Cellular senescence is a fundamental yet complex defense mechanism that restricts excessive proliferation, maintains cellular homeostasis under various stress conditions-such as oncogenic activation and inflammation-and serves as a dynamic stress response program involved in development, aging, and immunity. Its reversibility depends on essential maintenance components. Cellular senescence is a "double-edged sword": on one hand, it limits the malignant proliferation of damaged cells, thereby preventing tumor development. However, by retaining secretory functions, senescent cells can also induce persistent changes in the microenvironment and disrupt homeostasis, leading to tissue inflammation, fibrosis, and carcinogenesis. Senescence plays a critical role in the pathogenesis of various chronic liver diseases, including chronic viral hepatitis, liver fibrosis, and hepatocellular carcinoma. It exerts a dual influence by facilitating immune evasion and inflammation in chronic viral hepatitis, modulating hepatic stellate cell activity in fibrosis, and reshaping the tumor microenvironment to accelerate hepatocarcinogenesis. This article reviews the characteristics of cellular senescence and its role in the pathogenesis of these chronic liver diseases while exploring potential treatment and prevention strategies. The aim is to provide a comprehensive reference for future clinical and research investigations into chronic liver disease.

HCC ranks as the third leading cause of cancer-related death, yet current surveillance strategies miss over one-third of cases at an early stage. SerpinB3-PD (SB3-PD), a polymorphic isoform of a serine-protease inhibitor involved in tumorigenesis and fibrogenesis, has been related to a more rapid cirrhosis decompensation. This study investigates the prognostic role of SB3-PD in patients with HCC.

SB3-PD polymorphism was assessed in 140 patients with HCC, followed up in our outpatient Clinic. Cell invasion analysis was conducted on HepG2 cells either overexpressing the SB3 wild-type (HepG2/SB3WT) or the PD isoform (HepG2/SB3PD). The effect of recombinant SB3-WT or SB3-PD on the production of molecules that impair immunosurveillance was also assessed in the THP-1 monocytic cell line.

Patients carrying SB3-PD polymorphism showed worse tumour characteristics, associated with significantly lower survival and SB3-PD was an independent predictor of mortality. HepG2/SB3PD cells had a significantly higher invasion capacity than the HepG2/SB3WT. In THP-1 cells recombinant SB3-PD induced higher levels of PDL1 and IL-13 than SB3-WT.

SB3-PD isoform is associated with worse clinical prognosis in patients with HCC. These findings were supported in vitro by increased cellular invasion and higher production of molecules impairing immunosurveillance.

The detection kit for plasma Chitinase-3-like Protein 1 was developed using the magnetic bead chemiluminescence method, in order to investigate the diagnostic value of DD, FDP, CHI3L1, AFP-L3 and PIVKA-II in hepatocellular carcinoma.

The CHI3L1 detection kit was developed using the chemiluminescence method. The luminescence value obtained from the chemiluminescence analyzer was utilized for sensitive detection of CHI3L1, and the performance of the kit was evaluated accordingly. Moreover, this study enrolled 200 patients with hepatocellular carcinoma who were treated at the Oncology Department of the Affiliated Hospital of Jiangnan University between August 2022 and November 2023 as study subjects, while 100 healthy individuals undergoing physical examinations during the same period served as a control group. The plasma CHI3L1 levels in these subjects were measured using our institute's developed kit. Simultaneously, DD, FDP, AFP-L3, and PIVKA-II levels were assessed in all subjects to investigate their relationship with general pathology in patients with hepatocellular carcinoma. Additionally, ROC curves were generated to evaluate both single and combined detections' diagnostic efficacy for hepatocellular carcinoma.

The serological index changes of DD, FDP, AFP-L3, PIVKA-II, and CHI3L1 were not associated with patient gender. The concentrations of AFP-L3 and PIVKA-II in the 45-59 age group were significantly higher than in other groups (P < 0.05). Additionally, DD, CHI3L1, and PIVKA-II levels were markedly elevated in patients with tumors > 5 cm, medium-to-high differentiation, nerve invasion, lymph node metastasis, or distant metastasis. In advanced liver cancer (stages III-IV), DD, FDP, and CHI3L1 concentrations were significantly higher than in early-stage patients (stages I-II). For single diagnostic analysis, the AUC for CHI3L1 was 0.923, while the combined AUC for all five indices was 0.961, indicating greater diagnostic value when used together. The CHI3L1 chemiluminescence detection kit had a minimum detection limit of 1.50 ng/mL, with precision and accuracy within 10%, and R > 0.99. Compared to a clinical reference kit, the correlation coefficient (R) was 0.994, meeting clinical performance evaluation criteria.

The CHI3L1 chemiluminescence kit developed meets clinical requirements. CHI3L1 can be used as an indicator for early screening of liver cancer, and the detection value of combined five indicators DD, FDP, AFP-L3, PIVKA-II and CHI3L1 is higher than that of single detection.

Prediction of prognosis in patients with hepatocellular carcinoma (HCC) by single-omics profiling has been widely studied. However, the prognosis related to biomarkers of multiple omics has not been investigated. We aimed to establish and validate a prediction model for prognosis prediction of resectable HCC combining multi-omics and clinicopathological factors.

The training cohort involved multi-omics data of 330 patients with resectable HCC (stage I-IIIA) at mutational, copy number variation (CNV), transcriptional, and methylation levels from The Cancer Genome Atlas (TCGA) database, along with clinicopathological information. The validation cohort involved samples from 40 HCC patients of Beijing Youan Hospital. Univariate and multivariate analyses were performed in single-omics with clinicopathological variables regarding patient prognosis, and independent risk factors were combined to establish the multi-omics model. The predictive accuracy was assessed by the receiver operating characteristic (ROC) method.

