Cause Of Hepatocellular Carcinoma Research Articles

Treatment decisions based on HBV DNA.

The most common cause of hepatocellular carcinoma (HCC) worldwide is chronic hepatitis B virus (HBV) infection (CHB). Long-term suppression of HBV replication by antiviral treatment reduces the risk of HCC and mortality. Nonetheless, only 2.2% of CHB patients globally received the treatment in 2019. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage as evidenced by elevation of alanine aminotransferase (ALT). This review aims to provide existing evidence that the risk of HCC is significantly associated with serum levels of HBV DNA, and the association is non-linear parabolic, in both untreated and treated CHB patients, regardless of HBeAg status or ALT levels. Therefore, the decision for the antiviral treatment should be based on serum HBV DNA levels and age, rather than ALT levels or liver biopsy, to reduce or prevent the risk of HCC in CHB patients. The potential impact and cost-effectiveness data on early antiviral treatment initiation were also collated.

Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality. This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease. This makes the management of patients more challenging, since physicians must take into consideration two different conditions, the chronic liver disease and the tumor. The underlying liver disease has several implications in clinical practice, because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC, obstacles in surveillance, and differences in the efficacy of the treatment against HCC. A shift in the prevalence of liver diseases has been evident over the last few years, with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance. Therefore, in an era of personalized medicine, it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

Survey of hepatitis B virus infection for liver cancer screening in China: A population-based, cross-sectional study.

Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC) in China. The target population for HCC screening comprises individuals who test positive for hepatitis B surface antigen (HBsAg). However, current data on the prevalence of HBV infection among individuals who are eligible for HCC screening in China are lacking. We aimed to assess the seroepidemiology of HBV infection among Chinese individuals eligible for HCC screening to provide the latest evidence for appropriate HCC screening strategies in China. Questionnaires including information of sex, age, ethnicity, marital status, educational level, source of drinking water, as well as smoking and alcohol consumption history and serum samples were collected from females aged 45-64 years and males aged 35-64 years in 21 counties from 4 provinces in eastern and central China between 2015 and 2023. Enzyme-linked immunosorbent assay methods were used to detect the serum HBV marker HBsAg. A total of 603,082 individuals were enrolled, and serum samples were collected for analysis from January 1, 2015 to December 31, 2023. The prevalence of HBsAg positive in the study population was 5.23% (31,528/603,082). The prevalence of HBsAg positive was greater in males than in females (5.60% [17,660/315,183] vs. 4.82% [13,868/287,899], χ2=187.52, P<0.0001). The elderly participants exhibited a greater prevalence of HBV infection than younger participants (χ2=41.73, P<0.0001). Birth cohort analysis revealed an overall downward trend in HBV prevalence for both males and females. Individuals born in more recent cohorts exhibited a lower prevalence of HBV infection as compared to those born earlier. The current prevalence of HBV infection remains above 5% in populations eligible for HCC screening in China. Further efforts should be made to increase the accessibility of HCC screening among individuals with HBV infection.

Current Management of Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of other causes of liver fat accumulation. The prevalence of NAFLD is increasing and now among top causes of hepatocellular carcinoma. The diagnosis of NAFLD requires evidence from liver biopsy. There are currently no specific drugs for therapy of NAFLD. Current mainstay for management of NAFLD is lifestyle interventions focused around weight loss. Lifestyle interventions can be done by dietary modification or increasing physical activity level. Pioglitazone and vitamin E are only recommended for patient whom was confirmed NAFLD by liver biopsy. New agents such as obeticholic acid, elafibranor, selonsertib, and cenicriviroc are still waiting for phase III result to be recommended as therapy for NAFLD. Bariatric surgery can be advised for NAFLD patient with obesity who is not adequately controlled by medical therapy.

TRIM45 facilitates NASH-progressed HCC by promoting fatty acid synthesis via catalyzing FABP5 ubiquitylation.

