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Background: In recent years, the capacity of tumor cells to maintain high levels of glycolysis, even in the presence of oxygen, has emerged as one of the main metabolic traits and garnered considerable attention. The purpose of this meta-analysis is to investigate the prognostic value of glycolysis markers in liver cancer., Methods: PubMed, Embase, and Cochrane Library databases were searched for articles on glycolytic marker expression levels associated with the prognosis of liver cancer until April 2023. Stata SE14.0 was used to calculate the aggregate hazard ratios and 95% confidence intervals., Results: Thirty-five studies were included. The worse overall survival (OS) (P < 0.001), disease-free survival (DFS) (P = 0.001), recurrence-free survival (RFS) (P = 0.004), and time to recurrence (TTR) (P < 0.001) were significantly associated with elevated expression of glycolysis markers. Higher expression of PKM2 (P < 0.001), STMN1 (P = 0.002), MCT4 (P < 0.001), GLUT1 (P = 0.025), HK-2 (P < 0.001), and CA9 (P < 0.001) were significantly related to shorter OS. Increased levels of PKM2 (P < 0.001), CA9 (P = 0.005), and MCT4 (P < 0.001) were associated with worse DFS. Elevated PKM2 expression (P = 0.002) was also associated with poorer RFS in hepatocellular carcinoma patients. GLUT2 expression was not correlated with the prognosis of liver cancer (P = 0.134)., Conclusions: Elevated expression of glycolysis markers was associated with worse OS, DFS, RFS, and TTR in patients with liver cancer. Therefore, these glycolysis markers could serve as potential prognostic markers and therapeutic targets in liver cancer., Trial Registration: PROSPERO registration: CRD42023469645., (© 2023. The Author(s).)

Estrogen receptor alpha (ESR1) has been implicated in the pathological process of Hepatitis B virus (HBV) infection and is probably an important determinant for gender differences. In this study, a total of 975 subjects including 368 healthy controls, 323 hepatocellular carcinoma (HCC) patients with HBsAg positive, and 284 HBV-infected subjects without HCC were included. Three single nucleotide polymorphisms of ESR1 (rs2234693, rs2077647, rs2228480) were detected to investigate the correlation between ESR1 polymorphisms and the susceptibility to HBV persistence and the clinical outcomes. The association of ESR1 polymorphisms with HCC prognosis was investigated in our cohort enrolling 376 HBV-HCC patients. The frequency of rs2234693 C allele was lower in chronic Hepatitis B (CHB) and liver cirrhosis (LC) than that in HCC patients in the males (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.41-0.96). rs2228480 A allele was associated with increased risk of LC (AOR = 2.20, 95% CI = 1.06-4.56) in HBV genotype C, and significantly decreased the risk of HCC recurrence (p = 0.010) and ESR1 mRNA level in tumor tissues (p = 0.032). Haplotype C-G-G was associated with significantly increased risk of HBV persistence (OR = 1.37, 95% CI = 1.08-1.73), while it was opposite for C-A-G and T-G-G (OR = 0.41, 95% CI = 0.27-0.62; OR = 0.53, 95% CI = 0.32-0.85, respectively). These results imply that combinations of these ESR1 polymorphisms may be valuable for the prediction of HBV persistence., (© 2023 Wiley Periodicals LLC.)

