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The high incidence of hepatocellular carcinoma (HCC) recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies. Over the past few decades, the emergence of transcriptome analysis tools, including real-time quantitative reverse transcription PCR, microarrays, and RNA sequencing, has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures. In recent years, the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment, which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets. In the present article, we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains: primary cancer cells; carcinogenic stimuli; and tumor microenvironment. We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics, surveillance, and treatment of HCC recurrence., Competing Interests: Conflict-of-interest statement: The authors report having no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background/aim: The benefit of direct-acting antiviral therapy (DAA) in chronic hepatitis C (CHC) infected patients who received curative treatment for early-stage hepatocellular carcinoma (HCC) is well known, but is unclear for intermediate stage HCC., Patients and Methods: CHC patients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC receiving chemoembolization were identified. Univariate, multivariate analyses, and Kaplan-Meier curve were used to identify factors associated with survival outcomes., Results: Among 113 included patients, the median survival of DAA treated group (n=14) and non-treated group (n=99) were 40.1 months and 22.9 months, respectively. Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) score, DAA, and serum albumin were key independent factors associated with overall survival. Moreover, the time-to-complete remission (TTCR) was improved in the DAA treated group., Conclusion: ECOG, DAA, and serum albumin were prognostic factors for CHC/intermediate-stage HCC patients. DAA was also a beneficial factor for TTCR.

Mitochondrial DNA (mtDNA) mutations are highly associated with cancer progression. The poor prognosis of hepatocellular carcinoma (HCC) is largely due to high rates of tumor metastasis. This emphasizes the urgency of identifying these patients in advance and developing new therapeutic targets for successful intervention. However, the issue of whether mtDNA influences tumor metastasis in hepatoma remains unclear. In the current study, multiple mutations in mtDNA were identified by sequencing HCC samples. Among these mutations, mitochondrially encoded 12S rRNA (MT-RNR1) G709A was identified as a novel potential candidate. The MT-RNR1 G709A polymorphism was an independent risk factor for overall survival and distant metastasis-free survival. Subgroup analysis showed that in patients with cirrhosis, HBV-related HCC, α-fetoprotein ≥ 400 ng/mL, aspartate transaminase ≥ 31 IU/L, tumor number > 1, tumor size ≥ 5 cm, and histology grade 3-4, MT-RNR1 G709A was associated with both shorter overall survival and distant metastasis-free survival. Mechanistically, MT-RNR1 G709A was clearly associated with hexokinase 2 (HK2) expression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel associations among MT-RNR1 G709A and HK2 are an important risk factor in HCC patients.