Non-alcoholic steatohepatitis (NASH) is rapidly surpassing viral hepatitis as the primary cause of hepatocellular carcinoma (HCC). However, understanding of NASH-progressed HCC remains poor, which might impede HCC diagnosis and therapy. In this study, we aim to identify shared transcriptional changes between NASH and HCC, of which we focused on E3 ligase TRIM45. We found TRIM45 exacerbates HCC cells proliferation and metastasis in vitro and in vivo. Further transcriptome analysis revealed TRIM45 predominantly affects fatty acid metabolism and oleic acid restored impaired proliferation and metastasis of TRIM45-deficient HCC cells. IP-tandem mass spectrum and FABP5 depriving experiment indicated that TRIM45 enhance fatty acid synthesis depending on FABP5 presence. Interestingly, we found TRIM45 directly added K33-type and K63-type poly-ubiquitin chains to FABP5 NLS domain, which ultimately promoted FABP5 nuclear translocation. Nuclear FABP5 interacted with PPARγ to facilitate downstream lipid synthesis gene expression. We observed TRIM45 accelerated NASH-to-HCC transition and exacerbated both NASH and NASH-HCC with the enhanced fatty acid production in vivo. Moreover, high concentration of fatty acid increased TRIM45 expression. The established mechanism was substantiated by gene expression correlation in TCGA-LIHC. Collectively, our research revealed a common lipid reprograming process in NASH and HCC and identified the cyclical amplification of the TRIM45-FABP5-PPARγ-fatty acid axis. This signaling pathway offers potential therapeutic targets for therapeutic intervention in NASH and NASH-progressed HCC.

PSPC1 Binds to HCV IRES and Prevents Ribosomal Protein S5 Binding, Inhibiting Viral RNA Translation.

Hepatitis C virus (HCV) infects the human liver, and its chronic infection is one of the major causes of Hepatocellular carcinoma. Translation of HCV RNA is mediated by an Internal Ribosome Entry Site (IRES) element located in the 5'UTR of viral RNA. Several RNA Binding proteins of the host interact with the HCV IRES and modulate its function. Here, we demonstrate that PSPC1 (Paraspeckle Component 1), an essential paraspeckle component, upon HCV infection is relocalized and interacts with HCV IRES to prevent viral RNA translation. Competition UV-crosslinking experiments showed that PSPC1 interacts explicitly with the SLIV region of the HCV IRES, which is known to play a vital role in ribosomal loading to the HCV IRES via interaction with Ribosomal protein S5 (RPS5). Partial silencing of PSPC1 increased viral RNA translation and, consequently, HCV replication, suggesting a negative regulation by PSPC1. Interestingly, the silencing of PSPC1 protein leads to an increased interaction of RPS5 at the SLIV region, leading to an overall increase in the viral RNA in polysomes. Overall, our results showed how the host counters viral infection by relocalizing nuclear protein to the cytoplasm as a survival strategy.

Comparative outcomes of trans-arterial radioembolization in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease-induced HCC: a retrospective analysis.

Tumorigenesis in NAFLD/NASH-induced HCC is unique and may affect the effectiveness of trans-arterial radioembolization in this population. The purpose of this study was to retrospectively compare the effectiveness of trans-arterial radioembolization for the treatment of hepatocellular carcinoma (HCC) between patients with non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD) and non-NASH/NAFLD liver disease. Consecutive patients with HCC who underwent TARE at a single academic institution were retrospectively reviewed. Outcome measures including overall survival (OS), local progression-free survival (PFS), and hepatic PFS as assessed by modified response evaluation criteria in solid tumors (mRECIST) were recorded. Kaplan-Meier and Cox proportional hazard models were utilized to compare progression-free survival and overall survival. 138 separate HCCs in patients treated with TARE between July 2013 and July 2022 were retrospectively identified. Etiologies of HCC included NASH/NAFLD (30/122, 22%), HCV (52/122, 43%), alcoholic liver disease (25/122, 21%), and combined ALD/HCV (14/122, 11%). NASH/NAFLD patients demonstrated a significantly higher incidence of type 2 diabetes mellitus (p < 0.0001). There was no significant difference in overall survival (p = 0.928), local progression-free survival (p = 0.339), or hepatic progression-free survival between the cohorts (p = 0.946) by log-rank analysis. When NASH/NAFLD patients were compared to all combined non-NASH/NAFLD patients, there was no significant difference in OS (HR 1.1, 95% C.I. 0.32-3.79, p = 0.886), local PFS (HR 1.2, 95% C.I. 0.58-2.44, p = 0.639), or hepatic PFS (HR 1.3, 95% C.I. 0.52-3.16, p = 0.595) by log-rank analysis. TARE appears to be an equally effective treatment for NASH/NAFLD-induced HCC when compared to other causes of HCC. Further studies in a larger cohort with additional subgroup analyses are warranted.

