Most patients with hepatocellular carcinoma (HCC) have liver cirrhosis, which develops following long periods of chronic liver disease. Cirrhosis is characterized by a decrease in hepatocyte ...proliferation, indicating an exhaustion of the regenerative capacity of the liver, and results in an increase in fibrous tissue and a destruction of liver cells, which may ultimately lead to the development of cancerous nodules. Half of all cases of HCC are associated with hepatitis B virus infection, with a further 25% associated with hepatitis C virus. Other risk factors for developing HCC include alcoholic liver disease, nonalcoholic steatohepatitis, intake of aflatoxin‐contaminated food, diabetes, and obesity. There are multiple factors involved in the etiology of HCC, all of which have a direct impact on patient characteristics and disease course, and although a causative agent can often be identified, HCC remains an extremely complex condition associated with a poor prognosis. Additionally, the geographic variation in etiology means that information from different countries is needed in order to optimize surveillance methods and develop effective chemoprevention strategies. Unfortunately, there are still many gaps in our current understanding, and further research efforts are needed to fully elucidate the diverse mechanisms involved in the pathogenesis of HCC and offer optimal prevention strategies for those at risk.
The etiology of hepatocellular carcinoma and the mechanisms thought to be involved in hepatocarcinogenesis are reviewed, and the influence of differing etiologies on patient management is considered.
Sustained virologic suppression is a primary goal of therapy for chronic hepatitis B (CHB). In study entecavir (ETV)‐022, 48 weeks of entecavir 0.5 mg was superior to lamivudine for virologic ...suppression for hepatitis B e antigen (HBeAg)‐positive CHB. A total of 183 entecavir‐treated patients from ETV‐022 subsequently enrolled in study ETV‐901. We present the results after up to 5 years (240 weeks) of continuous entecavir therapy. The entecavir long‐term cohort consists of patients who received ≥1 year of entecavir 0.5 mg in ETV‐022 and then entered ETV‐901 with a treatment gap ≤35 days. In ETV‐901 the entecavir dose was 1.0 mg daily. For patients with samples available at Year 5, proportions with hepatitis B virus (HBV) DNA <300 copies/mL, normal alanine aminotransferase (ALT) levels, HBeAg loss, and HBeAg seroconversion were determined. In all, 146 patients met criteria for inclusion in the entecavir long‐term cohort. At Year 5, 94% (88/94) had HBV DNA <300 copies/mL and 80% (78/98) had normal ALT levels. In addition to patients who achieved serologic responses during study ETV‐022, 23% (33/141) achieved HBeAg seroconversion and 1.4% (2/145) lost hepatitis B surface antigen (HBsAg) during study ETV‐901. Through 5 years, entecavir resistance emerged in one patient. The safety profile of entecavir was consistent with previous reports. Conclusion: Extended therapy with entecavir through 5 years maintained or increased rates of HBV DNA suppression and ALT normalization. Additional patients also achieved HBeAg loss and seroconversion. Entecavir provides sustained viral suppression with minimal resistance during long‐term treatment of HBeAg‐positive CHB. (HEPATOLOGY 2010.)
Background and Aims
Epitranscriptomic modification of RNA has emerged as the most prevalent form of regulation of gene expression that affects development, differentiation, metabolism, viral ...infections, and most notably cancer. We have previously shown that hepatitis B virus (HBV) transcripts are modified by N6 methyladenosine (m6A) addition. HBV also affects m6A modification of several host RNAs, including phosphatase and tensin homolog (PTEN), a well‐known tumor suppressor. PTEN plays a critical role in antiviral innate immunity and the development of hepatocellular carcinoma (HCC). Reports have shown that PTEN controlled interferon regulatory factor 3 (IRF‐3) nuclear localization by negative phosphorylation of IRF‐3 at Ser97, and PTEN reduced carcinogenesis by inhibiting the phosphatidylinositol‐3‐kinase (PI3K)/AKT pathway.
Approach and Results
Here, we show that HBV significantly increases the m6A modification of PTEN RNA, which contributes to its instability with a corresponding decrease in PTEN protein levels. This is reversed in cells in which the expression of m6A methyltransferases is silenced. PTEN expression directly increases activated IRF‐3 nuclear import and subsequent interferon synthesis. In the absence of PTEN, IRF‐3 dephosphorylation at the Ser97 site is decreased and interferon synthesis is crippled. In chronic HBV patient biopsy samples, m6A‐modified PTEN mRNA levels were uniformly up‐regulated with a concomitant decrease of PTEN mRNA levels. HBV gene expression also activated the PI3K/AKT pathway by regulating PTEN mRNA stability in HCC cell lines.
Conclusions
The m6A epitranscriptomic regulation of PTEN by HBV affects innate immunity by inhibiting IRF‐3 nuclear import and the development of HCC by activating the PI3K/AKT pathway. Our studies collectively provide new insights into the mechanisms of HBV‐directed immune evasion and HBV‐associated hepatocarcinogenesis through m6A modification of the host PTEN mRNAs.
The use of tenofovir (TDF) and entecavir (ETV) in patients with chronic hepatitis B (CHB) has led to a decrease in the incidence of hepatocellular carcinoma (HCC) and liver-related events. However, ...whether there is a difference between the two agents in the extent of improving such outcomes has not been clarified thus far. Therefore, we aimed to compare TDF and ETV on the risk of HCC and mortality.
A total of 7015 consecutive patients with CHB who were treated with TDF or ETV between February 2007 and January 2018 at the liver units of the Catholic University of Korea were screened for study eligibility and 3022 patients were finally analysed. Study end points were HCC and all-cause mortality or liver transplantation (LT) within 5 years after the initiation of antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting methods were used.