The mutational, copy number, transcriptional, and methylation alterations in HCC were characterized. TP53, CTNNB1, and TTN were among the genes with the top mutational frequency, and FBN1 and MAP1B mutations were independent risk factors for patient overall survival (OS). 1q21.3 and 1q23.3 ranked the highest in copy number amplifications, and 8p12 and 8p23.3 ranked the highest in deletions, and CSMD1, TP53, and RB1 were genes with the most frequent CNVs. AFP, GPC3, and TERT were among genes with the most significant aberrant transcription, and the transcription of CCNJL, FRMD1, and GRPEL2 were independent risk factors for OS. Both hypermethylation and hypomethylation can be observed. The aberrant methylation of CXorf15, DACT2, GP6, KIAA1522, and PDIA3 were independent risk factors. Single-omics models were established with independent risk factors, and were validated by internal and external datasets. A prognostic model for OS with multi-omics independent risk factors and clinicopathlogical information was established. Internal and external validation achieved an optimal maximal area under the curve (AUC) of 0.98 at 1 year and 0.88 at 2 years, respectively.

A multi-omics model combining molecular aberrancies and clinicopathological information was established and proved to be optimal for prognosis prediction of resectable HCC. This model may be helpful for therapeutic strategy selection and survival assessment.

Drug resistance reflects the evolution of tumors and represents the leading factor behind recurrence and death. Lenvatinib is the first-line therapy for hepatocellular carcinoma (HCC), but its effectiveness is limited by rapid development of resistance. Therefore, we aimed to identify lenvatinib resistance-related genes and assess their influence on prognosis and treatment response in HCC.

The GSE186191 dataset served as the discovery cohort to identify lenvatinib resistance-related genes. A Venn diagram analysis delineated the intersection between lenvatinib resistance-related genes and prognostic-associated genes derived from The Cancer Genome Atlas (TCGA) database. The LASSO Cox regression model was implemented to construct a multigene signature in the TCGA cohort. A nomogram was built by integrating the TNM stage and our prognostic model. The gene signature and nomogram were further validated using HCC patients from the International Cancer Genome Consortium (ICGC) cohort. Mutation signatures, therapeutic response, functional enrichment, and immune profile analyses were performed in the two groups. Two lenvatinib-resistant (LR) HCC cells were established using a concentration gradient increment method. PFKFB4 expression was detected via qRT-PCR and western blot assay. The CCK-8 assay and flow cytometry were utilized to evaluate the proliferation and apoptosis of LR cells under different interventions.

We developed a lenvatinib resistance-related gene signature (ALPK3, SLC2A2, CTSV, and PFKFB4), and demonstrated that's a precise, independent, and specific prognostic model for HCC patients. High-risk patients were characterized by a predisposition to TP53 mutations, aggressive tumor features, and treatment resistance. The risk score was significantly associated with immune cell infiltration, immune checkpoint expression, angiogenesis, and tumor stemness. PFKFB4 was overexpressed in LR cells, and its knockdown significantly enhances the antiproliferative and pro-apoptotic effects of lenvatinib on resistant cells.

The lenvatinib resistance-related prognostic signature exhibits strong predictive power for prognosis in HCC patients and may serve as an effective tool for guiding treatment decisions. PFKFB4 promotes tumor progression and lenvatinib resistance, highlighting its potential as a novel therapeutic target for HCC.

Not applicable.

Cancers of the gastrointestinal tract exhibit a high detection rate, ranking as the fifth most common malignant tumor and the fourth leading cause of cancer-related death. In addition to primary malignant tumors of the gastrointestinal tract, secondary metastatic tumors significantly impact patient survival. The differentiation between primary and secondary gastrointestinal tumors remains a critical issue requiring further research and analysis.

This is a retrospective, observational study conducted from 2000 to 2023. We systematically searched the literature in PubMed, EMBASE, and COCHRANE databases from January 1, 2000, to November 31, 2023. Patients diagnosed with gastrointestinal (GI) tract metastasis were included in the study.

A total of 165 patients were enrolled in this study. The most prevalent primary tumors were breast cancer (50.30%), renal cancer (16.96%), lung cancer (16.36%), melanoma (12.72%), and liver cancer (3.63%). The median interval between the diagnosis of the primary tumor and the detection of GI metastatic lesions was 8.53 years (range: 1-25 years). The most frequent endoscopic finding was a solitary mucosal or submucosal lesion situated in the gastric body. Metastases to extra-gastrointestinal organs were observed in the majority of patients. The integration of endoscopic biopsy with pathological and immunohistochemical analyses is essential for identifying the tumor origin. Surgical intervention in patients lacking extra-gastrointestinal metastases may improve prognosis.

Breast, renal, lung, liver cancer, and melanoma were identified as the most frequent primary tumors. Clinical symptoms and endoscopic features were unable to predict the primary sites, which still require immunohistochemical analysis for accurate identification. The intervention modality and the presence or absence of distant metastasis significantly influenced patient prognosis.

Hepatocellular carcinoma (HCC) is a chronic liver disease characterized by persistent tumor growth, contributing significantly to mortality rates worldwide. Consequently, there is an urgent need to develop effective diagnostic and treatment strategies for HCC. This study aims to identify crucial genes for early HCC diagnosis to mitigate disease progression and to investigate differences in immune cell infiltration between early-stage and late-stage HCC. We integrated two published datasets for a comprehensive analysis, identifying 575 DEGs subjected to GSEA to reveal pathways distinguishing early-stage from late-stage HCC. Notably, the gene SLC6A8 emerged as a potential diagnostic biomarker for late-stage HCC through machine learning (LASSO-LR/SVM-RFE/RF-Boruta). ROC curves for SLC6A8 were utilized to evaluate diagnostic accuracy. The ImmuCellAI algorithm assessed immune cell composition differences between early and late-stage HCC, revealing that SLC6A8 expression positively correlates with resting Tfh cells and Th2, while negatively correlating with B cells, indicating its association with immune cell infiltration patterns. To strengthen our results, we further analyzed SLC6A8 expression using single-cell transcriptome data, confirming notably overexpression in late-stage HCC, particularly in key liver cell types such as Hepatocyte cells. Overall, our study nominates SLC6A8 as a dual biomarker for HCC Staging and precision therapy.

