Poorly Differentiated Hepatocellular Carcinoma Cells Avoid Apoptosis by Interacting with T Cells via CD40-CD40 Ligand Linkage.

Hepatocellular carcinoma (HCC) is associated with increased soluble CD40 levels. This study aimed to investigate CD40's role in liver tumor progression. CD40 levels were examined in HCC patient tissues and various HCC cell lines, and their interaction with CD4+T cells was studied. RNA sequencing analysis was performed to explore the mechanisms of CD40 induction. Poorly differentiated HCC tumor tissues exhibited high membrane-bound CD40 expression, in contrast to nontumor areas. Poorly differentiated HCC cell lines showed high expression of membrane-bound CD40 with low CD40 promoter methylation, which was the opposite of that observed in the well-differentiated HCC cell lines. Solely modulating CD40 expression in HCC cells exerted no direct consequences on cell growth or appearance. Interestingly, the human hepatoma cell line HLF co-cultured with activated (CD40 ligand+) CD4+ T cells had increased CD40 levels and a modest 3.2% dead cells. The percentage of dead cells increased to 10.9% and underwent preneutralizing CD40 condition, whereas preblocking both CD40 and integrin α5ß1 concomitantly caused only 1.9% cell death. RNA sequencing of co-cultured HLFs with activated CD4+ T cells revealed the up-regulation of interferon and immune-response pathways. Increased interferon-γ levels in the activated T-cell media stimulated the Janus kinase/signal transducer and activator of transcription 3 pathway, resulting in increased CD40 expression in HLF. Collectively, CD40 expression in poorly differentiated HCC cells prevented cell death by interacting with CD40 ligand in activated T cells. Targeting CD40 may represent a promising anticancer therapy.

Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside/nucleotide analog therapy.

AIM: A recombinant monoclonal antibody against the hepatitis B surface antigen glycan isomer (HBsAgGi) was newly developed using the O-glycosylated PreS2 peptide in M-HBsAg of hepatitis B virus (HBV) genotype C. However, the association between HBsAgGi and the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy remains unknown. METHODS: A total of 112 HBV genotype C-infected patients who were treated with NA were included in this study. We assessed the association between HBV markers, including HBsAgGi and other conventional markers, and the development of HCC during NA therapy. RESULTS: Ten patients developed HCC during the follow-up period. Of the HBV markers, HBsAg (≤3.53 log IU/mL; p = 0.047), HBsAgGi/HBsAg ratio (≥1.10; p = 0.035), and HBV DNA (≤6.3 log copies/mL; p = 0.012) at baseline and HBsAg (≤3.19 log IU/mL; p = 0.033) and HBsAgGi/HBsAg ratio (≥1.09; p = 0.003) at 48 weeks after NA therapy were significantly associated with the development of HCC according to the log rank test. In contrast, no significant association was observed between HBsAgGi and the development of HCC. Multivariate analysis revealed that a platelet count at baseline ≤88 × 103/mm3 (p = 0.026; hazard ratio [HR], 10.577) and an HBsAgGi/HBsAg ratio at 48 weeks after NA therapy ≥1.09 (p = 0.040; HR, 10.099) were independently and significantly associated with the development of HCC. CONCLUSIONS: Our findings suggest that a combination of on-treatment HBsAgGi and HBsAg predicts the development of HCC during NA therapy.

Transcriptomics of a cytoglobin knockout mouse: Insights from hepatic stellate cells and brain.

The vertebrate respiratory protein cytoglobin (Cygb) is thought to exert multiple cellular functions. Here we studied the phenotypic effects of a Cygb knockout (KO) in mouse on the transcriptome level. RNA sequencing (RNA-Seq) was performed for the first time on sites of major endogenous Cygb expression, i.e. quiescent and activated hepatic stellate cells (HSCs) and two brain regions, hippocampus and hypothalamus. The data recapitulated the up-regulation of Cygb during HSC activation and its expression in the brain. Differential gene expression analyses suggested a role of Cygb in the response to inflammation in HSCs and its involvement in retinoid metabolism, retinoid X receptor (RXR) activation-induced xenobiotics metabolism, and RXR activation-induced lipid metabolism and signaling in activated cells. Unexpectedly, only minor effects of the Cygb KO were detected in the transcriptional profiles in hippocampus and hypothalamus, precluding any enrichment analyses. Furthermore, the transcriptome data pointed at a previously undescribed potential of the Cygb- knockout allele to produce cis-acting effects, necessitating future verification studies.

Validation of Noninvasive Markers for HCC Risk Stratification in 1389 Patients With Biopsy-proven NAFLD.

Background and Aims: Nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) can cause hepatocellular carcinoma (HCC). We examined histological features and reported noninvasive markers/models for stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH. Methods: A total of 1389 patients who had a histological diagnosis of NAFLD or NASH based on liver biopsy and underwent regular surveillance for HCC were included. The ability to predict HCC development was compared between histological features including liver fibrosis and NAFLD activity score, and noninvasive markers/models including aMAP (age, male, albumin-bilirubin, and platelet) score, FIB-4 (Fibrosis-4) index, and ALBI (albumin-bilirubin) score calculated at the time of biopsy. Results: The C index of aMAP score was 0.887, which was consistent with the original report, comparable to FIB-4 index (0.878), and higher than those of ALBI score (0.789), histological liver fibrosis (0.723), and NAFLD activity score (0.589). The hazard ratios for HCC development in the aMAP intermediate and high-risk groups were 21.0 (95% confidence interval [CI], 3.6-402.0) and 110.3 (95% CI, 16.3-2251.4), respectively, in comparison to the aMAP score low-risk group. Those in the FIB-4 index moderate- and high-fibrosis groups were 10.3 (95% CI, 1.7-199.8) and 93.1 (95% CI, 16.3-1773.8), respectively, in comparison to the FIB-4 index mild-fibrosis group. No patients in the aMAP score low-risk group developed HCC during the study period. Conclusion: For stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH, both aMAP score and FIB-4 index showed high discriminative ability as noninvasive markers, which were superior histological features.