Alcohol-related Hepatocellular Carcinoma Research Articles

Causal effect of porphyria biomarkers on alcohol-related hepatocellular carcinoma through Mendelian Randomization.

According to some cohort studies, an association exists between acute intermittent porphyria (AIP) and liver cancer. However, establishing a definitive causal relationship between porphyria and hepatocellular carcinoma (HCC) remains challenging. Prexisting studies regarding porphyria biomarkers and alcohol-related hepatocellular carcinoma (AR-HCC) make possible an entry point. In this study, we aimed to investigate the causal relationships between biomarkers of two types of porphyria, AIP and congenital erythropoietic porphyria (CEP), and AR-HCC. Single-nucleotide polymorphisms (SNPs) associated with porphobilinogen deaminase (PBGD) and uroporphyrinogen-III synthase (UROS), along with outcome data on AR-HCC, were extracted from public genome-wide association studies (GWAS). The GWAS data were then used to explore the potential causal relationships via a two-sample Mendelian randomization (MR) analysis. The effect estimates were calculated using the random-effect inverse-variance-weighted (IVW) method. Additionally, the Cochrane's Q test, MR-Egger test, and leave-one-out analysis were conducted to detect heterogeneity and pleiotropy in the MR results. Using the IVW method as the primary causal effects model in the MR analyses, we found that both PBGD (effect estimate = 1.51; 95% CI, from 1.08 to 2.11, p = 0.016) and UROS (effect estimate = 1.53; 95% CI, from 1.08 to 2.18, p = 0.018) have a significant causal effect on AR-HCC. Our findings revealed a causal effect of both PBGD and UROS on AR-HCC, suggesting that both AIP and CEP have a causal association with AR-HCC.

Hepatitis B virus-related hepatocellular carcinoma has superior overall survival compared with other etiologies.

Whether the etiology of chronic liver disease (CLD) impacts the overall survival (OS) of patients with hepatocellular carcinoma (HCC) remains unclear. We aim to clarify this issue. Between 2011 and 2020, 3941 patients who were newly diagnosed with HCC at our institution were enrolled in this study. In patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related > all negative. All negative was defined as negative for HCV, HBV, and alcohol use disorder. Among 3941 patients, 1407 patients were classified with HCV-related HCC, 1677 patients had HBV-related HCC, 145 patients had alcohol-related HCC, and 712 patients had all-negative HCC. Using the all-negative group as the reference group, multivariate analysis showed that HBV is an independent predictor of mortality (hazard ratio: 0.856; 95% confidence interval: 0.745-0.983; p = 0.027). Patients with HBV-related HCC had superior OS compared with patients with other CLD etiologies (p<0.001). Subgroup analyses were performed, for Barcelona Clinic Liver Cancer (BCLC) stages 0-A (p<0.001); serum alpha-fetoprotein (AFP) levels≧20 ng/ml (p<0.001); AFP levels < 20 ng/ml (p<0.001); age > 65 years (p<0.001); and the use of curative treatments (p = 0.002). No significant difference in OS between HBV and other etiologies was observed among patients aged ≤ 65 years (p = 0.304); with BCLC stages B-D (p = 0.973); or who underwent non-curative treatments (p = 0.1). Patients with HBV-related HCC had superior OS than patients with other HCC etiologies.

Establishment and characterization of a highly metastatic hepatocellular carcinoma cell line

ABSTRACT The prevalence of alcohol-related hepatocellular carcinoma (HCC) has been increasing during the last decade. Cancer research requires cell lines suitable for both in vitro and in vivo assays. However, there is a lack of cell lines with a high in vivo metastatic capacity for this HCC subtype. Herein, a new HCC cell line was established, named HCC-ZJ, using cells from a patient diagnosed with alcohol-related HCC. The karyotype of HCC-ZJ was 46, XY, del (p11.2). Whole-exome sequencing identified several genetic variations in HCC-Z that occur frequently in alcohol-associated HCC, such as mutations in TERT, CTNNB1, ARID1A, CDKN2A, SMARCA2, and HGF. Cell counting kit-8 assays, colony formation assays, and Transwell assays were performed to evaluate the proliferation, migration, and sensitivity to sorafenib and lenvatinib of HCC-Z in vitro. HCC-ZJ showed a robust proliferation rate, a weak foci-forming ability, a strong migration capacity, and a moderate invasion tendency in vitro. Finally, the tumorigenicity and metastatic capacity of HCC-Z were evaluated using a subcutaneous xenograft model, an orthotopic xenograft model, and a tail-veil injection model. HCCZJ exhibited strong tumorigenicity in the subcutaneous xenograft and orthotopic tumor models. Moreover, HCC-ZJ spontaneously formed pulmonary metastases in the orthotopic tumor model. In summary, a new HCC cell line derived from a patient with alcohol-related HCC was established, which showed a high metastatic capacity and could be applied for in vitro and in vivo experiments during pre-clinical research. Highlights • An alcohol-related HCC cell line, HCC-ZJ, was established • HCC-ZJ was applicable for in vitro functional experiment and gene editing • HCC-ZJ was applicable for in vivo tumor growth and spontaneous metastasis models