Hepatocellular carcinoma is frequently unrecognized in its early stage limiting the access to the first therapeutic steps resulting in a low cure rate. Therefore, an early diagnosis is crucial. In this scenario the analysis of lipidome and metabolome emerged as a promising tool for early detection.

Aim of the study was to characterize metabolomic profiles as novel markers of early hepatocellular carcinoma.

Serum basal levels of metabolites, isolated from a cohort of 90 patients (n = 30 early stage; n = 30 advanced stage; n = 30 liver cirrhosis) were analysed using a nuclear magnetic resonance spectroscopy platform. To assess the predictive value of nuclear magnetic resonance profiles, we included the magnetic resonance imaging follow up of control patients with liver cirrhosis.

Significant differences were observed in the levels of individual parameters that included total cholesterol, LDL and HDL subclasses, Isoleucine, Valine, Triglycerides, Lactate, Alanine, Albumin, alpha Fetoprotein, Dimethylamine, Glycerol, and total Bilirubin levels in cancer compared to liver cirrhosis (p < 0.05). Furthermore, a significant difference in glycerol levels (p < 0.05) and a decreasing trend in dimethylamine were observed in cirrhotic patients who later developed HCC (16%, n = 5). Retrospective MRI analysis revealed precursor lesions in 3/5 patients, initially not classified as HCC due to their size and hemodynamic features.

Nuclear magnetic resonance based assessment of lipidomic and metabolomic profiles permit the differentiation of cancer from liver cirrhosis. The data obtained suggests a possible role of lipidomic based serum profiles for early detection.

To evaluate the reliability of serum human phosphorylated exospindle polar-like proteinase 1 (ESPL1) as a serum biomarker for early diagnosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV-HCC).

This retrospective study was conducted on 266 patients with chronic hepatitis B (CHB), liver cirrhosis (LC), and HBV-related HCC. Data on demographics and clinical information were collected, and ESPL1 levels were measured using enzyme linked immunosorbent assay. Levels of ESPL1, alpha-fetoprotein (AFP), and protein induced by vitamin K absence -II (PIVKA-II) were compared at different disease stages, and spearman correlation analysis was used to assess their relationship with clinical markers. The diagnostic accuracy of ESPL1, AFP, and PIVKA-II for early HBV- HCC was assessed using ROC curve analysis.

The study comprised 121 patients diagnosed with CHB, 98 patients with LC, and 47 patients with HBV-HCC. Serum ESPL1 levels show an increasing trend across groups with chronic HBV infection, CHB, LC, and HBV-HCC, with levels at 224.6 ng/L, 285.8 ng/L, and 440.4 ng/L (in pairwise comparison, P<0.05). Serum AFP and PIVKA-II levels displayed no significant statistical differences between the CHB and LC groups. Spearman correlation analysis revealed that levels of ESPL1, PIVKA-II, and AFP are not influenced by clinical characteristics and show no correlation with each other. ROC curve analysis indicated that the optimal diagnostic threshold for ESPL1 in HBV-HCC is 345.7 ng/L, with AUC values for ESPL1, PIVKA-II, and AFP being 0.797 (95% CI: [0.708-0.886]), 0.788 (95% CI: [0.718-0.858]), and 0.572 (95% CI: [0.523-0.624]). In AFP and PIVKA-II negative patients, the AUC values for ESPL1 diagnosis of HBV-HCC were 0.79 and 0.83.

ESPL1 is a potential biomarker for tracking chronic HBV infection and predicting the development of HBV-HCC. Monitoring ESPL1 levels in serum could help with early detection and personalized screening HBV-HCC for individuals with chronic HBV infection.

Hepatitis B virus (HBV)-related liver cancer is the third most common cause of cancer-related death globally. Hepatocyte remodeling, also known as hepatocyte transformation and immortalization, and hepatocellular carcinoma (HCC), are brought on by persistent inflammation caused by HBV in the host hepatocytes. One of the main concerns in the perspective of HBV-induced hepatocyte remodeling and liver cancer is accurately identifying cancer stages to maximize early screening and detection. Biological signatures have a significant impact on solving this problem.

This review article aimed to discuss the novel serum protein biomarkers for HBV-induced hepatocyte remodeling and HCC.

The information was collected from various peer-reviewed journals through electronic searches utilizing various search engines, including PubMed, Google Scholar, HINARI, and Cochrane Library from 2017 to 2024. Keywords for searches included "serum protein biomarkers in HBV-HCC," "blood-based biomarkers in HBV-HCC," and "viral biomarkers for HBV-HCC."

Recently, novel protein signatures have been discovered for the early diagnosis, treatment, and prognosis of HBV-induced hepatic cell remodeling and HCC from proteomic data sets. We have discussed the recent literature on the clinical utility of the protein signatures for the diagnosis and forecasting of HBV-associated hepatocyte remodeling and HCC, including golgi protein 73 (GP73), glypican-3 (GPC3), midkine (MDK), des-γ-carboxy-prothrombin (DCP), von Willebrand factor (vWF), pentraxin 3 (PTX3), pseudouridine synthases 7 (PUSs 7), squamous cell carcinoma antigen (SCCA), and osteopontin (OPN).

All these protein markers also exhibit the survival of HBV-related HCC patients, the proliferation, migration, antiapoptosis, mitogenesis, transformation, and angiogenesis of HBV-infected hepatocytes.

