Hepatocellular Carcinoma Death Research Articles

Trends in Hepatocellular Carcinoma Mortality Rates in the US and Projections Through 2040

ImportanceThe burden of liver cancer varies worldwide. An upward trend in both hepatocellular carcinoma (HCC) incidence and mortality in the past 2 decades has been observed.ObjectiveTo assess observed HCC-related age-standardized mortality rates (ASMRs) in the US for 2006 to 2022 and provide ASMR projections through 2040.Design, Setting, and ParticipantsThis cross-sectional study used data from the National Vital Statistics System, which is accessible through the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website. Data on deaths attributed to HCC (from January 1, 2006, to December 31, 2022) were obtained for adults 25 years or older and were stratified by liver disease etiology, age, sex, and race and ethnicity. Etiologies included alcohol-associated liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction–associated steatotic liver disease (MASLD).Main Outcomes and MeasuresThe main outcomes were (1) observed ASMRs of HCC per 100 000 persons using Joinpoint regression (National Cancer Institute) to assess trends during 2006 to 2022 and (2) ASMRs projected for 2023 to 2040 using Prophet and AutoARIMA modeling.ResultsThis study included 188 280 HCC-related deaths from 2006 to 2022. Most deaths occurred among males (77.4%). The annual percentage change was 4.1% (95% CI, 2.2% to 7.7%) for 2006 to 2009 and decreased to 1.8% (95% CI, 0.7% to 2.0%) for 2009 to 2022, with an overall observed ASMR of 5.03 per 100 000 persons in 2022 and a projected ASMR of 6.39 per 100 000 persons by 2040, with consistent trends for both sexes. By etiology, ASMRs decreased for HCV- and HBV-related mortality but increased for ALD- and MASLD-related mortality. In 2022, MASLD surpassed HBV as the third-leading cause of HCC-related death and was projected to overtake HCV in 2032 as the second-leading cause; ALD was projected to be the leading cause of HCC-related death in 2026. In 2022, the ASMR was higher among individuals aged 65 years or older compared with those aged 25 to 64 years (18.37 vs 1.79 per 100 000 persons). The American Indian or Alaska Native population had the largest increase in projected ASMR by 2040 (14.71 per 100 000 persons) compared with the Asian population (3.03 per 100 000 persons).Conclusions and RelevanceIn this cross-sectional study, ASMRs for ALD- and MASLD-related HCC death increased rapidly from 2006 to 2022; ALD-related HCC was projected to be the leading cause by 2026, with MASLD as the second-leading cause by 2032. These findings may serve as a reference for public health decision-making and timely identification of groups at high risk of HCC death.

Enhancing Radiofrequency Ablation for Hepatocellular Carcinoma: Nano-Epidrug Effects on Immune Modulation and Antigenicity Restoration.

Radiofrequency ablation (RFA), a critical therapy for hepatocellular carcinoma (HCC), carries a significant risk of recurrence and metastasis, particularly owing to mechanisms involving immune evasion and antigen downregulation via epigenetic modifications. This study introduces a "nano-epidrug" named MFMP. MFMP, which is composed of hollow mesoporous manganese dioxide (MnO2) nanoparticles, FIDAS-5 as an MAT2A inhibitor, macrophage membrane, and anti-PD-L1 (aPD-L1), targets HCC cells. By selectively binding to these cells, MFMP initially reverses immune suppression via PD-L1 inhibition. After endocytosis, MFMP disassembles in the tumor microenvironment, releasing FIDAS-5 and Mn2+. FIDAS-5 prevents cGAS methylation, whereas Mn2+ aids STING pathway restoration. In addition, FIDAS-5 reduces m6A RNA modification, suppressing EGFR expression. These changes enhance HCC antigenicity to promote cytotoxic T cell recognition and cytotoxic killing. Furthermore, MFMP mediates immunogenic cell death in HCC by synergizing with RFA through cGAS DNA demethylation, EGFR mRNA demethylation, and TBK1 protein phosphorylation, thereby inhibiting recurrence and metastasis and enhancing immune memory. Thus, MFMP is a potential adjunctive therapy requiring clinical validation.