Prevalence and prediction of hepatocellular carcinoma in alcohol-associated liver disease: a retrospective study of 136 571 patients with chronic liver diseases

Background and aimsTo explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated...

Abstinence is associated with better outcomes in patients with alcohol-related hepatocellular carcinoma: Results of an observational study

BackgroundPatients with alcohol-related cirrhosis and hepatocellular carcinoma (HCC) may have reduced survival compared to those with HCC related to other causes. The impact of abstinence in alcohol-related HCC is unknown. We compared access to curative treatment and the prognosis of patients with HCC according to the cause of cirrhosis and evaluated the impact of abstinence on the prognosis of patients with alcohol-related HCC. Patients and methodsData for patients with cirrhosis and HCC were prospectively collected in a single center. A logistic regression model was used to identify factors associated with access to curative treatment. Multivariate Fine and Gray proportional hazards models were used to identify factors associated with 5-year survival after adjustment for lead-time bias. ResultsTwo hundred patients were included, 114 (57 %) with non-alcohol-related HCC and 86 (43 %) with alcohol-related HCC (35 abstainers, 51 consumers). During follow-up, 21 patients were transplanted and 156 died. The proportion of patients who had access to curative treatment was 65 % in abstainers, 44 % in consumers, and 57 % in patients with non-alcohol-related cirrhosis (p = 0.06). In multivariate analyses, abstinence was not associated with better access to curative treatment. After adjustment for lead-time bias, the 5-year cumulative incidence of overall death was significantly lower in abstainers than in consumers and in patients with non-alcohol-related cirrhosis (52 % vs. 78 % vs. 81 %, respectively, p = 0.04). In multivariate analyses, abstainers had lower risk of death than consumers (SHR: 0.47, 95 % CI: 0.28–0.80, p = 0.005). ConclusionAbstinence improves the outcome of patients with alcohol-related cirrhosis once HCC has occurred.

Clinical characteristics of hepatocellular carcinoma in patients with cirrhosis: a comparative cohort study.

The epidemiology of cirrhosis has changed over the last two decades. We aimed to assess whether the epidemiology and clinical presentation of hepatocellular carcinoma (HCC) occurring in cirrhosis has changed. The patients were recruited from the Cirrhosis Registry. This database included patients with cirrhosis who had attended the outpatient' liver clinic at the Centre Hospitalier Jolimont in La Louvière, Belgium, since January 1995. We extracted data on two cohorts of patients with cirrhosis collected over an identical time period and followed up for the same duration. Cohort 1 included 504 patients enrolled from 1995 to 2005; among them, 89 patients developed HCC during the defined follow-up period (group 1). Cohort 2 included 566 patients enrolled from 2006 to 2016, among whom 73 patients developed HCC during the defined follow-up period (group 2). When patients with HCC in both groups were compared, no differences were found in the age at HCC diagnosis, the test that alerted on the presence of HCC, the extension, and the stage of the lesion at diagnosis. In the group 1, hepatitis C virus-related HCC occurred in 53% of the cases compared with 18% in the group 2 (P<0.001). Alcohol-related HCC occurred in 27% in the group 1 compared with 60% in the group 2 (P<0.001). The prevalence of metabolic dysfunction-associated steatotic liver disease-related HCC accounted for 10% in all groups. The general epidemiology of HCC has not changed; however the etiology of underlying cirrhosis has changed.