Background: Hepatitis B virus (HBV) variants in the preS region have been associated with hepatocellular carcinoma (HCC). However, the effect of the preS variants on HCC prognosis remains largely unknown. We aimed to identify the preS variants that reliably predict postoperative prognosis in HCC., Methods: RNA-seq data of 203 HCC patients retrieved from public database were screened for the preS variants related to HCC prognosis. The variants in the sera and tumors were then validated in our prospective cohort enrolling 103 HBV-associated HCC patients., Results: By analyzing prognosis-related gene sets in the RNA-seq data, 12 HBV preS variants were associated with HCC recurrence. Of those, G40C and C147T in the sera predicted an unfavorable recurrence-free survival in our cohort (hazard ratio [HR]=2.18, 95% confidence interval [CI]=1.37-3.47, p =0.001 for G40C; HR=1.84, 95% CI=1.15-2.92, p =0.012 for C147T). G40C and C147T were significantly associated with microscopic vascular invasion, larger tumor size, and abnormal liver function. Multivariate Cox regression analysis showed that G40C significantly increased the risk of HCC recurrence in patients with postoperative antiviral treatment. The HCC prognosis-prediction model consisting of α-fetoprotein and G40C in the sera achieved the best performance (sensitivity=0.80, specificity=0.70, and area under the curve=0.79). Functional analysis indicated that these two variants were associated with cell proliferation, chromosome instability, carcinogenesis, metastasis, and anticancer drug resistance., Conclusions: G40C and C147T are serological biomarkers for HCC prognosis and the prognostic model consisting of serological α-fetoprotein and G40C achieved the best performance in predicting postoperative prognosis.

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011-15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genetic predisposition of human leucocyte antigen (HLA)-DR has been linked to nonresponse to hepatitis B virus (HBV) vaccination. We sought to reveal their effects on chronic infection and evolution of HBV and development of hepatocellular carcinoma (HCC). Genetic polymorphisms at HLA-DR enhancer regions were genotyped in 4588 participants using quantitative PCR. HBV mutations were determined by sequencing. A dual-luciferase assay was applied to detect the enhancer activity. Associations between HLA-DR polymorphisms and postoperative prognosis were investigated in another cohort of 397 HBV-infected HCC patients. Variant alleles (rs3135395-T, rs3135338-C and rs477515-T) were significantly associated with a decreased risk of HBV persistence in Chinese patients. rs3135395-T, rs3135338-C, rs477515-T and rs2395178-G also significantly decreased HCC risk. rs3135395-T, rs477515-T and rs2395178-G were inversely associated with the generation of A1762T/G1764A, T1753V and C1653T, the HCC-risk HBV mutations. Multiplicative interactions of the variant genotypes with the HCC-risk HBV mutations were significantly associated with a decreased risk of HCC. In multivariate Cox analysis, rs477515-T independently predicted a favourable prognosis, with a hazard ratio of 0.48 (P = .002). The activity of the HLA-DRB1 enhancer with rs477515-T was significantly higher than that with rs477515-C. The activity of the HLA-DRB1 enhancer with rs477515-T and that with rs477515-C was significantly up-regulated by interferon-γ and interleukin-4, respectively. Interleukin-6 significantly inhibited the HLA-DRB1 enhancer activity, and this effect was more evident in those carrying rs477515-T. Polymorphisms predisposing to down-regulation of HLA-DR facilitate the Th1-to-Th2 transition and promote HCC development, possibly via selecting the HCC-risk HBV mutations. This can be transformed into specific prophylaxis of HCC., (© 2020 John Wiley & Sons Ltd.)

Objective: To investigate the effects of hepatitis B virus (HBV) genotype and mutations on the development of hepatocellular carcinoma (HCC) and to establish a new qualified HCC risk scores. Methods: A cohort study enrolling patients with chronic HBV infection was conducted. HBV genotypes were identified by nested multiplex PCR. HBV mutations in the basic core promoter region and PreS region were sequenced after PCR amplification. Scores on risk factors were set based on nomogram. Results: Totally, 1 525 patients were followed-up in this research. A total of 1 110 patients infected with genotype C were followed-up for 8.52 ( Q(R) : 5.36-11.68) years on average, of whom the incidence of HCC was 11.93/1 000 person-years. In genotype C HBV infected patients, male gender, aged 40 years and over, and four DNA mutations (T1674CG, A1762T/G1764A, A3120T, and A2962G) can increase the risk of HCC ( P <0.05); interferon therapy can reduce the risk of HCC ( P <0.05). A new HCC predicting model was established according to the results. After validation, the predicted disease-free survival rate was consistent with the real one. Conclusions: Hepatitis B virus genotypes and mutations were closely associated with HCC. The new risk scoring system can well predict HCC occurrence in genotype C HBV infected patients.