Potassium channel-related genes (PCRGs) play an important role in hepatocellular carcinoma (HCC) development, recurrence, and immunotherapy tolerance. We aimed to develop a new prognostic model associated with PCRGs that can be used for prognosis and immunotherapy prediction in HCC patients. The transcriptional profiles and clinical data related to HCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed PCRGs were identified using the "edgeR" package. Prognostic model associated with PCRGs were constructed using univariate analysis, least absolute shrinkage and selection operator (LASSO), and multivariate regression analysis. The prognostic value of the model was evaluated through Kaplan-Meier (K-M) survival analysis and receiver operating characteristic (ROC) curves. Additionally, the tumor immune microenvironment was assessed using single sample gene set enrichment analysis (ssGSEA) and the CIBERSORT algorithm. Finally, potential drugs targeting signature genes were predicted. We successfully constructed a prognostic signature based on PCRGs, and the prognostic results were superior in the low-risk group. The nomogram demonstrated satisfactory predictive performance in estimating overall survival (OS) in HCC patients. The results of immune cell infiltration and predictions of immunotherapy response revealed that the low-risk group exhibited a more favorable response to immunotherapy. In addition, signature gene expression was significantly correlated with antitumor drug sensitivity. In conclusion, the characteristics of PCRGs serve as valuable tools for accurately assessing the prognosis and tumor microenvironment of HCC patients. Additionally, PCRGs markers can facilitate precision therapy in HCC management.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by a high rate of postoperative recurrence and poor long-term survival outcomes. Structural maintenance of chromosome 4 (SMC4) is frequently overexpressed in various types of cancer and plays a pivotal role in tumor cell growth, migration, and invasion. Bioinformatics analysis has revealed a significant correlation between the tumor-node metastasis (TNM) stage (P < 0.01) and SMC4 expression (P < 0.05), and SMC4 was associated with poor prognosis in HCC. Furthermore, SMC4 was identified as an independent prognostic factor for HCC. Ubiquitin-specific peptidase 39 (USP39) was found whether the regulation was observed to affect protein synthesis or stability through bioinformatics analysis and immunoprecipitation. The expression levels and cellular localization of SMC4 and USP39 in hepatoma cells were evaluated using quantitative real-time PCR (qPCR), western blotting, and immunohistochemistry (IHC), all of which indicated significantly elevated expression of USP39 and SMC4 in HCC. The roles of the SMC4/USP39 were further investigated through several assays, including the 3-(4,5-Dimethylthiazol-2-yl) -2,5- diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and wound healing assay. The results demonstrated that USP39/SMC4 plays a crucial role in enhancing the viability and proliferation of HepG2 cells. Additionally, bioinformatics analysis identified ZNF207 and TIAL1 as potential target proteins of SMC4. Drug-resistant hepatoma cell lines were established, and both MTT and EdU assays were performed to assess cell viability and proliferation. The results demonstrated that HepG2/5-FU cells regained their sensitivity to 5-FU following the knockdown of SMC4. Additionally, the knockdown of either TIAL1 or ZNF207 also restored 5-FU sensitivity in HepG2/5-FU cells, effectively inhibiting cell viability and proliferation. Our study underscores the significant role of the USP39/SMC4 in HCC development and suggests that SMC4 may contribute to the regulation of drug resistance in hepatoma cell lines, potentially through interactions with TIAL1 and ZNF207.

Although Cell growth regulator with EF-hand domain 1 (CGREF1) has been predicted to be upregulated in multiple cancer types, its definitive function role in carcinogenesis, particularly in hepatocellular carcinoma (HCC), remains poorly characterized.

Comprehensive bioinformatics analysis was initially conducted using the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate CGREF1 mRNA expression patterns in HCC tissues and their clinical correlation with patient survival outcomes. Experimental validation was subsequently performed through real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), and Western blot techniques. Functional characterization studies employing genetic knockdown and overexpression models in HCC cell lines demonstrated CGREF1's regulatory effects on malignant phenotypes, as evidenced by 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and Transwell migration and invasion assays. were adopted to investigate the role of CGREF1 in the proliferation, invasion, and migration of HCC cells. Mechanistic investigations integrating bioinformatics predictions with Western blot analysis revealed CGREF1 mediated-modulation of the Wnt/β-Catenin signaling axis, elucidating its molecular underpinnings in HCC progression.

The results demonstrated that CGREF1 is highly expressed in HCC tissues, and HCC patients with elevated CGREF1 expression exhibited significantly shorter survival times. Upregulation of CGREF1 promoted the proliferation, migration, and invasion of HCC cells, whereas inhibition of CGREF1 expression suppressed these phenotypes. Mechanistically, CGREF1 activates the Wnt/β-Catenin signaling pathway through the upregulation of eukaryotic translation initiation factor 3 H subunit (EIF3H). Furthermore, partial inhibition of EIF3H attenuated the effects of CGREF1 overexpression on the proliferation, migration, and invasion of HCC cells.

CGREF1 is upregulated in HCC and acted as an oncogene through the CGREF1/EIF3H/Wnt/β-Catenin signaling axis. These findings suggest that CGREF1 may emerge as a potential therapeutic target for HCC.

While the value of Des-γ-carboxy prothrombin in hepatocellular carcinoma diagnosis has been widely acknowledged, whether or how Des-γ-carboxy prothrombin could be used in recurrence evaluation remains largely unexplored.

We performed a multicenter retrospective analysis including an Exploration Cohort (1074 patients, 5133 Des-γ-carboxy prothrombin measurements) and a Validation Cohort (263 patients, 612 Des-γ-carboxy prothrombin measurements) to investigate whether Des-γ-carboxy prothrombin could evaluate patients' prognosis. We introduced the Des-γ-carboxy prothrombin dynamic rate as a normalized quantitative measurement of Des-γ-carboxy prothrombin dynamic change. Des-γ-carboxy prothrombin dynamic rates were further applied in a high-risk liver cirrhosis patient cohort (PreCar Cohort, 542 liver cirrhosis patients, 2023 Des-γ-carboxy prothrombin measurements).