No difference was observed between TDF and ETV in the incidence rates of HCC in the entire cohort (HR 1.030; 95% CI 0.703 to 1.509, PSM model, p=0.880) and subgroups of patients with chronic hepatitis and cirrhosis. Also, no difference was observed between TDF and ETV in the incidence rates of all-cause mortality or LT in the entire cohort (HR 1.090; 95% CI 0.622 to 1.911, PSM model, p=0.763), and patients with chronic hepatitis and cirrhosis.
This study has demonstrated the clinical outcomes in patients with CHB who received TDF or ETV treatment. There was no difference in the intermediate-term risk of HCC and mortality or LT between the two drugs.
Virus-like particles (VLPs) possess great potential for organ-specific transport of therapeutic agents due to their central cavity surrounded by viral capsid proteins and similar tropism to their ...original viruses. The N-terminal truncated second open reading frame (Nt-ORF2) of the hepatotropic hepatitis E virus (HEV) forms VLPs via self-assembly. In the present study, we investigated whether HEV-LPs could deliver foreign genes specifically to the liver. HEV-LPs were obtained from Nt-ORF2 expression in Huh7 cells that were transduced with recombinant baculoviruses and purified by continuous density gradient centrifugation. The purified HEV-LPs efficiently penetrated liver-derived cell lines and the liver tissues. To evaluate HEV-LPs as gene delivery tools, we encapsulated foreign plasmids in HEV-LPs with disassembly/reassembly systems. Green fluorescence was detected at higher frequency in liver-derived Huh7 cells treated with HEV-LPs bearing GFP-encoding plasmids than in control cells. Additionally, HEV-LPs bearing Bax-encoding plasmids induced apoptotic signatures in Huh7 cells. In conclusion, HEV-LPs produced in mammalian cells can encapsulate foreign genes in their central cavity and specifically transport these genes to liver-derived cells, where they are expressed. The present study could contribute to advances in liver-targeted gene therapy.
Tumor-associated immune response plays a critical role in cancer pathogenesis. This study evaluated clinical implications of T cell cytokines and regulatory T cells (Tregs) in HCC patients treated ...with TACE. Whole blood was obtained for analysis of T cell cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-22, IFN-γ, and TNF-α) and Tregs from 142 HCC patients. Patients with CTP class A had a significantly lower proportion of detectable IL-4 or IL-6, but a higher proportion of detectable IL-22 than patients with CTP class B/C. IL-6 level was well correlated with tumor stage and undetectable IL-17A was associated with extrahepatic metastasis. The overall survival rate was significantly higher in patients who had undetectable IL-6 or detectable IL-22 than patients who did not. IL-6 among cytokines remained independently predictive factor for survival. Increased IFN-γ/IL-10 ratio and no increase in IL-6 level following TACE were associated with prolonged survival, and baseline Tregs could affect Th1/Th2 balance. T cell cytokines are associated with a variety of clinical aspects of HCC, and IL-6 is the most significant predictor of survival. A shift toward increased Th1 response and no increase in IL-6 level exert favorable immunologic effects on HCC prognosis.
Radiation therapy is an effective cancer therapy, but damage to normal tissues surrounding the tumor due to radiotherapy causes severe complications. The importance of the therapeutic area between ...tumor suppression and normal tissue injury has long been highlighted in radiation therapy. Recent advances in stem cell biology have shown that stem cell (SC) responses to genotoxic stresses of ionizing radiation can improve the therapeutic effect of radiation by repairing damaged cells. In contrast, cancer stem cells (CSCs), a small subpopulation of cells within tumors, are generally resistant to chemotherapy and radiotherapy and cause tumor recurrence. Although the underlying mechanisms are not clearly understood in detail, efforts are still underway to identify SC treatment or CSC resistant pathogenesis of DNA damage agents such as radiation therapy. In response to radiation, CSCs differ from normal SCs in their biological properties due to severe deregulation of the self-renewal ability in CSCs. Differences of cleavage mode, cell cycle characteristics, replication potential, and activation/inactivation of DNA damage treatment and cancer-specific molecular pathways between normal SCs and CSCs confer a malignant phenotype upon CSCs. However, further studies are needed to identify normal SC and CSC-specific targets. In this review, we summarize the current advances in research regarding how normal SCs and CSCs respond to ionizing radiation, with a special emphasis on cell toxicity, radiosensitivity, signaling networks, DNA damage response (DDR) and DNA repair. In addition, we discuss strategies to develop new diagnostic and therapeutic techniques for predicting responses to cancer treatment and overcoming radiation-related toxicity.
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease ...(NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio OR 2.12, 95% CI 1.69-2.66) and incident (hazard ratio HR 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.
Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. Unlike other types of cancer, HCC can be treated with locoregional treatments (LRTs) such as radiofrequency ...ablation (RFA) or transarterial chemoembolization (TACE). However, recurrences following LRTs are common, and strategies to improve long-term outcomes need to be developed. The exhaustion of anti-tumor immunity in HCC has been well established in many reports and the immunomodulatory effects of LRTs (enhancement of tumor antigen-specific T cell responses after RFA, reduction of effector regulatory T cells after TACE) have also been reported in several previous studies. However, a comprehensive review of previous studies and the possible roles of immunotherapy following LRTs in HCC are not known. In this review, we discuss the immunological evidence of current clinical trials using LRTs and combined immunotherapies, and the possible role of this strategy.
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