The extremely poor prognosis of patients with symptomatic hepatocellular carcinoma (HCC) diagnosed clinically at advanced stages suggests an urgent need for biomarkers that can be used for prospective surveillance and pre-clinical screening for early presence of pre-malignant lesions and tumors. In a retrospective longitudinal phase 3 biomarker study in seven medical centers of China, time-series and 6 months interval-serum samples were collected from chronic hepatitis B virus infected (CHB) patient cohorts at the pre-malignant or pre-clinical stages (average 6 months prior to clinical diagnosis) and CHB patients that did not develop cancer, and circulating miRNAs measured. A set of serum miRNAs including miR-193a-3p, miR-369-5p, miR-672, miR-429 and let-7i* were identified in pre-clinical HCC patients and have the potential to screen for CHB patients at high risk to develop HCC 6-12 months after miRNAs measurement. These circulating miRNAs combined with the conventional screening tools using α-fetoprotein and ultrasound, may have great promise for the prediction and prevention of HCC in high-risk populations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

We aimed to evaluate whether hepatitis B virus (HBV) mutations at the core promoter region could improve the prediction and specific prophylaxis of hepatocellular carcinoma (HCC) in chronic HBV-infected patients. A total of 2,114 HBV-infected patients enrolled between August 1998 and December 2007 were followed-up for 18,406 person-years. Of those, 612 received ≥48 week treatments with nucleos(t)ide analogue (NA) and/or IFNα. Baseline HBV mutations were identified by sequencing. Propensity score matching was applied to reduce baseline differences between antiviral and control cohorts. Multivariate Cox regression analyses, including baseline characteristics of 2,114 patients, showed that age, male, cirrhosis, and HBV mutations (C1653T, T1753V, and A1762T/G1764A) independently increased HCC risk. In control patients carrying A1762T/G1764A, addition of C1653T and/or T1753V significantly increased HCC risk (HR, 1.57; P = 0.038); combo mutations with C1653T, T1753V, and A1762T/G1764A improved the validity of HCC prediction by age, male, and cirrhosis (P = 0.002). In the matched cohorts, antiviral treatment reduced HCC incidence (13.90/1,000 vs. 7.70/1,000 person-years, P = 0.005); NA treatment for ≥60 months was required for the prophylaxis of HCC in cirrhotic patients (P = 0.03); antiviral treatment reduced HCC risk in patients carrying A1762T/G1764A (HR, 0.40; P = 0.002) or C1653T (HR, 0.45; P = 0.04) and in those without T1753V (HR, 0.42; P = 0.005), but could not reduce HCC risk in patients without A1762T/G1764A or C1653T and in those with T1753V. In summary, HBV mutation A1762T/G1764A, C1653T, and T1753V in combination improve HCC prediction in HBV-infected patients. To prevent HCC, patients infected with HBV carrying A1762T/G1764A or C1653T, but not T1753V, should be given priority of receiving antiviral treatments., (©2015 American Association for Cancer Research.)

Background: Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). Some HBV mutants and dysregulation of phosphatase and tensin homolog (PTEN) may promote the development of HCC synergistically. We aimed to test the effects of PTEN genetic polymorphisms and their interactions with important HBV mutations on the development of HCC in HBV-infected subjects., Methods: Quantitative polymerase chain reaction was applied to genotype PTEN polymorphisms (rs1234220, rs2299939, rs1234213) in 1012 healthy controls, 302 natural clearance subjects, and 2011 chronic HBV-infected subjects including 1021 HCC patients. HBV mutations were determined by sequencing. The associations of PTEN polymorphisms and their interactions with HBV mutations with HCC risk were assessed using multivariate logistic regression analysis., Results: Rs1234220 C allele was significantly associated with HCC risk compared to healthy controls (adjusted odds ratio [AOR] = 1.35, 95% confidence interval [CI] = 1.07-1.69) and HCC-free HBV-infected subjects (AOR = 1.27, 95% CI = 1.01-1.57). rs1234220 C allele was significantly associated with increased frequencies of HCC-risk A1652G, C1673T, and C1730G mutations in genotype B HBV-infected subjects. Rs2299939 GT genotype was inversely associated with HCC risk in HBV-infected patients (AOR = 0.75, 95% CI = 0.62-0.92). The interaction of rs2299939 variant genotypes (GT+TT) with A3054T mutation significantly increased HCC risk (AOR = 2.41, 95% CI = 1.08-5.35); whereas its interaction with C3116T mutation significantly reduced HCC risk (AOR = 0.34, 95% CI = 0.18-0.66). These significant effects were only evident in males after stratification., Conclusions: PTEN polymorphisms and their interactions with HBV mutations may contribute to hepatocarcinogenesis in males. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.