Here, we show a post-operative decrease of Des-γ-carboxy prothrombin in the Exploration Cohort, making the Des-γ-carboxy prothrombin threshold in diagnosis unsuitable for prognosis, while Des-γ-carboxy prothrombin dynamic rates significantly associate with recurrence risk. Categorizing patients based on Des-γ-carboxy prothrombin dynamic rates and final concentrations shows that patients negative for both exhibit the best median recurrence-free survival and patients positive for both show the worst median recurrence-free survival. Patients with consistently positive status have a significantly lower median recurrence-free survival compared to those whose status reverted to negative. These findings are validated in the Validation Cohort. Furthermore, the Des-γ-carboxy prothrombin dynamic rates in the PreCar Cohort can identify an additional 28% of cirrhosis patients progressing to hepatocellular carcinoma.

These results expand on the clinical utilization of the hepatocellular carcinoma diagnosis biomarker, Des-γ-carboxy prothrombin, by proposing a quantification measurement of Des-γ-carboxy prothrombin dynamics to monitor hepatocellular carcinoma recurrence. This measurement is not limited in prognosis but can also improve the sensitivity of early hepatocellular carcinoma screening.

Hepatocellular carcinoma (HCC) can be classified into several subtypes based on molecular traits, aiding in prognostic stratification. The subtype with a poor prognosis is often associated with stem/progenitor features. This study focused on identifying circulating biomarkers for aggressive HCC.

We searched for secretory proteins whose expression was positively associated with the stem/progenitor markers KRT19, EPCAM, and PROM1 in 2 independent HCC cohorts. Serum folate receptor 1 (FOLR1) levels were measured in 238 chronic liver disease and 247 HCC patients, evaluating their diagnostic and prognostic capabilities.

FOLR1 was identified as a secretory protein that was positively correlated with all 3 stem/progenitor markers and a poor prognosis in both the discovery and validation cohorts. Higher FOLR1 expression was detected in tumor than nontumor tissues and was associated with aggressive subtypes, and activation of p53, DNA repair, Myc, E2F, and PI3K/AKT/mTOR pathways. Serum FOLR1 levels correlated with tumoral FOLR1 expression in HCC patients and were significantly elevated compared with those in patients with chronic hepatitis or nonliver disease. Serum FOLR1 levels demonstrated diagnostic performance for HCC comparable to that of alpha-fetoprotein (AFP), and their combination increased the diagnostic accuracy. Elevated serum FOLR1 levels were associated with poor prognosis in HCC patients, regardless of treatment, especially in patients with early-stage disease. The multivariate analysis revealed that the serum FOLR1 level and the Gender, Age, AFP-L3, AFP, and Des-gamma-carboxy prothrombin (GALAD) score were independent predictors of a poor prognosis with their combination further stratifying prognosis.

FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.

Large language models (LLMs) hold significant promise in the field of medical diagnosis. There are still many challenges in the direct diagnosis of hepatocellular carcinoma (HCC). α-Fetoprotein (AFP) is a commonly used tumor marker for liver cancer. However, relying on AFP can result in missed diagnoses of HCC. We developed an artificial intelligence (AI) agent centered on LLMs, named ChatExosome, which created an interactive and convenient system for clinical spectroscopic analysis and diagnosis. ChatExosome consists of two main components: the first is the deep learning of the Raman fingerprinting of exosomes derived from HCC. Based on a patch-based 1D self-attention mechanism and downsampling, the feature fusion transformer (FFT) was designed to process the Raman spectra of exosomes. It achieved accuracies of 95.8% for cell-derived exosomes and 94.1% for 165 clinical samples, respectively. The second component is the interactive chat agent based on LLM. The retrieval-augmented generation (RAG) method was utilized to enhance the knowledge related to exosomes. Overall, LLM serves as the core of this interactive system, which is capable of identifying users' intentions and invoking the appropriate plugins to process the Raman data of exosomes. This is the first AI agent focusing on exosome spectroscopy and diagnosis, enhancing the interpretability of classification results, enabling physicians to leverage cutting-edge medical research and artificial intelligence techniques to optimize medical decision-making processes, and it shows great potential in intelligent diagnosis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Unfortunately, the effective targeted therapies for HCC are lacking at present. While the regulation of microRNA-1246 (miR-1246) has been identified in HCC, its specific mechanism in exosomes derived from HCC remains elusive. This study aimed to explore the regulation of tumor-derived exosome miR-1246 in HCC cell invasion, migration, proliferation, and epithelial-mesenchymal transition (EMT).

Exosomes secreted by HepG2 cells were characterized via Western blotting, nanoparticle tracking analysis, and transmission electron microscopy, followed by transfection with a miR-1246 inhibitor. RT-qPCR was employed for measuring the miR-1246 levels. Also, the impacts of the exosome miR-1246 inhibitor on HepG2 cell migration, invasion, proliferation, and EMT were evaluated.

The findings revealed elevated miR-1246 levels in HCC tissues relative to adjacent non-cancerous tissues, with a greater enrichment of miR-1246 in HepG2-derived exosomes than in HepG2 cells. HCC cell invasion, migration, proliferation, and EMT were significantly enhanced by HCC-derived exosomes, while exosomes loaded with miR-1246 inhibitor inhibited these biological functions. Further mechanistic studies illustrated an association of the regulatory role of miR-1246 with FSTL5 and ERK/p38 MAPK signaling.

In conclusion, tumor-derived miR-1246 enters hepatocellular carcinoma cells in the form of exosomes and promotes cancer cell invasion, EMT, and migration. The potential mechanism of miR-1246 is potentially relevant to the targeted gene FSTL5 as well as the ERK/p38 signaling.