Risk Score for Hepatocellular Cancer in Adults Without Viral Hepatitis or Cirrhosis

Hepatocellular carcinoma (HCC) is typically detected only at advanced stages when treatment options are limited. Most of the current HCC risk models focus on patients with viral hepatitis or diagnosed cirrhosis or require variables not routinely available in clinical care. To identify modifiable HCC risk factors in the general population and to develop a risk score to inform HCC screening and risk-factor modification interventions for high-risk individuals without viral hepatitis or decompensated cirrhosis. This cohort study analyzed demographic, clinical, laboratory, and diagnostic data from the US Department of Veterans Affairs (VA) electronic health records. Data were divided into development and validation samples. Veterans aged 30 to 95 years were included, and those with hepatitis B or C virus infection, hepatic decompensation, or prevalent HCC were excluded. Patients were followed up until the occurrence of HCC diagnosis, death, or December 31, 2021. A Cox proportional hazards regression model for 10-year risk of HCC was developed and used to create an HCC risk score, and performance in development and validation samples and in patient subgroups was evaluated. One outpatient visit date per person at least 18 months after VA entry, between October 1, 2007, and March 31, 2020, was randomly selected and used as the index date for the start of follow-up. Analyses were performed from March 2023 to May 2024. Age, sex, race and ethnicity, body mass index, liver fibrosis (detected with Fibrosis-4 Index [FIB-4]), diabetes status, smoking status, and alcohol use. First HCC diagnosis during follow-up. This information was ascertained from VA national cancer registry topography and histology codes and from International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for the inpatient or outpatient visits. This study of 6 509 288 veterans included 6 048 917 males (92.9%), with a median (IQR) age of 65 (54-74) years, who identified as being of Hispanic (5.3%), non-Hispanic Black (15.0%), non-Hispanic White (68.9%), or other (4.6%) race and ethnicity. Overall, 15 142 patients (0.2%) developed HCC, 69.5% of whom had FIB-4 of 3.25 or lower at baseline. While FIB-4 was the most important variable, age, sex, race and ethnicity, body mass index, diabetes, smoking, and alcohol use were also informative. Discrimination in the development sample was better than FIB-4 alone (C statistic, 0.83 [95% CI, 0.82-0.85] vs 0.79 [95% CI, 0.77-0.80]). The HCC risk score performed consistently well in the validation sample and in all subgroups. A FIB-4 threshold of 3.25 would screen 5.0% of the cohort at a cost of 28 false-positives for every true-positive; a model risk score of 58 would screen 4.7% of the cohort at a cost of 23 false-positives for every true-positive. Results of this study suggest that a multivariable risk score that uses routinely available clinical data outperforms FIB-4 alone in identifying patients at risk of HCC who do not have viral hepatitis or hepatic decompensation at baseline.

Lobetyolin Suppresses the Proliferation of Hepatocellular Carcinoma through Activating DUSP1-ERK1/2 Signaling Pathway.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with limited treatment options. Lobetyolin (LBT), a polyacetylene glycoside mainly extracted from the roots of Codonopsis pilosula, has been reported to have anti-tumor efficancy in various cancers. However, the role of LBT as well as its underlying mechanisms in HCC remain unclear. Here we investigated the impact of LBT on the phenotype in HepG2 and Huh7 cells. We found that LBT significantly induced cell growth inhibition and mitochondria-dependent apoptosis in HCC cells. Moreover, LBT upregulated dual specificity phosphatase-1 (DUSP1) expression and knockingdown DUSP1 markedly attenuated those effects induce by LBT. Meanwhile, LBT decreased the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2), a well-recognized downstream effector of DUSP1, and knockingdown DUSP1 partially recovered LBT-induced inactivation of ERK1/2. In conclusion, the present study indicated that LBT could induce cell death of HCC via promotion of DUSP1-mediated ERK1/2 inhibition. These data will help to establish the evidence of LBT to treat HCC.