A Longitudinal Analysis of Mortality Related to Chronic Viral Hepatitis and Hepatocellular Carcinoma in the United States.

(1) Background: Hepatocellular carcinoma (HCC) contributes to the significant burden of cancer mortality in the United States (US). Despite highly efficacious antivirals, chronic viral hepatitis (CVH) remains an important cause of HCC. With advancements in therapeutic modalities, along with the aging of the population, we aimed to assess the contribution of CVH in HCC-related mortality in the US between 1999-2020. (2) Methods: We queried all deaths related to CVH and HCC in the multiple-causes-of-death files from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) database between 1999-2020. Using the direct method of standardization, we adjusted all mortality information for age and compared the age-adjusted mortality rates (AAMRs) across demographic populations and by percentile rankings of social vulnerability. Temporal shifts in mortality were quantified using log-linear regression models. (3) Results: A total of 35,030 deaths were identified between 1999-2020. The overall crude mortality increased from 0.27 in 1999 to 8.32 in 2016, followed by a slight reduction to 7.04 in 2020. The cumulative AAMR during the study period was 4.43 (95% CI, 4.39-4.48). Males (AAMR 7.70) had higher mortality rates compared to females (AAMR 1.44). Mortality was higher among Hispanic populations (AAMR 6.72) compared to non-Hispanic populations (AAMR 4.18). Higher mortality was observed in US counties categorized as the most socially vulnerable (AAMR 5.20) compared to counties that are the least socially vulnerable (AAMR 2.53), with social vulnerability accounting for 2.67 excess deaths per 1,000,000 person-years. (4) Conclusions: Our epidemiological analysis revealed an overall increase in CVH-related HCC mortality between 1999-2008, followed by a stagnation period until 2020. CVH-related HCC mortality disproportionately affected males, Hispanic populations, and Black/African American populations, Western US regions, and socially vulnerable counties. These insights can help aid in the development of strategies to target vulnerable patients, focus on preventive efforts, and allocate resources to decrease HCC-related mortality.

Co-Transcriptional Regulation of HBV Replication: RNA Quality Also Matters.

Chronic hepatitis B (CHB) virus infection is a major public health burden and the leading cause of hepatocellular carcinoma. Despite the efficacy of current treatments, hepatitis B virus (HBV) cannot be fully eradicated due to the persistence of its minichromosome, or covalently closed circular DNA (cccDNA). The HBV community is investing large human and financial resources to develop new therapeutic strategies that either silence or ideally degrade cccDNA, to cure HBV completely or functionally. cccDNA transcription is considered to be the key step for HBV replication. Transcription not only influences the levels of viral RNA produced, but also directly impacts their quality, generating multiple variants. Growing evidence advocates for the role of the co-transcriptional regulation of HBV RNAs during CHB and viral replication, paving the way for the development of novel therapies targeting these processes. This review focuses on the mechanisms controlling the different co-transcriptional processes that HBV RNAs undergo, and their contribution to both viral replication and HBV-induced liver pathogenesis.

The Role of Hepatitis Viruses as Drivers of Hepatocancerogenesis.

Recently, metabolic associated steatotic liver disease (MASLD) became the leading cause of chronic liver disease worldwide and one of the most frequent causes of hepatocellular carcinoma (HCC). Nonetheless, in this epidemiological trend, viral hepatitis remains the major driver in hepatic carcinogenesis. Globally, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma, with an overall attributable risk of approximately 40%, followed by hepatitis C virus (HCV), which accounts for 28-30% of cases, with significant geographic variations between the Eastern and Western world. Considering all the etiologies, HCC risk increases proportionally with the progression of liver disease, but the risk is consistently higher in patients with viral triggers. This evidence indicates that both direct (due to the oncogenic properties of the viruses) and indirect (through the mechanisms of chronic inflammation that lead to cirrhosis) mechanisms are involved, alongside the presence of co-factors contributing to liver damage (smoking, alcohol, and metabolic factors) that synergistically enhance the oncogenic process. The aim of this review is to analyze the oncogenic role of hepatitis viruses in the liver, evaluating epidemiological changes and direct and indirect viral mechanisms that lead to liver cancer.