The most susceptible loci of hepatocellular carcinoma (HCC) identified by genome-wide association studies are located in non-coding regions. The antisense non-coding RNA at the INK4 locus (ANRIL), also known as cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), is a long non-coding (lnc)RNA situated within and antisense to genes encoding CDKN2A/B on chromosome 9p21.3. Single-nucleotide polymorphisms (SNPs) within CDKN2B-AS1 are associated with several cancer types, but their impacts on HCC remain unclear. In this study, we investigated the effects of CDKN2B-AS1 SNPs on both the susceptibility to HCC and its clinicopathological development. Five CDKN2B-AS1 SNP loci-rs564398 (T/C), rs1333048 (A/C), rs1537373 (G/T), rs2151280 (A/G) and rs8181047 (G/A)-were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 810 HCC patients and 1190 healthy controls. Under the dominant model, HCC patients with at least one minor C-allele of rs564398 showed a lower risk of liver cirrhosis (odds ratio (OR) = 0.677). Additionally, HCC patients with the GT + TT genotype of rs1537373 had a reduced risk of developing large tumours (T3 + T4) and advanced clinical stages (III/IV), particularly in the male population (OR = 0.644 and 0.679). Furthermore, data from The Cancer Genome Atlas revealed that CDKN2B-AS1 expression levels were elevated in HCC tissues compared to normal tissues and were correlated with advanced T stages, high histological grades and poor prognoses. Our findings suggest that CDKN2B-AS1 levels and its polymorphic variants at rs564398 and rs1537373 may influence the clinicopathological development and progression of HCC in a Taiwanese population.

Incidental hepatocellular carcinoma (iHCC) is a growing concern in liver transplantation, where tumors are unexpectedly discovered during histopathological examination of explanted livers. The prevalence of iHCC varies widely, with reported rates between 1.6 % and 40 %, influenced by differences in diagnostic practices and patient populations. Recent studies, including that by Kerstens et al., highlight the clinical significance of iHCC, revealing its association with alcohol-related liver disease and the limitations of current surveillance strategies. Conventional imaging techniques, such as ultrasound, often fail to detect small tumors, leading to delayed diagnosis. Advanced imaging modalities, including MRI, and emerging biomarkers, such as des-γ-carboxy prothrombin (DCP), are improving detection, but further research is needed to refine diagnostic protocols. The growing recognition of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) complicates the surveillance of iHCC, particularly as patients with MASLD often present with subtle or atypical clinical profiles. Personalized surveillance, incorporating advanced technologies like liquid biopsy and artificial intelligence, holds promise for improving early detection. Additionally, individualized post-transplant management strategies are crucial, given the lower survival rates observed in iHCC patients. As our understanding of iHCC evolves, a shift toward more tailored approaches in diagnosis, surveillance, and treatment is essential to improve outcomes and reduce the burden of incidental HCC in liver transplantation.

Hepatocellular carcinoma (HCC) is a serious and often lethal cancer, particularly in patients with chronic liver disease. Currently, no specific treatment has been utilised to prevent HCC. The detailed mechanism of HCC is still elusive, and this study aims to identify and characterise the functional activity changes in residual tumour cells following intraoperative cell salvage (IOCS) treatment during HCC surgery. This research is a retrospective case-control study, involving the selection of 60 patients with HCC who underwent radical surgery; then blood and tumour tissue were collected for further testing. GC-MS assay, immunofluorescence, Western blot and qRT-PCR techniques were employed. Our study found comparable demographic and baseline clinical characteristics between the experimental group (n = 30), which received IOCS treatment during surgery, and the control group (n = 30), which did not receive IOCS treatment, validating subsequent analyses. Metabolomic analysis revealed six key metabolites differing between groups, indicating improvement in liver tumours in the experimental group. TP53 expression was significantly upregulated, potentially mediating therapeutic effects. The intervention reduced HCC cell migration and apoptosis, decreased E2F1 and MDM2 protein and mRNA levels, and increased TP53 and CTNNB1 levels. These findings support the potential clinical application of the intervention in improving treatment outcomes for HCC patients, warranting further investigation to elucidate the underlying mechanisms and optimise therapeutic strategies.

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor, and the current treatment methods exhibit various limitations. In recent years, the role of mitochondrial permeability transition-driven necrosis-related genes (MPT-DNRGs) in the pathogenesis and progression of severe diseases, particularly tumors, has garnered significant attention. This study aimed to identify new targets and concepts for MPT-DNRG-targeted therapy in HCC.

In this study, we utilized HCC-related datasets and MPT-DNRGs to identify differentially expressed genes (DEGs) between HCC patients and control groups. By conducting a cross-analysis of the results of DEGs and MPT-DNRGs, we screened candidate genes. Subsequently, univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis methods were employed to identify prognostic genes, which were used to construct a risk model and calculate individual risk scores for HCC patients. Additionally, we performed univariate and multivariate Cox regression analyses to identify independent prognostic factors and constructed a column chart based on these factors to predict the survival probability of HCC patients. Furthermore, gene set enrichment analysis (GSEA), the immune microenvironment, chemotherapy drugs, and the expression of prognostic genes between the two groups were analyzed. Finally, the expression of these prognostic genes was further confirmed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) technology.

In this study, we identified 8,515 DEGs between HCC and control samples. By performing intersection analysis between DEGs and MPT-DNRGs, we pinpointed 15 candidate genes. Subsequently, through univariate Cox regression and LASSO regression analysis, we identified six genes (LMNB2, LMNB1, BAK1, CASP7, LMNA, and AKT1) that were significantly associated with overall survival (OS) in patients. Based on the median risk score, we categorized HCC patients into high-risk and low-risk groups. Kaplan-Meier (KM) survival analysis results demonstrated a significant difference in OS between the two groups, which was further validated through additional assessment. Furthermore, we constructed a nomogram to predict the survival probability of HCC patients. Moreover, GSEA revealed a crucial correlation between these genes and HCC, and highlighted a close association between risk scores and regulatory T cells. We also identified four chemotherapy drugs related to HCC. Finally, in both the training and validation cohorts, LMNB2, LMNB1, and LMNA exhibited high expression levels in tumor samples. Further validation using RT-qPCR confirmed that the expression of all prognostic genes was significantly higher in HCC group compared to the control group.

This study explored six prognostic genes (LMNB2, LMNB1, BAK1, CASP7, LMNA and AKT1) associated with MPT-DNRGs in HCC, which provides a reference for further research on HCC.