Sudden mode change of permanent pacemaker during living donor liver transplantation.

Pacemakers assist circulation by generating electrical impulses. Patients with pacemakers scheduled to undergo surgery are vulnerable to device-related complications. Therefore, careful perioperative management is required to prevent undesirable events. A 66-year-old man with alcohol-related hepatocellular carcinoma was referred for liver transplantation. The pacemaker was inserted preoperatively to manage sick sinus syndrome and paroxysmal atrial fibrillation. Overall liver transplantation was performed without any adverse events. However, the pacemaker suddenly failed to provide regular pacing rhythm during abdominal closure. Fortunately, the native heart rate was maintained above 70 beats per minute and blood pressure did not fluctuate after pacing failure. After retrospective analysis, the duration setting of preoperative pacemaker reprogramming (24 h) was revealed as the cause of unexpected pacing failure. Anesthesiologists should be alert in patients with pacemakers because minor errors may lead to inadvertent failure of pacing or severe hemodynamic instability.

Landscape of alcohol-related hepatocellular carcinoma in the last 15 years highlights the need to expand surveillance programs

Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006-2020) in Italy. Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006-2010; 2011-2015; 2016-2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia, <50% of HCCs were detected by surveillance programmes. The tumour burden at diagnosis was slightly reduced but not enough to change the distribution of the ITA.LI.CA cancer stages. Intra-arterial and targeted systemic therapies increased across quinquennia. A modest improvement in survival was observed in the last quinquennia, particularly after 12 months of patient observation. Cancer stage, HCC treatment, and presence of oesophageal varices were independent predictors of survival. In the past 15 years, modest improvements have been obtained in outcomes of alcohol-related HCC, attributed mainly to underuse of surveillance programmes and the consequent low amenability to curative treatments. Metabolic dysfunction-associated fatty liver disease is a widespread condition in alcohol abusers, but its presence did not show a pivotal prognostic role once HCC had developed. Instead, the presence of oesophageal varices, an independent poor prognosticator, should be considered in patient management and refining of prognostic systems. Alcohol abuse is a leading and growing cause of hepatocellular carcinoma (HCC) worldwide and is associated with a worse prognosis compared with other aetiologies. We assessed the evolutionary landscape of alcohol-related HCC over 15 years in Italy. A high cumulative prevalence (78%) of metabolic dysfunction-associated fatty liver disease, with signs of metabolic dysfunction, was observed in HCC patients with unhealthy excessive alcohol consumption. The alcohol+ metabolic dysfunction-associated fatty liver disease condition tended to progressively increase over time. A modest improvement in survival occurred over the study period, likely because of the persistent underuse of surveillance programmes and, consequently, the lack of improvement in the cancer stage at diagnosis and the patients' eligibility for curative treatments. Alongside the known prognostic factors for HCC (cancer stage and treatment), the presence of oesophageal varices was an independent predictor of poor survival, suggesting that this clinical feature should be carefully considered in patient management and should be included in prognostic systems/scores for HCC to improve their performance.

Lack of substantial improvements in the landscape of alcohol-related hepatocellular carcinoma in the last 15 years: The need to improve cancer prevention and surveillance

Lack of substantial improvements in the landscape of alcohol-related hepatocellular carcinoma in the last 15 years: The need to improve cancer prevention and surveillance

Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma

Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma

Development and Validation of a nomogram for forecasting survival of alcohol related hepatocellular carcinoma patients.

With the increasing incidence and prevalence of alcoholic liver disease, alcohol-related hepatocellular carcinoma has become a serious public health problem worthy of attention in China. However, there is currently no prognostic prediction model for alcohol-related hepatocellular carcinoma. The retrospective analysis research of alcohol related hepatocellular carcinoma patients was conducted from January 2010 to December 2014. Independent prognostic factors of alcohol related hepatocellular carcinoma were identified by Lasso regression and multivariate COX proportional model analysis, and the nomogram model was constructed. The reliability and accuracy of the model were assessed using the concordance index(C-Index), receiver operating characteristic (ROC) curve and calibration curve. Evaluate the clinical benefit and application value of the model through clinical decision curve analysis (DCA). The prognosis was assessed by the Kaplan-Meier (KM) survival curve. In sum, 383 patients were included in our study. Patients were stochastically assigned to training cohort (n=271) and validation cohort (n=112) according to 7:3 ratio. The predictors included in the nomogram were splenectomy, platelet count (PLT), creatinine (CRE), Prealbumin (PA), mean erythrocyte hemoglobin concentration (MCHC), red blood cell distribution width (RDW) and TNM. Our nomogram demonstrated excellent discriminatory power (C-index) and good calibration at 1-year, 3-year and 5- year overall survival (OS). Compared to TNM and Child-Pugh model, the nomogram had better discriminative ability and higher accuracy. DCA showed high clinical benefit and application value of the model. The nomogram model we established can precisely forcasting the prognosis of alcohol related hepatocellular carcinoma patients, which would be helpful for the early warning of alcohol related hepatocellular carcinoma and predict prognosis in patients with alcoholic hepatocellular carcinoma.