Can Patient Characteristics and Pre-Treatment MRI Features Predict Survival After Stereotactic Ablative Radiotherapy (SABR) Treatment in Hepatocellular Carcinoma (HCC): Preliminary Assessment.

The study purpose was to develop a machine learning (ML)-based predictive model for event-free survival (EFS) in patients with hepatocellular carcinoma (HCC) undergoing stereotactic ablative radiotherapy (SABR). Patients receiving SABR for HCC at a single institution, between 2017 and 2020, were included in the study. They were split into training and test (85%:15%) cohorts. Events of interest were HCC recurrence or death. Three ML models were trained, the features were selected, and the hyperparameters were tuned. The performance was measured using Harrell's C index with the best-performing model being tested on the unseen cohort. Overall, 41 patients were included (training = 34, test = 7) and 64 lesions were analysed (training = 50, test = 14), resulting in 30 events (60% rate) in the training set (death = 6, recurrence = 24) and 8 events (57% rate) in the test set (death = 5, recurrence = 3). A Cox regression model, using age at treatment, albumin, and intra-lesional fat identified through MRI as variables, had the best performance with a mean training score of 0.78 (standard deviation (SD) 0.02), a mean validation of 0.78 (SD 0.18), and a test score of 0.94. Predicting the outcomes in patients with HCC, following SABR, using a novel model is feasible and warrants further evaluation.

Glycaemic control is a modifiable risk factor for hepatocellular carcinoma and liver-related mortality in patients with diabetes.

Optimal glycaemic control has well-established health benefits in patients with diabetes mellitus (DM). It is uncertain whether optimal glycaemic control can benefit liver-related outcomes. To examine the association of optimal glycaemic control with hepatocellular carcinoma (HCC) and liver-related mortality. In a population-based cohort, we identified patients with newly diagnosed DM between 2001 and 2016 in Hong Kong. Optimal glycaemic control was defined as mean haemoglobin A1c (HbA1c) <7% during the 3-year lead-in period after DM diagnosis. By applying propensity score matching to balance covariates, we analysed glycaemic control via competing risk models with outcomes of interest being HCC and liver-related mortality. We identified 146,430 patients (52.2% males, mean age 61.4 ± 11.8 years). During a median follow-up duration of 7.0 years, 1099 (0.8%) and 978 (0.7%) patients developed HCC and liver-related deaths. Optimal glycaemic control, when compared to suboptimal glycaemic control, was associated with reduced risk of HCC (subdistribution hazard ratio [SHR] 0.70, 95% CI 0.61-0.79). The risk of HCC increased with incremental HbA1c increases beyond >7% (SHR 1.29-1.71). Significant associations with HCC were also found irrespective of age (SHR 0.54-0.80), sex (SHR 0.68-0.69), BMI <25 or ≥25 kg/m2 (SHR 0.63-0.75), smoking (SHR 0.61-0.72), hepatic steatosis (SHR 0.67-0.68) and aspirin/statin/metformin use (SHR 0.67-0.75). A lower risk of liver-related mortality in relation to optimal glycaemic control was also observed (SHR 0.70, 95% CI 0.61-0.80). Glycaemic control is an independent risk factor for HCC and liver-related mortality, and should be incorporated into oncoprotective strategies in the general DM population.