Interferon-Induced Protein with Tetratricopeptide Repeats 3 (IFIT3) plays a dual role in innate immunity and tumor immunity, functioning as both a viral defense molecule and a regulator of tumor progression. This review explores the mechanisms through which IFIT3 modulates immune responses, including interferon signaling, RIG-I-like receptors, and the NF-κB pathway. IFIT3 facilitates immune evasion and promotes inflammation-mediated tumor growth by regulating immune checkpoints and the tumor microenvironment, its emerging role as a target for cancer immunotherapy opens new avenues for therapeutic strategies. Finally, this paper underscores IFIT3's potential clinical applications in the modulation of tumor immunity, highlighting the need for further research on IFIT3-targeted therapies.

This article highlights Peru's experience in establishing a national tumor bank network, serving as a model for low- and middle-income countries. Launched in 2005 at the National Institute of Neoplastic Diseases, efforts accelerated under the 2021 National Cancer Act, which formalized the National Tumor Bank and its integration with the National Oncology Network. This initiative connects tumor banks across regional cancer institutes, enabling systematic biological sample collection, particularly from underrepresented populations, such as those with high Amerindian ancestry. Ethical oversight, technical standards, and specialized management software ensure efficient data sharing and genomic research. The network supports cancer research through integration with the Population Cancer Registry, providing unique insights into cancer incidence and outcomes. To date, 5992 cases have been documented. Through international collaboration with Latin American countries, Peru provides a framework for inclusive cancer research, enriching global genomic datasets and strengthening research capacity in diverse and vulnerable populations.

Alpha-fetoprotein (AFP) is a key biomarker for hepatocellular carcinoma (HCC), but 30-40% of cases are AFP-negative. Prothrombin induced by vitamin K absence II (PIVKA-II) is more sensitive for HCC detection, though its role in systemic therapy remains underexplored. This study aimed to evaluate PIVKA-II in non-AFP-secreting HCC treated with systemic therapy.

Patients with unresectable HCC undergoing systemic therapy were enrolled. Baseline imaging and PIVKA-II levels were recorded. After 8-12 weeks of treatment, response was evaluated through imaging and repeat PIVKA-II measurements.

A total of 116 treatment assessments from 61 cases were analyzed. Baseline PIVKA-II levels correlated with tumor size, but not tumor number or liver function. PIVKA-II regression (≥ 50% reduction) and progression (≥ 50% increase) were defined using ROC analysis. Imaging showed 71.0% objective response in the regression group, 50.0% stable disease in the stable group, and 83.7% progressive disease in the progression group (p < 0.001). This association held for targeted therapies, immune checkpoint inhibitors, and chemotherapy. Progression-free survival (PFS) for the regression, stable, and progression groups was non-reached, 6.7, and 3.2 months (p = 0.0002), and overall survival (OS) was non-reached, non-reached, and 18.5 months (p = 0.02).

This study is the first to establish the "50-50 rule" for PIVKA-II response in non-AFP-secreting HCC treated with systemic therapy, highlighting its value as a surrogate marker for radiological outcomes and prognosis.

The detection of disease-related protein biomarkers plays a crucial role in the early diagnosis, treatment, and monitoring of diseases. The concentrations of protein biomarkers can vary significantly in different diseases or stages of the same disease. However, most of the existing analytical methods cannot simultaneously meet the requirements of high sensitivity and a wide dynamic range. Herein, we developed a digital and analog immunoassay method based on submicron magnetic beads and fluorescent microspheres. The digital analysis achieves a limit of detection as low as 46 fg/mL (1.8 fM) for IL-6, and the analog analysis has a wide dynamic range spanning from 0.2 pg/mL to 10 ng/mL. Furthermore, the analog analysis can be used to quickly and roughly assess higher concentration proteins via visual detection, and the practical application potential of this method was verified by the detection of alpha-fetoprotein in serum samples from 12 healthy individuals and hepatocellular carcinoma patients. The established method does not involve the use of enzymes or costly instruments, which greatly simplifies the experimental steps, shortens the experimental time, and reduces the experimental cost. In view of those advantages, the proposed method has great application prospects in point-of-care applications.

The indication of laparoscopic liver resection (LLR) for treating large hepatocellular carcinoma (HCC) is controversial. In this study, we compared the short-term and long-term outcomes of LLR and open liver resection (OLR) for large HCC.

We searched eligible articles about LLR versus OLR for large HCC in PubMed, Cochrane Library, and EMBASE and performed a meta-analysis.

Eight publications involving 1,338 patients were included. Among them, 495 underwent LLR and 843 underwent OLR. The operation time was longer in the LLR group (MD: 22.23, 95% CI: 4.14-40.33, p = 0.02). but the postoperative hospital stay time was significantly shorter (MD : -4.88, CI: -5.55 to -4.23, p < 0.00001), and the incidence of total postoperative complications and major complications were significantly fewer (OR: 0.49, 95% CI:0.37-0.66, p < 0.00001; OR: 0.54, 95% CI:0.36 - 0.82, p = 0.003, respectively). Patients in the laparoscopic group had no significant difference in intraoperative blood loss, intraoperative transfusion rate, resection margin size, R0 resection rate, three-year overall survival (OS) and three-year disease-free survival (DFS).

LLR for large HCC is safe and feasible. This surgical strategy will not affect the long-term outcomes of patients.

Despite numerous attempts to understand the molecular mechanisms behind the development of liver cancer, it continues to pose a significant worldwide health challenge. Transcriptome sequencing, a powerful tool in molecular biology, has played a pivotal role in uncovering the intricate gene expression profiles underlying hepatocellular carcinoma (HCC). In the present study, we identified a total of 808 differentially expressed genes (DEGs), with 584 exhibiting downregulation, and 224 showing upregulation following apigetrin treatment. We utilized a combination of bioinformatics tools and platforms, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and mapping, Protein-Protein Interaction (PPI), and GEPIA. We found that DEGs were related to the apoptotic cell death process and identified hub genes, namely CASP8, RB1, and TGFBR2. These genes were further validated through both GEPIA analysis and western blot experiments. Our findings collectively demonstrate that apigetrin has the potential to modulate genes related to liver cancer and trigger molecular pathways that lead to apoptotic cell death in liver cancer cells. This study underscores the potential of apigetrin as an innovative treatment strategy for HCC, emphasizing the need for additional research to elucidate its mechanisms of action and evaluate its clinical efficacy.