Epidemic characteristics of alcohol-related liver disease in Asia from 2000 to 2020: A systematic review and meta-analysis.

To systematically summarize the prevalence of alcohol-related liver disease (ALD) and the alcohol-attributable proportions of liver cirrhosis and hepatocellular carcinoma (HCC) cases in Asia. The Embase, PubMed, Web of Science, Cochrane, CINAHL, WanfangMed and China National Knowledge Infrastructure databases were searched from 01 January 2000 to 01 December 2021 for reports of ALD prevalence and alcohol-attributable proportions of liver cirrhosis/HCC in Asian populations. Study characteristics were extracted, and meta-analyses were conducted. Our literature search identified 13 studies reporting the ALD prevalence, 62 studies reporting the alcohol-attributable proportion of liver cirrhosis and 34 studies reporting the alcohol-attributable proportion of HCC. The overall prevalence of ALD was 4.81% (95% confidence interval [CI] 3.67%, 6.09%). The ALD prevalence was higher in men (7.80% [95% CI 5.70%, 10.19%]) than in women (0.88% [95% CI 0.35%, 1.64%]) and increased significantly over time from 3.82% (95% CI 2.74%, 5.07%) between 2000 and 2010 to 6.62% (95% CI 4.97%, 8.50%) between 2011 and 2020. Among 469 640 cases of liver cirrhosis, the pooled alcohol-attributable proportion was 12.57% (95% CI 10.20%, 15.16%). Among 82 615 HCC cases, the pooled alcohol-attributable proportion was 8.30% (95% CI 6.10%,11.21%). Significant regional differences were observed in alcohol-attributable proportions of liver cirrhosis and HCC. The prevalence of ALD and the proportions of alcohol-related liver cirrhosis and HCC in Asia are lower than those in western populations. However, a gradual increasing trend was observed over the last 21 years. ALD is likely to emerge as a leading cause of chronic liver disease in Asia.

Alcohol-related hepatocellular carcinoma is a heterogenous condition: Lessons from a latent class analysis.

BackgroundAlcohol‐associated hepatocellular carcinoma (AL‐HCC) poor prognosis has been attributed to diagnosis at a later stage. However, host factors and specific health trajectories have been associated with severe outcomes in alcohol‐related liver disease. We hypothesize AL‐HCC is not a homogeneous condition but encompasses subgroups yielding different outcomes.AimsOur aim was to provide a first attempt at a clinical phenotyping of AL‐HCC.MethodsWe analysed data for the calendar years 2007–2013 from the French nationwide administrative hospital database. We selected patients with AL‐HCC only. Clustering of AL‐HCC phenotypes was performed by latent class analysis (LCA).ResultsThe study included 11 363 patients with AL‐HCC, mainly male (89.6%), median age 67 years [IQR: 61; 74] of which 71.2% had at least one metabolic comorbidity. Five phenotypes were identified. Phenotype 1 (41.4%) displayed high rates of unrecognized cirrhosis prior to HCC diagnosis (81%), low rates of metabolic comorbidities (diabetes 13%), and mostly compensated liver disease at HCC diagnosis while the four other phenotypes displayed high rates of metabolic comorbidities (diabetes up to 100%), various patterns of liver disease trajectories and overall 42% unrecognized cirrhosis. In adjusted survival analysis, compared to phenotype 1, risk of death after HCC diagnosis was significantly different for all phenotypes.ConclusionLCA uncovers AL‐HCC is a heterogeneous condition with distinct phenotypes yielding specific survival outcomes. Frequent unrecognized cirrhosis prior to HCC underlines the urgent need for implementing strategies to identify the underlying liver disease prior to HCC onset in patients with documented alcohol use disorders and metabolic comorbidities.