Background & Aims: MicroRNA-218 (miR-218) can function as a tumour suppressor and inactivate cancer-promoting inflammation. However, role of miR-218 on hepatocellular carcinoma (HCC) remains unclear. To determine the contribution of miR-218 genetic predisposition and its interaction with hepatitis B virus (HBV) mutations to HCC risk., Methods: rs11134527 located at putative promoter region of pre-miR-218 was genotyped in 1012 healthy controls, 302 hepatitis B surface antigen (HBsAg) seroclearance subjects and 2011 subjects with chronic HBV infection (1021 with HCC) using quantitative PCR. HBV mutation was determined by sequencing., Results: rs11134527 variant genotypes in dominant model was associated with HCC risk compared with all HCC-free subjects [odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.04-1.43], HCC-free HBsAg-positive subjects (OR = 1.23, 95% CI = 1.02-1.50) and HBsAg seroclearance subjects (OR = 1.45, 95% CI = 1.08-1.96), adjusting for age and gender, and also associated with the generation of HBV preS deletion in men (adjusted OR = 1.85, 95% CI = 1.23-2.76). In multivariate regression analyses, rs11134527 in dominant model was associated with HCC risk (OR = 1.50, 95% CI = 1.05-2.13), whereas its multiplicative interaction with viral mutation T1674C/G was inversely associated with HCC risk (OR = 0.44, 95% CI = 0.21-0.96), adjusting for covariates including HBV mutations in the enhancer II-precore region; its interaction with HBV preS1 start codon mutation was associated with HCC risk (OR = 4.44, 95% CI = 1.27-15.55), adjusting for covariates including HBV mutations in the preS region., Conclusion: rs11134527 may be a novel genetic risk factor of HCC in HBV-exposed subjects, can facilitate HBV preS deletion generation and predispose the host to the effect of T1674C/G and preS1 start codon mutation in hepatocarcinogenesis., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Genetic polymorphisms of HLA-DP have been associated with hepatitis B virus (HBV) persistence. We aimed to determine the effect of HLA-DP polymorphisms on the generation of HBV mutations and their interactions on the outcomes of HBV infection. rs3077, rs3135021, rs9277535, and rs2281388 were genotyped in 1,342 healthy controls, 327 HBV clearance subjects, and 2,736 HBV-positive subjects, including 1,108 hepatocellular carcinoma (HCC) patients, using quantitative PCR. HBV mutations were determined by sequencing. Multiplicative interactions of HLA-DP polymorphisms and viral mutations were assessed by multivariate logistic regression. rs3077 (from subjects with genotype CT combined with those from subjects with genotype TT [CT+TT] versus CC), rs3135021 (GA+AA versus GG), rs9277535 (GA+AA versus GG), and rs2281388 (CC versus CT+TT) significantly decreased HBV persistence. This effect was found only in genotype B HBV-infected subjects compared to HBV clearance subjects. HLA-DP polymorphisms promoting HBV clearance were associated with a lower prevalence of mutations increasing HCC risk (C1653T, T1674C/G, A1846T, G1896A and pre-S2 mutations and pre-S deletion in genotype C) and a higher prevalence of mutations decreasing HCC risk (G1652A, T1673C, T1674C, G1719T, G1730C, and G1799C in genotype B and A1727T in genotype C). Significant effects of viral mutations on cirrhosis and HCC were selectively evident in those with HLA-DP polymorphisms promoting HBV persistence. The interactions of C1653T, T1674C/G, and G1896A mutations with HLA-DP polymorphisms promoting HBV clearance significantly decreased cirrhosis risk. The interaction of rs9277535 AA with the T1674C/G or G1719T mutation in genotype C significantly decreased HCC risk. In conclusion, HLA-DP polymorphisms affect genotype B HBV clearance, regulate immune selection of viral mutations, and influence cirrhosis and HCC risks contributed by HBV mutations.