Hepatocellular carcinoma surveillance among people living with hepatitis B in Senegal (SEN-B): insights from a prospective cohort study

Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in west Africa, yet data on the incidence of HBV-related hepatocellular carcinoma remain scarce. We aimed to describe the uptake and early outcomes of systematic ultrasound-based hepatocellular carcinoma screening in SEN-B, which is a prospective HBV cohort in Senegal. In this prospective cohort study, we included treatment-naive, HBsAg-positive individuals who were referred to the two infectious diseases clinics (the Department of Tropical and Infectious Diseases and Ambulatory Treatment Center) at Fann University Hospital of Dakar, Senegal, between Oct 1, 2019, and Oct 31, 2022. All participants resided within the Dakar region. Participants underwent abdominal ultrasound, transient elastography, and clinical and virological assessments at inclusion and every 6 months. Liver lesions at least 1 cm in diameter on ultrasound were assessed using four-phase CT, MRI, or liver biopsy. Adherence to hepatocellular carcinoma surveillance was measured using the proportion of time covered, calculated by dividing the cumulative months covered by abdominal ultrasound examinations by the overall follow-up time, defined as the number of months from the date of cohort entry until the last recorded visit, hepatocellular carcinoma diagnosis, or death. Optimal adherence was defined as a proportion of time covered of 100%. Overall, 755 (99·6%) of 758 participants had at least one abdominal ultrasound performed. The median age of the enrolled participants was 31 years (IQR 25-39), 355 (47·0%) of 755 participants were women, and 82 (10·9%) had a family history of hepatocellular carcinoma. 15 (2·0%) of 755 individuals were HBeAg positive, 206 (27·3%) of 755 individuals had HBV DNA of more than 2000 IU/mL, and 27 (3·6%) of 755 had elastography-defined liver cirrhosis. Of ten (1·3%) participants with a focal lesion at least 1 cm at initial assessment, CT or MRI ruled out hepatocellular carcinoma in nine, whereas imaging and subsequent liver biopsy confirmed one patient with hepatocellular carcinoma. Two further patients with hepatocellular carcinoma were diagnosed at study presentation due to the presence of portal thrombosis on ultrasound. Excluding the three participants with hepatocellular carcinoma identified at baseline, 752 participants were eligible for screening every 6 months. Median follow-up time was 12 months (IQR 6-18) and the median number of ultrasounds per patient was 3 (2-4). During 809·5 person-years of follow-up, one incident hepatocellular carcinoma was reported, resulting in an incidence rate of 1·24 cases per 1000 person-years (95% CI 0·18-8·80). Overall, 702 (93·0%) of 755 participants showed optimal hepatocellular carcinoma surveillance, but this proportion decreased to 77·8% (42 of 54 participants) after 24 months. Hepatocellular carcinoma screening is feasible in HBV research cohorts in west Africa, but its longer-term acceptability needs to be evaluated. Long-term hepatocellular carcinoma incidence data are crucial for shaping tailored screening recommendations. Swiss National Science Foundation, the Swiss Cancer Research Foundation, the National Cancer Institute, and Roche Diagnostics. For the French translation of the abstract see Supplementary Materials section.

Abstract 3402: Integration of microRNAs and transcriptome signatures identifies the persistent infection of hepatitis C virus-induced hepatocellular carcinoma