A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B

The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from six centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n= 944), internal validation (n= 1,102), and external validation (n= 2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. During a median follow-up of 55.2 (IQR 30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. The model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and seven variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all p <0.001; area under the receiver-operating characteristic curve: 0.86 vs. 0.62-0.72, all p <0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all p <0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test p >0.05) and these results were reproduced in the internal and external validation cohorts. This novel machine learning model consisting of seven variables provides reliable risk prediction of LROs after HBsAg seroclearance that can be used for personalized surveillance. Using large-scale multinational data, we developed a machine learning model to predict the risk of liver-related outcomes (i.e., hepatocellular carcinoma, decompensation, and liver-related death) after the functional cure of chronic hepatitis B (CHB). The new model named PLAN-B-CURE was constructed using seven variables (age, sex, alcohol consumption, diabetes, cirrhosis, serum albumin, and platelet count) and a gradient boosting machine algorithm, and it demonstrated significantly better predictive accuracy than previous models in both the training and validation cohorts. The inclusion of diabetes and significant alcohol intake as model inputs suggests the importance of metabolic risk factor management after the functional cure of CHB. Using seven readily available clinical factors, PLAN-B-CURE, the first machine learning-based model for risk prediction after the functional cure of CHB, may serve as a basis for individualized risk stratification.

Hepatocellular Carcinoma in Metabolic Dysfunction-Associated Steatotic Liver Disease

In the US, hepatocellular carcinoma (HCC) has been the most rapidly increasing cancer since 1980, and metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to soon become the leading cause of HCC. To develop a prediction model for HCC incidence in a cohort of patients with MASLD. This prognostic study was conducted among patients aged at least 18 years with MASLD, identified using diagnosis of MASLD using International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes; natural language processing of radiology imaging report text, which identified patients who had imaging evidence of MASLD but had not been formally diagnosed; or the Dallas Steatosis Index, a risk equation that identifies individuals likely to have MASLD with good precision. Patients were enrolled from Kaiser Permanente Northern California, an integrated health delivery system with more than 4.6 million members, with study entry between January 2009 and December 2018, and follow-up until HCC development, death, or study termination on September 30, 2021. Statistical analysis was performed during February 2023 and January 2024. Data were extracted from the electronic health record and included 18 routinely measured factors associated with MASLD. The cohort was split (70:30) into derivation and internal validation sets; extreme gradient boosting was used to model HCC incidence. HCC risk was divided into 3 categories, with the cumulative estimated probability of HCC 0.05% or less classified as low risk; 0.05% to 0.09%, medium risk; and 0.1% or greater, high risk. A total of 1 811 461 patients (median age [IQR] at baseline, 52 [41-63] years; 982 300 [54.2%] female) participated in the study. During a median (range) follow-up of 9.3 (5.8-12.4) years, 946 patients developed HCC, for an incidence rate of 0.065 per 1000 person-years. The model achieved an area under the curve of 0.899 (95% CI, 0.882-0.916) in the validation set. At the medium-risk threshold, the model had a sensitivity of 87.5%, specificity of 81.4%, and a number needed to screen of 406. At the high-risk threshold, the model had a sensitivity of 78.4%, a specificity of 90.1%, and a number needed to screen of 241. This prognostic study of more than 1.8 million patients with MASLD used electronic health record data to develop a prediction model to discriminate between individuals with and without incident HCC with good precision. This model could serve as a starting point to identify patients with MASLD who may need intervention and/or HCC surveillance.

Hernandonine-mediated autophagic cell death in hepatocellular carcinoma: Interplay of p53 and YAP signaling pathways

Hepatocellular carcinoma (HCC), the primary form of liver cancer, is the third leading cause of cancer-related death globally. Hernandonine is a natural alkaloid derived from Hernandia nymphaeifolia that has been shown to exert various biological functions. In a previous study, hernandonine was shown to suppress the proliferation of several solid tumor cell lines without affecting normal human cell lines. However, little is known about the effect of hernandonine on HCC. Therefore, this study aimed to investigate the effect and mechanism of hernandonine on HCC in relation to autophagy. We found that hernandonine inhibited HCC cell growth in vitro and in vivo. In addition, hernandonine elicited autophagic cell death and DNA damage in HCC cells. RNA-seq analysis revealed that hernandonine upregulated p53 and Hippo signaling pathway-related genes in HCC cells. Small RNA interference of p53 resulted in hernandonine-induced autophagic cell death attenuation. However, inhibition of YAP sensitized HCC cells to hernandonine by increasing the autophagy induction. This is the first study to illustrate the complex involvement of p53 and YAP in the hernandonine-induced autophagic cell death in human HCC cells. Our findings provide novel evidence for the potential of hernandonine as a therapeutic agent for HCC treatment.