GWAS reveals variants for alcohol-related hepatocellular carcinoma.

GWAS reveals variants for alcohol-related hepatocellular carcinoma.

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

Rs708113 in WNT3A-WNT9A and hepatocellular carcinoma risk.

Hepatocellular carcinoma is the most frequent primary liver malignancy and fourth most common cause of cancer-related mortality worldwide. 1 Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3: 524-548 Crossref PubMed Scopus (2549) Google Scholar Although chronic viral hepatitis, particularly due to hepatitis B virus (HBV) infection, is the most common underlying liver disease leading to hepatocellular carcinoma in southeast Asia, alcohol-related liver disease and non-alcoholic fatty liver disease are the predominant causes in Europe and North America. Alcohol-related liver disease and non-alcoholic fatty liver disease are expected to become the leading causes of hepatocellular carcinoma in the future, with HBV and hepatitis C virus infections declining as a result of effective vaccination strategies and treatments. With few exceptions, most hepatocellular carcinoma cases in high-income countries develop in patients with established cirrhosis; alcohol-related cirrhosis is the second most common risk factor for hepatocellular carcinoma in high-income countries, 2 West J Card TR Aithal GP Fleming KM Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study. Aliment Pharmacol Ther. 2017; 45: 983-990 Crossref PubMed Scopus (40) Google Scholar with an annual risk of hepatocellular carcinoma of up to 2·5%. 3 Mancebo A González-Diéguez ML Cadahía V et al. Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. Clin Gastroenterol Hepatol. 2013; 11: 95-101 Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar Alcohol-related hepatocellular carcinoma is a complex disease, but easily discernible clinical risk factors include type 2 diabetes, obesity, and older age. 4 Llovet JM Kelley RK Villanueva A et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7: 6 Crossref PubMed Scopus (708) Google Scholar Sequence variations in specific genes that modify the risk of alcohol-related hepatocellular carcinoma have been identified, mostly by means of candidate gene case-control studies, which either enhance or alleviate the risk of developing hepatocellular carcinoma. However, the genetic risk loci recognised until now only represent a fraction of the heritability risk, suggesting that additional genetic modulators might exist. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar The involvement of the rs738409 locus (in the gene coding for PNPLA3) is widely supported by numerous case-control studies, which show the largest effect size among all previously identified genetic risk variants. Additional loci in genes coding for TM6SF2 (rs58542926) and HSD17B13 (rs72613567:TA) were found to increase and alleviate the risk of hepatocellular carcinoma, respectively. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar , 6 Stickel F Lutz P Buch S et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology. 2020; 72: 88-102 Crossref PubMed Scopus (52) Google Scholar However, unlike in viral hepatitis-associated hepatocellular carcinoma, 7 Jiang DK Sun J Cao G et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013; 45: 72-75 Crossref PubMed Scopus (242) Google Scholar , 8 Kumar V Kato N Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011; 43: 455-458 Crossref PubMed Scopus (303) Google Scholar a comprehensive and hypothesis-free genome-wide study to detect risk loci that might have remained unidentified for alcohol-related hepatocellular carcinoma so far has been lacking. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association studyWNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. Full-Text PDF

Comprehensive Analysis of Aldehyde Dehydrogenases (ALDHs) and Its Significant Role in Hepatocellular Carcinoma

Oxidative DNA damage is closely related to the occurrence and progression of cancer. Oxidative stress plays an important role in alcohol-induced hepatocellular carcinoma (HCC). Aldehyde dehydrogenase (ALDH) is a family of enzymes that plays an essential role in the reducing oxidative damage. However, how ALDHs family affects alcohol-related HCC remains obscure. We aimed to explore the correlation between the differential expression of ALDHs in patients with HCC and pathological features, as well as the relationship between ALDHs and prognosis, and finally analyze the possible mechanism of ALDHs in targeted therapy of HCC. The data of HCC were downloaded from The Cancer Genome Atlas (TCGA) database. This research explored the expression and prognostic values of ALDHs in HCC using Oncomine, UALCAN, Human Protein Atlas, cBioPortal, Kaplan–Meier plotter, GeneMANIA, Tumor Immune Estimation Resource, GEPIA databases, and WebGestalt. Low mRNA and protein expressions of ALDHs were found to be significantly associated with tumor grade and clinical cancer stages in HCC patients. In particular, the loss of ALDH expression is more obvious in Asians, and its effect on prognosis is far more significant than that in the White race. Our findings play an important role in the study of prognostic markers and anti-liver cancer therapeutic targets for the members of the ALDHs family, especially in patients with liver cancer in Asia.

