-term outcomes of Asian HBV carriers vary widely; however, a significant proportion of them will finally develop end-stage liver disease. Over the past decade, several host and HBV factors predictive of clinical outcomes in Asian HBV carriers have been identified. The community-based REVEAL-HBV study illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time, and male gender, older age, high serum alanine aminotransferase (ALT) level, positive HBeAg, higher HBV-DNA level, HBV genotype C infection and core promoter mutation are independently associated with a higher hepatocellular carcinoma (HCC) risk. Another hospital-based ERADICATE-B cohort further validated the HCC risk started to increase when HBV-DNA level was higher than 2,000 IU/mL. Of particular note, in patients with low viral load (HBV-DNA level <2,000 IU/mL), HBsAg level > or =1,000 IU/mL was a new independent risk factor for HCC. With the results from REVEAL-HBV study, a risk calculator for predicting HCC in adult non-cirrhotic patients has been developed and validated by independent international cohorts (REACH-B). With the combination of HBV-DNA, HBsAg, and ALT levels, ERADICATE-B study proposed an algorithm to predict disease progression and categorize risk levels of HCC as well as corresponding management in Asian HBV carriers. The introduction of transient elastography may further enhance the predictive power. In conclusion, HBsAg level can complement HBV-DNA level for the risk stratification of disease progression in Asian adult patients with chronic HBV infection.
Carcinoma, Hepatocellular/etiology ; DNA, Viral/blood ; Genotype ; Hepatitis B/*pathology ; Hepatitis B Surface Antigens/blood ; Hepatitis B virus/*genetics ; Humans ; Liver Neoplasms/etiology ; Risk Factors

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers closely associated with chronic infection by the hepatitis B virus (HBV) or the hepatitis C virus (HCV) throughout the world. In this study, the genetic associations of 20 known polymorphisms in eight candidate genes, including angiotensinogen (AGT), cadherin 1 (CDH1), cyclooxygenase 2 (COX2), monocyte chemotactic protein-1 (MCP1), multidrug resistance 1 (MDR1), chemokine ligand 5 (RANTES), thrombospondin 2 (THBS2), and thrombospondin 4 (THBS4), were analyzed in a large chronic hepatitis B cohort (n=1,095) recruited from the Korean population. In addition, three polymorphisms in chemokine receptor 4 (CXCR4) and vimentin (VIM) identified in this study were also genotyped. Using logistic regression analysis controlling possible confounding factors, one common (freq.=0.367) promoter polymorphism of MCP1 (MCP1-2518G>A) among analyzed polymorphisms was significantly associated with clearance of HBV infection. The frequency of homozygotes for the MCP1-2518A allele (MCP1-2518A/A) among chronic hepatitis B virus (HBV) carrier patients was significantly higher than that among spontaneously recovered (SR) subjects (17.7% vs. 10.4%)(OR=1.78, P=0.004). Our findings imply a plausible explanation for the contribution of host genetic determinants to the variable outcome of HBV infection, which might provide valuable information for future genetic study in this area.
Promoter Regions (Genetics)/*genetics ; Polymorphism, Genetic/*genetics ; Middle Aged ; Male ; Humans ; Hepatitis B virus/*physiology ; Hepatitis B/complications/*genetics/therapy/*virology ; Haplotypes/genetics ; Female ; Chemokine CCL2/*genetics ; Carcinoma, Hepatocellular/epidemiology/etiology/genetics/virology ; Aged, 80 and over ; Aged ; Adult

OBJECTIVETo analyze the gene expression level of fibroblast activation protein in HBV related hepatocellular carcinoma patients and discuss its clinical significance.

METHODSFAP gene expression in 33 hepatocellular carcinoma patients cancer tissues, peficancerous tissues, distant relative normal liver tissues and 13 normal liver tissues were examined by reverse transcription PCR; and real-time fluorescent quantitative PCR (qRT-PCR) was used to quantify their expression.

RESULTSFAP were expressed in all the tissues,the relative expression values in cancer tissues, peficancerous tissues and distant relative normal liver tissues were 5.14 +/- 6.69, 1.58 +/- 0.96, 1.63 +/- 0.94, respectively, the differences were statistically significant (F = 4.401, P < 0.05); and in TNM stage I, II, IIII, they were 2.89 +/- 3.35, 4.15 +/- 4.69, 10.09 +/- 9.51 respectively; in well-differentiated, differentiated and poorly differentiated hepatocellular carcinoma were 1.62 +/- 1.74, 3.84 +/- 3.79, 1.26 +/- 13.34 respectively. The differences were all statistically significant (P < 0.05).

CONCLUSIONFAP may play an important role in the occurrence and development of HBV related hepatocellular carcinoma.

Adult ; Aged ; Carcinoma, Hepatocellular ; etiology ; metabolism ; Female ; Gelatinases ; genetics ; physiology ; Gene Expression Regulation, Neoplastic ; Hepatitis B ; complications ; Humans ; Liver Neoplasms ; etiology ; metabolism ; Male ; Membrane Proteins ; genetics ; physiology ; Middle Aged ; RNA, Messenger ; analysis ; Serine Endopeptidases ; genetics ; physiology