The Influence of Urbanization on the Patterns of Hepatocellular Carcinoma Mortality From 1999 to 2020.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related fatalities despite early diagnosis and treatment progress, creating a significant public health issue in the United States. This investigation utilized death certificate data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database to investigate HCC mortality patterns and death locations from 1999 to 2020. The objective was to analyze trends in HCC mortality across different population groups, considering the impact of urbanicity. In this study, death certificate data obtained from the CDC WONDER database were utilized to investigate the trends in HCC mortality and location of death between 1999 and 2020. The annual percent change (APC) method was applied to estimate the average annual rate of change during the specified timeframe for the relevant health outcome. Furthermore, including data on the location of death and geographic areas allowed us to gain deeper insights into the patterns and characteristics of HCC and its impact on different regions. Between 1999 and 2020, there were 184,073 reported deaths attributed to HCC, and data on the location of death were available for all cases. Most deaths occurred during inpatient admissions (34.93%) or at home (41.19%). The study also found that the highest age-adjusted mortality rate (AAMR) for HCC was observed among male patients, particularly among those identified as Asian or Pacific Islander. Variations in AAMR were determined based on the level of urbanization or rurality of the area, with higher rates observed in more densely populated and urbanized regions. In contrast, less urbanized and populated areas experienced a profound increase in AAMR over the past two decades. The HCC-related AAMRs have worsened over time for most ethnic groups, except for Asian or Pacific Islanders, which showed a reduction in APC despite having the worst AAMR. Although rural and less densely populated areas have substantially increased AAMR over the past two decades, more urbanized areas continued to have higher AAMR rates.

SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells

ABSTRACT AQP3 (aquaporin 3 (Gill blood group)), a member of the AQP family, is an aquaglyceroporin which transports water, glycerol and small solutes across the plasma membrane. Beyond its role in fluid transport, AQP3 plays a significant role in regulating various aspects of tumor cell behavior, including cell proliferation, migration, and invasion. Nevertheless, the underlying regulatory mechanism of AQP3 in tumors remains unclear. Here, for the first time, we report that AQP3 is a direct target for ubiquitination by the SCFFBXW5 complex. In addition, we revealed that downregulation of FBXW5 significantly induced AQP3 expression to prompt macroautophagic/autophagic cell death in hepatocellular carcinoma (HCC) cells. Mechanistically, AQP3 accumulation induced by FBXW5 knockdown led to the degradation of PDPK1/PDK1 in a lysosomal-dependent manner, thus inactivating the AKT-MTOR pathway and inducing autophagic death in HCC. Taken together, our findings revealed a previously undiscovered regulatory mechanism through which FBXW5 degraded AQP3 to suppress autophagic cell death via the PDPK1-AKT-MTOR axis in HCC cells. Abbreviation: BafA1: bafilomycin A1; CQ: chloroquine; CRL: CUL-Ring E3 ubiquitin ligases; FBXW5: F-box and WD repeat domain containing 5; HCC: hepatocellular carcinoma; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; 3-MA: 3-methyladenine; PDPK1/PDK1: 3-phosphoinositide dependent protein kinase 1; RBX1/ROC1: ring-box 1; SKP1: S-phase kinase associated protein 1; SCF: SKP1-CUL1-F-box protein.

Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review.

Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

Autophagy inhibition potentiates energy restriction-induced cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) significantly contributes to cancer-related mortality due to the limited response of HCC to current anticancer therapies, thereby necessitating more effective treatment approaches. Energy restriction mimetic agents (ERMAs) have emerged as potential therapies in targeting the Warburg effect, a unique metabolic process in cancer cells. However, ERMAs exhibit limited efficacy when used as monotherapy. Additionally, ERMAs have been found to induce autophagy in cancer cells. The role of autophagy in cancer survival remains a subject of debate. Thus, it is crucial to ascertain whether ERMA-induced autophagy is a mechanism for cell survival or cell death in HCC. Our study aims to investigate the effect of autophagy inhibition on the survival of HCC cells treated with ERMAs while also examining the potential of combining an autophagy inhibitor such as spautin-1 with ERMAs to enhance HCC cell death. Our results suggest a cytoprotective role for ERMA-induced autophagy in HCC cells, as combining the autophagy inhibitor spautin-1 with ERMAs effectively suppressed ERMA-induced autophagy and synergistically enhanced their antitumor activity. The treatment combination promoted HCC death through apoptosis, cell cycle arrest, and inhibition of AKT and ERK activation, which are known to play a key role in cellular proliferation. Collectively, our findings highlight a potential strategy to combat HCC by combining energy restriction with autophagy inhibition.

Transcriptomic sequencing analysis of key long noncoding RNAs and mRNAs expression profiles in postoperative recurrence of hepatocellular carcinoma.

Recurrence is the main cause of death in hepatocellular carcinoma (HCC) patients after liver resection. The long non-coding RNAs (lncRNAs) have been reported participated in progression and prognosis of HCC, however, the vital role of lncRNA in postoperative recurrence of HCC has rarely been systematically identified. RNA-sequencing (RNA-seq) was performed between orthotopic model of HCC and hepatoma postoperative recurrent model to comprehensively analyze the integrated transcriptome expression profiles of lncRNA and mRNA. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was then conducted to quantify the expression levels of DElncRNAs and their target mRNAs. In our study, 211 lncRNAs (P-value < 0.05) and 1125 mRNAs (P-adjust < 0.05) were significantly differentially expressed (DE) between two groups. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DElncRNAs and DEmRNAs were mainly enriched in lipid metabolism, including Arachidonic acid metabolism, PPAR signaling pathway, Steroid hormone biosynthesis, Linoleic acid metabolism, Inflammatory mediator regulation of TRP channels, and Fatty acid degradation. Furthermore, we constructed lncRNA-mRNA interaction networks and protein-protein interaction (PPI) network, and verified by qRT-PCR, suggesting that increased DEIncRNAs (XLOC_063499 and XLOC_042016) may prevent HCC recurrence after surgery by upregulating on targeted cytochrome P450 (CYP) family genes in the lipid metabolism pathway, such as cyp3a16, cyp3a44, cyp2c39, cyp2c40 and cyp2c68. Overall, Our findings provided new insights for further investigation of biological function in lncRNA related HCC recurrence.

Noncoding RNAs and programmed cell death in hepatocellular carcinoma: Significant role of epigenetic modifications in prognosis, chemoresistance, and tumor recurrence rate.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high death rate in the world. The molecular mechanisms related to the pathogenesis of HCC have not been precisely defined so far. Hence, this review aimed to address the potential cross-talk between noncoding RNAs (ncRNAs) and programmed cell death in HCC. All related papers in the English language up to June 2023 were collected and screened. The searched keywords in scientific databases, including Scopus, PubMed, and Google Scholar, were HCC, ncRNAs, Epigenetic, Programmed cell death, Autophagy, Apoptosis, Ferroptosis, Chemoresistance, Tumor recurrence, Prognosis, and Prediction. According to the reports, ncRNAs, comprising long ncRNAs, microRNAs, circular RNAs, and small nucleolar RNAs can affect cell proliferation, migration, invasion, and metastasis, as well as cell death-related processes, such as autophagy, ferroptosis, necroptosis, and apoptosis in HCC by regulating cancer-associated genes and signaling pathways, for example, phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase/MAPK, and Wnt/β-catenin signaling pathways. It seems that ncRNAs, as epigenetic regulators, can be utilized as biomarkers in diagnosis, prognosis, survival and recurrence rates prediction, chemoresistance, and evaluation of therapeutic response in HCC patients. However, more scientific evidence is suggested to be accomplished to confirm these results.