Unlabelled: Hepatitis B virus (HBV) mutations and signal transducer and activator of transcription 3 (STAT3) activation are closely associated with hepatocellular carcinoma (HCC). However, single nucleotide polymorphisms (SNPs) of STAT3 have not been implicated in HCC susceptibility. This study was designed to evaluate the effect of STAT3 SNPs and their interactions with HBV mutations on HCC risk. A total of 2,011 HBV-infected subjects (including 1,021 HCC patients) and 1,012 healthy controls were involved in this study. SNPs rs4796793 (-1697, C>G), rs2293152 (intron 11, C>G), and rs1053004 (3' untranslated region, T>C) were genotyped using quantitative polymerase chain reaction. HBV mutations were determined via direct sequencing. It was found that rs2293152 (GG versus CC) was significantly associated with HCC risk compared with the subjects without HCC, adjusting for age and sex (adjusted odds ratio [AOR], 1.30; 95% confidence interval [CI], 1.04-1.62). The impact of rs2293152 was greater in women compared with men. Compared with HCC-free HBV-infected subjects, rs2293152 GG was solely associated with HCC in women (AOR, 2.04; 95% CI, 1.15-3.61). rs2293152 GG was significantly associated with high viral load (≥1 × 10(4) copies/mL) (AOR, 1.37; 95%, CI 1.01-1.88) and increased frequencies of T1674C/G (AOR, 1.61; 95% CI, 1.06-2.46) and A1762T/G1764A (AOR, 1.64; 95% CI, 1.14-2.35). In multivariate regression analyses, multiplicative interaction of rs1053004 with T1674C/G significantly increased HCC risk, whereas rs2293152 and A1726C interaction reduced it, adjusting for covariates including HBV mutations in the enhancer II/basal core promoter/precore region; the interaction of rs4796793 with preS2 start codon mutation significantly increased HCC risk, adjusting for covariates including HBV mutations in the preS region., Conclusion: STAT3 SNPs appear to predispose the host with HBV mutations to hepatocarcinogenesis, and this effect may differ in men versus women. STAT3 SNPs may have applicability in future HCC surveillance algorithms. (Hepatology 2013;57:2369-2377)., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Background: Genetic polymorphisms of pri-miR-34b/c and pre-miR-196a2 have been reported to be associated with the susceptibility to cancers. However, the effect of these polymorphisms and their interactions with hepatitis B virus (HBV) mutations on the development of hepatocellular carcinoma (HCC) remains largely unknown. We hypothesized that these polymorphisms might interact with the HBV mutations and play a role in hepatocarcinogenesis., Methods: Pri-miR-34b/c rs4938723 (T>C) and pre-miR-196a2 rs11614913 (T>C) were genotyped in 3,325 subjects including 1,021 HBV-HCC patients using quantitative PCR. HBV mutations were determined by direct sequencing. Contributions of the polymorphisms and their multiplicative interactions with gender or HCC-related HBV mutations to HCC risk were assessed using multivariate regression analyses., Results: rs4938723 CC genotype was significantly associated with HCC risk compared to HBV natural clearance subjects, adjusted for age and gender (adjusted odds ratio [AOR] = 2.01, 95% confidence interval [CI] = 1.16-3.49). rs4938723 variant genotypes in dominant model significantly increased HCC risk in women, compared to female healthy controls (AOR = 1.85, 95% CI = 1.20-2.84) or female HCC-free subjects (AOR = 1.62, 95% CI = 1.14-2.31). rs4938723 CC genotype and rs11614913 TC genotype were significantly associated with increased frequencies of the HCC-related HBV mutations T1674C/G and G1896A, respectively. rs11614913 was not significantly associated with HCC risk, but its CC genotype significantly enhanced the effect of rs4938723 in women. In multivariate regression analyses, rs4938723 in dominant model increased HCC risk (AOR = 1.62, 95% CI = 1.05-2.49), whereas its multiplicative interaction with C1730G, a HBV mutation inversely associated with HCC risk, reduced HCC risk (AOR = 0.34, 95% CI = 0.15-0.81); rs11614913 strengthened the G1896A effect but attenuated the A3120G/T effect on HCC risk., Conclusions: rs4938723 might be a genetic risk factor of HCC but its effect on HCC is significantly affected by the HBV mutations. rs11614913 might not be a HCC susceptible factor but it might affect the effects of the HBV mutations or rs4938723 on HCC risk.