Aqueous extracts from Tenebrio molitor larval and pupal stages inhibit early hepatocarcinogenesis in vivo.

Hepatocellular carcinoma (HCC), which is the most frequent primary liver malignancy, is ranked as the sixth most common cancer and the third leading cause of cancer-related deaths worldwide, with its incidence expected to continue rising. One of the reasons is that most patients are diagnosed at an advanced stage when therapeutic options are ineffective. The development of HCC is attributed to a chronic exposition to either one or a combination of low amounts of different hepatotoxins, such as in hepatitis virus infection, alcohol consumption, aflatoxin from contaminated foods, metabolic factors, and exposure to chemical carcinogens from tobacco smoke (Forner et al., 2018). Integrative studies combining exome sequencing, transcriptome analysis, and the genomic characterization of HCC have shown that these etiological factors may raise the frequency of particular genetic alterations, resulting in intra-tumor heterogeneity that presents a huge challenge for treatment. For example, mutations in the catenin β-1 (CTNNB1) gene (a proto-oncogene in the WNT signaling pathway that encodes the β‍-catenin transcription factor) are strongly associated with alcohol-related HCC, whereas mutations in the telomerase reverse transcriptase (TERT) promoter and tumor protein p53 (TP53) genes are the most commonly observed in hepatitis B virus (HBV)‍-associated HCC (Calderaro et al., 2017; Cancer Genome Atlas Research Network, 2017). The above findings emphasize the molecular diversity of HCC and the associations of different etiologies with distinct mechanisms in HCC progression. Consequently, prevention strategies are still attractive for HCC management.

Identification of a Prognostic Model Based on 2-Gene Signature and Analysis of Corresponding Tumor Microenvironment in Alcohol-Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors with the poor prognosis. Nowadays, alcohol is becoming a leading risk factor of HCC in many countries. In our study, we obtained the DEGs in alcohol-related HCC through two databases (TCGA and GEO). Subsequently, we performed enrichment analyses (GO and KEGG), constructed the PPI network and screened the 53 hub genes by Cytoscape. Two genes (BUB1B and CENPF) from hub genes was screened by LASSO and Cox regression analyses to construct the prognostic model. Then, we found that the high risk group had the worse prognosis and verified the clinical value of the risk score in alcohol-related HCC. Finally, we analyzed the tumor microenvironment between high and low risk groups through CIBERSORT and ESTIMATE. In summary, we constructed the two-gene prognostic model that could predict the poor prognosis in patients with alcohol-related HCC.

TNF-α/NF-κB signaling epigenetically represses PSD4 transcription to promote alcohol-related hepatocellular carcinoma progression.

BackgroundChronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N‐glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate‐ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression.MethodsR‐based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real‐time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation‐specific PCR. Phospho‐p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN‐induced and DEN only‐induced transgenic murine models of HCC.ResultsWe identified PSD4 as a hypermethylated, suppressed gene in alcohol‐related HCC tumors; however, PSD4 was not dysregulated in all‐cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF‐α‐induced phospho‐p65(S276)’s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro‐EMT CDC42 activity, resulting in downregulation of E‐cadherin and upregulation of N‐cadherin and vimentin. Hepatocyte‐specific PSD4 overexpression reduced ethanol/DEN‐induced HCC tumor progression and EMT marker expression in vivo.ConclusionsPSD4 is a hypermethylated, suppressed gene in alcohol‐related HCC tumors that negatively modulated pro‐EMT CDC42 activity. Furthermore, we present a novel phospho‐NF‐κB p65(S276)/DNMT1‐mediated promoter methylation mechanism by which TNF‐α/NF‐κB signaling represses PSD4 transcription in HCC cells.