Machine learning-based disulfidptosis-related lncRNA signature predicts prognosis, immune infiltration and drug sensitivity in hepatocellular carcinoma.

Disulfidptosis a new cell death mode, which can cause the death of Hepatocellular Carcinoma (HCC) cells. However, the significance of disulfidptosis-related Long non-coding RNAs (DRLs) in the prognosis and immunotherapy of HCC remains unclear. Based on The Cancer Genome Atlas (TCGA) database, we used Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression model to construct DRL Prognostic Signature (DRLPS)-based risk scores and performed Gene Expression Omnibus outside validation. Survival analysis was performed and a nomogram was constructed. Moreover, we performed functional enrichment annotation, immune infiltration and drug sensitivity analyses. Five DRLs (AL590705.3, AC072054.1, AC069307.1, AC107959.3 and ZNF232-AS1) were identified to construct prognostic signature. DRLPS-based risk scores exhibited better predictive efficacy of survival than conventional clinical features. The nomogram showed high congruence between the predicted survival and observed survival. Gene set were mainly enriched in cell proliferation, differentiation and growth function related pathways. Immune cell infiltration in the low-risk group was significantly higher than that in the high-risk group. Additionally, the high-risk group exhibited higher sensitivity to Afatinib, Fulvestrant, Gefitinib, Osimertinib, Sapitinib, and Taselisib. In conclusion, our study highlighted the potential utility of the constructed DRLPS in the prognosis prediction of HCC patients, which demonstrated promising clinical application value.

Stromal interaction molecule 1/microtubule-associated protein 1A/1B-light chain 3B complex induces metastasis of hepatocellular carcinoma by promoting autophagy.

Metastasis is the leading cause of death in hepatocellular carcinoma (HCC) patients, and autophagy plays a crucial role in this process by orchestrating epithelial-mesenchymal transition (EMT). Stromal interaction molecule 1 (STIM1), a central regulator of store-operated calcium entry (SOCE) in nonexcitable cells, is involved in the development and spread of HCC. However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear. Here, we demonstrate that STIM1 is temporally regulated during autophagy-induced EMT in HCC cells, and knocking out (KO) STIM1 significantly reduces both autophagy and EMT. Interestingly, STIM1 enhances autophagy through both SOCE-dependent and independent pathways. Mechanistically, STIM1 directly interacts with microtubule-associated protein 1A/1B-light chain 3B (LC3B) to form a complex via the sterile-α motif (SAM) domain, which promotes autophagosome formation. Furthermore, deletion of the SAM domain of STIM1 abolishes its binding with LC3B, leading to a decrease in autophagy and EMT in HCC cells. These findings unveil a novel mechanism by which the STIM1/LC3B complex mediates autophagy and EMT in HCC cells, highlighting a potential target for preventing HCC metastasis.

Assessing the impact of comorbid type 2 diabetes mellitus on the disease burden of chronic hepatitis B virus infection and its complications in China from 2006 to 2030: a modeling study

BackgroundChina bears a high burden of both hepatitis B virus (HBV) infection and type 2 diabetes mellitus (T2DM). T2DM accelerates the progression of liver disease among individuals infected with HBV. This study aims to assess the excess disease burden caused by comorbid T2DM among HBV-infected individuals in China.MethodsWe estimated the disease burden of HBV and its complications in China from 2006 to 2030 using individual-based Markov models. The baseline population consisted of 93 million HBV-infected individuals derived from the 2006 National Serological Epidemiological Survey. We developed two models: one incorporated the impact of T2DM on the disease progression of HBV infection, while the other did not consider the impact of T2DM. By comparing the outcomes between these two models, we estimated the excess disease burden attributable to comorbid T2DM among HBV-infected individuals.ResultsThe incidence of severe HBV complications, including cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths, exhibited an increasing trend from 2006 to 2030 among the Chinese HBV-infected population. Comorbid T2DM increased the annual incidence and cumulative cases of severe HBV complications. From 2006 to 2022, comorbid T2DM caused 791,000 (11.41%), 244,000 (9.27%), 377,000 (8.78%), and 796,000 (12.19%) excess cases of compensated cirrhosis, decompensated cirrhosis, HCC, and liver-related deaths, respectively. From 2023 to 2030, comorbid T2DM is projected to result in an 8.69% excess in severe HBV complications and an 8.95% increase in liver-related deaths. Among individuals aged 60 and older at baseline, comorbid T2DM led to a 21.68% excess in severe HBV complications and a 28.70% increase in liver-related deaths from 2006 to 2022, with projections indicating a further 20.76% increase in severe HBV complications and an 18.31% rise in liver-related deaths over the next seven years.ConclusionsComorbid T2DM imposes a substantial disease burden on individuals with HBV infection in China. Healthcare providers and health policymakers should develop and implement tailored strategies for the effective management and control of T2DM in individuals with HBV infection.