Non-coding RNA (ncRNA), a class of RNAs that do not code protein but have regulatory functions, can regulate gene expression and replication of hepatitis B virus or hepatitis C virus and play an important role in the virus-host interaction and the development of hepatocellular carcinoma (HCC). Deregulated ncRNAs in surgically removed hepatic tissues and circulation can be prognostic and diagnostic markers, respectively. ncRNAs functioning as either tumor suppressors or oncogenes can be therapeutic options. Here, we summarize the deregulated ncRNAs associated with the infections and HCC and focus on their roles on early diagnosis, prognosis prediction and therapeutic option of HCC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To elucidate the association of genetic polymorphisms of key molecules in JAK/STAT signaling pathway with susceptibility of hepatocellular carcinoma (HCC)., Methods: A total of 367 HCC patients and 367 healthy controls were recruited in this sex- and age-matched case-control study. Genetic polymorphisms of IL-6 (rs1800796, -572C > G), STAT3 (rs744166, +26312T > C; rs3816769, +42240T > C; rs6503695, +40980T > C), EGFR (rs11543848, +142530A > G), and mTOR (rs7211818, +170278A > G; rs9674559, +196983A > G; rs11653499, +65678G > A) were genotyped using a mass spectrometry method. Odds ratio (OR) and 95% confidence interval (CI) were calculated., Results: Genotype frequency of the 8 polymorphisms of IL-6, STAT3, EGFR, and mTOR were not significantly different between the patients with HCC and the controls. When stratified by sex, the female subjects who carried STAT3 +26312CC, +42240CC, or +40980CC had a decreased risk of HCC when compared to those who carried TT allele (OR = 0.192, 95%CI: 0.047 - 0.784; OR = 0.180, 95%CI: 0.045 - 0.725; OR = 0.198, 95%CI: 0.049 - 0.806, respectively). When compared with AA genotype on the site of EGFR +142530, the (AG + GG) genotype reduced the risk of HCC in women (OR = 0.422, 95%CI: 0.179 - 0.994)., Conclusion: The polymorphisms of IL-6 (rs1800796) and mTOR (rs7211818, rs9674559, and rs11653499) were not associated with the HCC susceptibility. Those carrying CC allele in three loci (rs744166, rs3816769, and rs6503695) of STAT3 and (AG + GG) in rs11543848 of EGFR had a decreased risk of HCC in women. However, these results need to be validated using larger sample size.

Objective: To observe the effect of SSd on reversing the malignant phenotype of HepG2 cells and to investigate its mechanism in order to prove that SSd is a new choice to prevent and treat HCC., Methods: HepG2 cells were cultured and treated by different concentration (0 mg/L, 2.5 mg/L, 5.0 mg/L, 10.0 mg/L and 20.0 mg/L) of SSd for 24 h, and treated by 10 mg/L of SSd for 0 h, 6 h, 12 h, 24 h, 48 h and 72h respectively. The cell inhibition rates were measured by MTT assay. Then cells were treated by 10 mg/L SSd for 48 hr in experimental group and treated by no SSd as a control, their morphological changes were observed by contrast phase microscope. The concentrations of ALB and AFP in clear supernatant liquid of cells were detected by radio-immunity and chemiluminescence. The cell migration rates were observed by transwell method, the relative expression levels of p27 mRNA were measured by RT-PCR., Results: The inhibitive effect of 10 mg/L SSd was the most significant among different concentrations ( F = 265.06, P less than 0.01). The shape of HepG2 from experimental group turned into small and round, and their volume ratios of nucleus to plasma decreased. ALB in supernatant liquid of HepG2 was higher ( t = 7.83, P less than 0.05, and its AFP was lower ( t = -10.72, P less than 0.01) as compared to control group. Cells migrated were fewer and p27 mRNA expression of HepG2 was higher in experimental group than that in control group (t = 22.00, P less than 0.05)., Conclusion: SSd could reverse the malignant phenotype of HepG2 cells. It was suggested that the up-regulation of p27 mRNA expression play an important role in the differentiation of HepG2 cells treated by SSd.