Abstract MicroRNAs (miRNAs) are short non-coding RNAs (ncRNAs) of ~22 nucleotides that mediate gene expression through various functions, including gene silencing, which can lead to translation repression and degradation of target mRNAs. Dysregulation of miRNA function has been associated with numerous diseases, particularly cancer, including hepatocellular carcinoma (HCC). During the progression of HCV-HCC, the function of miRNAs may be altered thereby altering gene expression to favor HCC. Therefore, the involved miRNA-mRNA interaction needs to be further studied. In addition, there are many clinical studies have shown that HCV patients who do not adequately control their diet which are prone to fatty liver accumulation (steatosis), it may increase the possibility of liver cirrhosis. In the current study, we aim to investigate the function and effects of persistent HCV-induced miRNAs expression in liver hepatocellular carcinoma progression and gene expression and to explore the mechanisms and regulatory genes of liver steatosis caused by HCV patients in a high-fat environment. We used the Huh751 cell line and the infected with the HCV JFH1 replicon of low-viral load S2 cells. We used an HCV miRNA array for initial identification of potential candidates. These miRNAs were analyzed for KEGG pathways via DIANA. Next, we identified miRNA-mRNA targets in 3 databases (miRDB; miRPathDB; TargetScan) and analyzed the targets for KEGG pathways using ShinyGO. The target miRNA-mRNA candidate genes were then compared with long-term JFH1 replicon infectious cell (L-HCV) NGS mRNA data to integrate miRNA-mRNA. The identified genes were analyzed in The Cancer Genome Atlas (TCGA) for survival, biological process, and expression in LIHC Big Data. Hsa-miR-215, hsa-mir-10b, and hsa-let-7a of L-HCV miRNAs group showed high significance for LIHC overall survival with a hazard ratio &amp;gt;1.0. Moreover, miRNAs associated with L-HCV survival were LIHC-specific but not in other cancers. Through systematic integration of these findings, we identified HMOX1 and BMF genes as being specifically associated with HCC and regulated by hsa-miR-215-5p, hsa-miR-10b-5p, and hsa-miR-7a-5p. In addition, we also found that the expression of the adipogenesis genes, FABP4 and adipogenesis gene, SREBP1, as well as the viral non-structural protein, NS3, was significantly increased in the HCV-high-fat group; and the expression of the gene IRS1, which is involved in hyperinsulinemia, showed a decreasing trend. The main cause of HCC is that HCV inhibits the expression of hsa-miR-215-5p, hsa-miR-10b-5p, and hsa-miR-7a-5p, leading to alter the expression of target genes, these have a significant effect on survival, suggesting that an essential role in virus-related liver cancer. In the future, we will further explore the regulatory mechanisms between these genes and HCV in a high-fat environment. Citation Format: Wen-Hsiu (Vivian) Su, Ciniso Sylvester Shabangu, Shu-Chi Wang. Integration of microRNAs and transcriptome signatures identifies the persistent infection of hepatitis C virus-induced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3402.

Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease.

Metabolic dysfunction associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of hepatocellular carcinoma (HCC). Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD. We considered individuals with MASLD-HCC (n=208) and controls with (n=414) and without (n=259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with VAF ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 and ASXL1, and correlated with age (p<0.0001) and advanced liver fibrosis (p=0.001). Higher AST levels predicted non-DNMT3A-CHIP, in particular with variant allele frequency (VAF)≥10% (OR 1.14, 1.03-1.28 and OR 1.30, 1.12-1.49, respectively, p<0.05). After adjustment for sex, diabetes and a polygenic risk score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30-3.15, p=0.02), and with HCC even after further adjustment for cirrhosis (OR 1.81, 1.11-2.00, 1.30-3.15, p=0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non-DNTM3A-CHIP and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR 2.45, 1.35-4.53; OR 4.8, 1.60-17.0, p=0.02). We observed an independent association between CHIP, particularly related to non-DNTM3A and TET2 genetic lesions, and MASLD-HCC.

The Influence of Diet and Its Components on the Development and Prevention of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is diagnosed annually in nearly a million people worldwide, with approximately half of them being diagnosed at an advanced stage of the disease. Non-infectious risk factors for the development of HCC include an unbalanced lifestyle, including poor dietary choices characterized by a low intake of antioxidants, such as vitamins E and C, selenium, and polyphenols, as well as an excessive consumption of energy and harmful substances. Repeated bad dietary choices that contribute to an unbalanced lifestyle lead to the accumulation of fatty substances in the liver and to it entering an inflammatory state, which, without intervention, results in cirrhosis, the main cause of HCC. This review of the English language literature aims to present the food components that, when included in the daily diet, reduce the risk of developing HCC, as well as identifying foods that may have a carcinogenic effect on liver cells.

Hepatocellular Carcinoma among Patients with Chronic Liver Disease in a Tertiary Care Centre: A Descriptive Cross-sectional Study

Introduction: Hepatocellular carcinoma is the most common primary liver cancer. Viral hepatitis, alcohol abuse, and autoimmune hepatitis are the common causes of hepatocellular carcinoma. Usually patients present at advanced stages where curative treatment is no longer possible. This study aimed to find the prevalence of hepatocellular carcinoma among patients with chronic liver disease in a tertiary care centre. Methods: This is a descriptive cross-sectional study conducted in a single tertiary care centre from March 2020 to August 2022. The study was done among inpatients of the Department of Gastroenterology after ethical approval from the Institutional Review Committee. A total population sampling method was used and data were collected using predetermined proformas. Point estimate at 95% Confidence Interval was calculated. Results: Among 1440 patients, hepatocellular carcinoma was seen in 54 (3.75%) (2.77-4.73, 95% Confidence Interval). At the time of diagnosis, 48 (88.89%) were symptomatic. The presenting symptoms were weight loss seen in 35 (64.81%) being the most common. Out of them, 37 (68.52%) consumed alcohol and 40 (74.07%) smoked cigarettes. Conclusions: Hepatocellular carcinoma is a notable concern. Alcohol-related liver cirrhosis is the most frequent condition encountered in patients with hepatocellular carcinoma in our setting.

Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma.

Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.

HBV promotes its replication by up-regulating RAD51C gene expression

Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC), pegylated-interferon-α(PEG-IFNα) and long-term nucleos(t)ide analogs (NUCs) are mainly drugs used to treat HBV infection, but the effectiveness is unsatisfactory in different populations, the exploration of novel therapeutic approaches is necessary. RAD51C is associated with DNA damage repair and plays an important role in the development and progression of tumors. Early cDNA microarray results showed that RAD51C expression was significantly increased in HBV-infected HCC cells, however, the relationship between HBV infection and abnormal expression of RAD51C has not been reported. Therefore, we conducted RT-PCR, western blot, Co-immunoprecipitation(Co-IP), and immunofluorescence(IF) to detect HBV-RAD51C interaction in RAD51C overexpression or interfering HCC cells. Our results showed that RAD51C and HBV X protein(HBX) produced a direct interaction in the nucleus, the HBV infection of HCC cells promoted RAD51C expression, and the increased expression of RAD51C promoted HBV replication. This indicated that RAD51C is closely related to the occurrence and development of HCC caused by HBV infection, and may bring a breakthrough in the the prevention and treatment study of HCC.

Pharmacological therapy of metabolic dysfunction-associated steatotic liver disease-driven hepatocellular carcinoma.

In light of a global rise in the number of patients with type 2 diabetes mellitus (T2DM) and obesity, non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of hepatocellular carcinoma (HCC), with the annual occurrence of MASLD-driven HCC expected to increase by 45%-130% by 2030. Although MASLD has become a serious major public health threat globally, the exact molecular mechanisms mediating MASLD-driven HCC remain an open problem, necessitating future investigation. Meanwhile, emerging studies are focusing on the utility of bioactive compounds to halt the progression of MASLD to MASLD-driven HCC. In this review, we first briefly review the recent progress of the possible mechanisms of pathogenesis and progression for MASLD-driven HCC. We then discuss the application of bioactive compounds to mitigate MASLD-driven HCC through different modulatory mechanisms encompassing anti-inflammatory, lipid metabolic, and gut microbial pathways, providing valuable information for future treatment and prevention of MASLD-driven HCC. Nonetheless, clinical research exploring the effectiveness of herbal medicines in the treatment of MASLD-driven HCC is still warranted.

Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma.

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

Paraneoplastic Cutaneous Manifestations of Hepatocellular Carcinoma. A Systematic Review and Meta-analysis.

Background: There remains a scarcity of published data on the clinical significance of paraneoplastic cutaneous manifestations in hepatocellular carcinoma (HCC). Method: A systematic search of MEDLINE was performed in December 2022. Inclusion criteria comprised studies reporting on patients with HCC, who had paraneoplastic cutaneous manifestations. Outcomes of interests comprise survival and response to cancer-directed and/or skin directed therapy. Results: A total of 48 studies comprising 60 HCC patients were included in the analysis. The most frequent reported skin abnormalities were dermatomyositis, pityriasis rotunda, and porphyria. Most patients presented with dermatomyositis had underlying viral hepatitis, while all reported porphyria and acanthosis cases were associated with metabolic causes of HCC, such as steatosis. Paraneoplastic skin changes were more common in patients with metastatic disease. Pityriasis Rotunda was associated with the lowest risk of death, (OR: 0.05, 95% CI: 0.003 to 0.89; p = 0.04), while dermatomyositis had a statistically significant higher risk of death (OR: 3.37, 95% CI: 1.01-12.1; p = 0.03). Most patients showed an improvement in their cutaneous abnormalities, following cancer-directed therapy. Conclusion: Paraneoplastic cutaneous manifestations are reported more frequently in patients with a higher burden of disease, especially presence of metastases. Certain cutaneous manifestations have prognostic implication.