Aim: A genome-wide association study (GWAS) had identified a single nucleotide polymorphism (SNP), GALNT14-rs9679162, capable of predicting chemotherapy responses in advanced hepatocellular carcinoma (HCC). Here, we revisited the GWAS database to search for necessary SNPs that could improve our outcome prediction., Methods: A cohort of 116 HCC patients receiving split-dose chemotherapy composed of 5-fluorouracil, mitoxantrone and cisplatin was enrolled. The GALNT14-rs9679162 together with four other leading candidate SNPs (rs6025211, rs715171, LOC105369482-rs1955024 and WWOX-rs13338697) was genotyped and correlated with time-to-tumor progression (TTP) and overall survival (OS)., Results: GALNT14-rs9679162-TT genotype remained an effective predictor for favorable TTP and OS (P = 0.012 and 0.002). Additionally, it was found that WWOX-rs13338697-CT genotype was associated with unfavorable TTP (P = 0.031), independent of GALNT14-rs9679162 genotype (adjusted P = 0.045), and rs6025211-CT genotype was associated with unfavorable OS (P = 0.014), independent of GALNT14-rs9679162 genotype (adjusted P = 0.025). Combinations of these SNPs stratified patients into three groups with differential treatment outcomes. Patients with GALNT14-rs9679162-TT/WWOX-rs13338697-non-CT genotypes achieved the most favorable treatment outcomes (n = 19; median TTP, median OS and response rate were 3.9 months, 6.8 months and 4/19 [21.1%], respectively); whereas patients with GALNT14-rs9679162-non-TT/rs6025211-CT genotypes associated with the most unfavorable treatment outcomes (n = 40; median TTP, median OS and response rate were 1.9 months, 3.5 months and 1/40 [2.5%], respectively). The remaining patients constituted a third subgroup with intermediate clinical outcomes., Conclusions: Three genetic variants, GALNT14-rs9679162, WWOX-rs13338697 and rs6025211, stratified advanced HCC patients into three groups with differential treatment outcomes., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: A lower neutrophil-to-lymphocyte ratio (NLR) was found to be associated with better clinical outcomes in hepatitis B-related liver cirrhosis and hepatocellular carcinoma. We aimed to identify pre-therapeutic variables capable of predicting NLR changes in patients with hepatitis B receiving peginterferon therapy., Patients and Methods: The baseline clinicopathological data were analyzed to correlate with NLR changes before and 1 year after peginterferon treatment in 71 patients with hepatitis B., Results: Univariate analysis revealed that pre-treatment NLR itself negatively predicted NLR changes following peginterferon treatment (odds ratio(OR)=0.320, p=0.013). Further analysis identified pre-treatment NLR, hemoglobin and hepatitis B surface antigen level as independent predictors for NLR changes (adjusted p=0.028, 0.005, and 0.028, respectively). A predictive score composed of these three factors had an area under the curve of 76.5% (p<0.001)., Conclusion: Pretreatment NLR, hemoglobin and hepatitis B surface antigen level in combination, effectively predicted NLR changes following peginterferon treatment., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Different types of hepatitis B virus (HBV) core gene deletion mutants were identified in chronic hepatitis B patients. However, their clinical roles in different stages of natural chronic HBV infection remained unclear. To address this issue, HBV core genes were sequenced in three gender- and age-matched patient groups diagnosed as chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC), respectively. Functional analysis of the identified mutants was performed. A novel type of large-fragment core gene deletion (LFCD) was identified exclusively in HCC patients and significantly associated with unfavorable postoperative survival. The presence of LFCDs resulted in generation of precore-polymerase fusion protein or brought the polymerase reading frame under direct control of HBV precore/core promoter, leading to its over-expression. Enhanced cell proliferation and increased tumorigenicity in nude mice were found in hepatoma cells expressing LFCDs. Because of the epsilon-binding ability of HBV polymerase, we hypothesized that the over-expressed polymerase carrying aberrant amino-terminal sequence could bind to cellular microRNAs. Screening of a panel of microRNAs revealed physical association of a precore-polymerase fusion protein with microRNA-100. A binding inhibition effect on microRNA-100 by the precore-polymerase fusion protein with up-regulation of its target, polo-like kinase 1 (PLK1), was discovered. The binding inhibition and growth promoting effects could be reversed by overexpressing microRNA-100. Together, HCC patients carrying hepatitis B large-fragment core gene deletion mutants had an unfavorable postoperative prognosis. The growth promoting effect was partly due to polymerase overexpression, leading to binding inhibition of microRNA-100 and up-regulation of PLK1.

The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a dual-specificity phosphatase that dephosphorylates Cdk2 and inhibits cell cycle progression. The overexpression of KAP has been found in breast, prostate and renal cell carcinomas. However, the role of KAP in hepatocellular carcinoma (HCC) remains unclear. Therefore, the aim of this study was to investigate the expression of KAP in HCC and elucidate its role in tumorigenesis. HCC tissues from 117 patients undergoing surgical resection were collected for western blot analysis and immuno-histochemichal analysis to establish clinical correlation. The antisense-mediated inhibition of KAP expression was performed in Huh-7 cell lines for tumorigenicity and growth regulation experiments. Clinicopathological analysis indicated that KAP was overexpressed in HCC tissue from alcoholic patients (P<0.001). It was significantly overexpressed in patients with a tumor number of <3 (P=0.0271), suggesting the potential role of KAP in tumorigenesis during early‑stage alcohol-related HCC. Additionally, the antisense-mediated inhibition of KAP in Huh-7 HCC cells interfered with cell cycle progression, decreased cell proliferation, reduced the colony‑forming ability of the cells and increased apoptosis. Tumorigenicity experiments showed that the KAP knockdown in Huh-7 cells generated smaller tumors in nude mice compared with the mock controls (P=0.018). In the cells in which KAP had been knocked down, the physical inter-action between KAP and Cdk2 significantly increased, despite the reduced expression levels of KAP. The phosphorylation of cell proliferation and apoptosis-associated proteins, including phosphatase and tensin homolog (PTEN), glycogen synthase kinase (GSK), p44/42 and Akt, was decreased. Therefore, it can be concluded that KAP is overexpressed in alcohol-related HCC. The antisense-mediated knockdown of KAP in Huh-7 cells decreased cell proliferation, reduced the colony‑forming ability of the cells, interfered with cell cycle progression and suppressed xenograft tumor formation, partly through enhanced KAP and Cdk2 interaction.

Hepatocellular carcinoma (HCC) invariably develops within a setting of chronic inflammation caused by either hepatotropic viruses, toxins, metabolic liver disease or autoimmunity. Mechanisms that link these two processes are not completely understood, but transcription factors of the NF-κB family and signal transducer and activator of transcription 3 (STAT3), cytokines such as IL-6 and IL-1α and ligands of the epidermal growth factor receptor (EGFR) family are clearly pivotal players. HCC may have its origins in either hepatocytes or hepatic progenitor cells (HPCs), and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.