This study aimed to determine hepatitis B virus (HBV) mutations associated independently with the risk of hepatocellular carcinoma (HCC), as adjusted with other mutations in the preS and core promoter regions of HBV genotypes B and C. One hundred and forty HBV-infected patients with HCC and 280 HBV-infected patients without HCC who had intact data of HBV genotyping and DNA sequencing in both regions were involved in this age-, sex-matched case-control study. Univariate and two-step stepwise multivariate regression analyses were performed to determine factors associated with the risk of HCC. Of 39 mutations evaluated, 23 in genotype C and 6 in genotype B were associated with an increased risk of HCC in the univariate analysis. Multivariate analyses established that genotype C (adjusted odds ratio [AOR] = 3.3; 95% confidence interval [CI] = 1.1-9.8), viral load (≥10(4) copies/ml) (AOR = 2.4; 95% CI = 1.0-5.8), A2962G (AOR = 18.7; 95% CI = 7.5-46.7), preS2 start codon mutation (AOR = 12.5; 95% CI = 3.4-45.5), C105T (AOR = 0.1; 95% CI = 0.0-0.2), T1753V (AOR = 3.1; 95% CI = 1.1-9.2), and A1762T/G1764A (AOR = 2.9; 95% CI = 1.1-7.3) were associated independently with HCC, adjusted for factors including mutations in both regions. By using an estimating haplotype frequencies program, it was found that a haplotypic carriage with 105C and 2962G was significantly more frequent in the patients with HCC than in those without HCC and the frequency of haplotype 2962G-preS2 start codon wildtype-105C-1762T/1764A was 47.9% in the patients with HCC and 4.3% in those without HCC. Conclusively, A2962G and T105C are novel factors associated independently with HCC. Further prospective studies are needed to confirm the role of these mutations in the development of HCC., (© 2010 Wiley-Liss, Inc.)

The association of viral mutations and haplotypic carriages with mutations in the preS region of hepatitis B virus (HBV) genotypes B and C with hepatocellular carcinoma (HCC) is of great significance for the prediction of this malignancy, but it remains obscure. We analyzed the preS sequences of HBV genotypes B and C from 1172 HBV-infected subjects including 231 patients with HCC. As compared with the HBV-infected subjects without HCC, C2875T, G2946C, A3054C, C3060A, T3066C, C3116T, A3120C, G3191A, A1C, C7A, C10A, A31C, C76T, G105C, and G147C in both genotypes were significantly associated with increased risks of HCC. C2875A, G2950A, G2951A, A3054T, C3060T, T3066A, T3069G, A3120T, and G3191C were significantly associated with increased risks of HCC in genotype C, whereas these mutations were inversely associated with HCC in genotype B. Multivariate regression analyses showed that C76A/T was a novel factor independently associated with an increased risk of HCC, as compared with those without HCC. The frequencies of haplotypes 2964A-3116T-preS2 start codon wild-type-7C, 2964C-3116T-7A-76C, and 2964A-3116T-7C-76A/T were significantly higher in the patients with HCC (P<0.001), whereas a haplotypic carriage with a single mutation and another three wildtypes were inversely associated with HCC. Conclusively, the association of HBV mutations in the preS region with HCC depends on HBV genotype and haplotypic carriage with two or more mutations that are each associated with an increased risk of HCC independently.