Self-heating mitochondrion-induced free radical blast for immunogenic cell death stimulation and HCC immunotherapy

Hepatocellular carcinoma (HCC) is an immunosuppressive tumor associated with high mortality. Photothermal and photodynamic therapies have been applied to induce immunogenic cell death (ICD) in HCC, successfully eliciting immune responses but facing limitations in penetration depth in clinical trials. Here, intrinsic mitochondrial hyperthermia was used to trigger thermosensitive drug release. The mitochondria were further self-heated through 2,4-dinitrophenol uncoupling, dramatically promoting free radical initiation and inducing tumor ICD. The synthesized mitochondrial-targeting TPP-HA-TDV nanoparticles specifically generated free radicals in the mitochondria without external stimulation, and obviously enhanced the release of ICD markers, subsequently evoking immune responses. The results showed that mitochondrial hyperthermia could be an endogenous target for thermosensitive drug release. Furthermore, self-heating mitochondria-induced free radical blast could be an efficient therapeutic for deep-seated tumor therapy.

Novel Chemo-Photothermal Therapy in Hepatic Cancer Using Gemcitabine-Loaded Hyaluronic Acid Conjugated MoS2/ZnO Nanocomposites.

Hepatocellular carcinoma is a serious illness with a high rate of mortality. A high dose of theranostic drugs with efficient diagnostic and therapeutic capabilities should be required. Chemo-photothermal therapy is presently recognized as a secure method of cancer treatment that specifically targets tumour tissue or cells. Additionally, the success of cancer therapy is increased by the use of targeted nanoparticles. The current study aims to investigate the interaction between phototherapy and the anti-hepatocellular carcinoma treatment combination HA-GEM-MoS2/ZnO nanocomposites (NCs) loaded with gemcitabine and molybdenum disulphide. NCs were synthesized and characterized using FT-IR, XRD, TEM, and DLS analyses. The present investigation shows that the synthesized HA-MoS2/ZnO nanocomposites were elongated spherical in shape and their sizes ranged from 62.3 to 75.7nm according to the estimation using XRD results, which is consistent with TEM findings. Further, HA-MoS2/ZnO nanocomposites could effectively encapsulate the GEM, showing dual pH and thermal triggered drug release behaviour. The result of cell uptake tests clearly demonstrated improved cellular uptake of synthesized nanocomposites following HA and GEM-loaded NCs in hepatocellular carcinoma cell lines. In addition, combination therapies caused the highest incidence of cell death in hepatocellular carcinoma, according to cytotoxicity experiments and showed a good compatibility. In vitro studies prove that HA-GEM-MoS2/ZnO nanocomposites enhanced tumour treatment that combines chemotherapy and photothermal therapy to remove the tumour and prevent relapses. Still, no studies have been done to see if gemcitabine-encapsulated HA-MoS2/ZnO NCs inhibit human hepatocellular carcinoma cell. Hence, the current study can give a new paradigm for the diagnosis and treatment of cancer and the outcome may be helpful to improve the quality of cancer patient's life.