Dysregulation of SF3A3 has been related to the development of many cancers. Here, we investigated the functional role of SF3A3 in hepatocellular carcinoma (HCC).

SF3A3 expression in HCC tissues and cell lines was examined using RT-qPCR. Changes in malignant behavior of HCC cells after downregulation of SF3A3 were assessed by EdU, colony formation, flow cytometry, wound healing, and Transwell invasion assays. Multiple datasets were combined to identify the upstream modifiers of SF3A3. The binding relationship between STIL and FOXM1 was explored by co-IP assay, and the effect of STIL and FOXM1 on the binding of FOXM1 at the SF3A3 promoter was detected by ChIP-qPCR assay. A xenograft tumor model was established to explore the changes of tumors in vivo, and the expression of Ki67, GPC3, and p53 in tumor tissues was detected by immunohistochemistry.

SF3A3 and STIL were overexpressed in HCC tissues and cells, and downregulation of SF3A3 or STIL inhibited the malignant behavior of HCC cells by promoting the expression of p53. An interaction between STIL and FOXM1 regulated the SF3A3 expression in HCC cells. Knockdown of FOXM1 further enhanced the anti-tumor effects of STIL loss on HCC cells in vitro and in vivo, whereas SF3A3 overexpression overturned the impact of STIL loss on HCC cells in vitro and in vivo.

Our findings indicate that STIL/FOXM1 expedites HCC development by activating SF3A3, which highlights the importance of SF3A3 as a promising prognostic marker and therapeutic target for HCC.

Liver cancer (LC) poses a significant global health challenge due to its high incidence and poor prognosis. Current systemic treatment options, such as surgery, chemotherapy, radiofrequency ablation, and immunotherapy, have shown limited effectiveness for advanced LC patients. Moreover, owing to the heterogeneous nature of LC, it is crucial to uncover more in-depth pathogenic mechanisms and develop effective treatments to address the limitations of the existing therapeutic modalities. Increasing evidence has revealed the crucial role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of LC. The specific mechanisms driving the JAK-STAT pathway activation in LC, participate in a variety of malignant biological processes, including cell differentiation, evasion, anti-apoptosis, immune escape, and treatment resistance. Both preclinical and clinical investigations on the JAK-STAT pathway inhibitors have exhibited potential in LC treatment, thereby opening up avenues for the development of more targeted therapeutic strategies for LC. In this study, we provide an overview of the JAK-STAT pathway, delving into the composition, activation, and dynamic interplay within the pathway. Additionally, we focus on the molecular mechanisms driving the aberrant activation of the JAK-STAT pathway in LC. Furthermore, we summarize the latest advancements in targeting the JAK-STAT pathway for LC treatment. The insights presented in this review aim to underscore the necessity of research into the JAK-STAT signaling pathway as a promising avenue for LC therapy.

Metastasis is a major cause of fatality in hepatocellular carcinoma (HCC), although the precise mechanisms driving the metastatic process remain incompletely understood. In this study, we have made several important findings. Firstly, we have discovered that elevated activation-induced cytidine deaminase (AID) expression is positively correlated with Jagged 1 (JAG1) levels in clinically metastatic HCC patients. Moreover, we observed that depletion of either AID or JAG1 leads to a reduction in HCC metastasis. Secondly, we have identified AID acts as a transcriptional regulator that regulates JAG1 transcription by interacting with histone acetyltransferase 1 (HAT1) in metastatic HCC cells. Furthermore, our results demonstrate that any domains of AID can cooperate with HAT1 to enhance JAG1 transcription. Importantly, we have determined that the AID/HAT1 complex directly binds to specific regions within the JAG1 gene body, specifically -1.504 kb to -1.104 kb region, thereby influencing the epigenetic state of the JAG1 promoter through modulating histone methylation, histone acetylation, and DNA methylation. Furthermore, we have elucidated that the AID-JAG1/NOTCH-c-FOS axis plays a pivotal role in facilitating HCC metastasis. Consequently, the inhibitory effects of MG149 on both AID and JAG1 significantly mitigate the progression of HCC. This investigation uncovers a heretofore unappreciated function of AID as a transcriptional regulator in the metastasis of HCC, heralding a promising therapeutic approach.

Hepatocellular carcinoma (HCC) ranks as the fifth most common neoplasm and the third leading cause of cancer-related deaths worldwide. Current serum biomarkers for HCC surveillance and early diagnosis, particularly alpha-fetoprotein (AFP) the most commonly used marker, lack satisfactory sensitivity and specificity, highlighting an urgent need for more effective markers with higher accuracy for early HCC detection. The downregulation of melanoma-associated antigen D1 (MAGE-D1) transcription plays a crucial role in apoptosis and inhibits cancer cell proliferation when expressed ectopically. Moreover, reduced MAGE-D1 expression correlates with improved prognosis in many cancers. Therefore, this study aims to evaluate the diagnostic role of MAGE-D1 in HCC, proposing it as a novel biomarker for early diagnosis and monitoring of tumor progression. Serum MAGE-D1 expression was measured using RT-qPCR on 198 subjects, divided into three groups: 88 with HCC, 56 with chronic liver conditions, and 54 as healthy controls. With a sensitivity of 93.3% and a specificity of 97.5%, MAGED-1 shows strong potential as a diagnostic marker for HCC. The performance of serum MAGED-1 expression in discrimination between HCC and chronic liver condition revealed an area under the curve (AUC) of 0.939 using the cutoff (0.752) yielded a sensitivity of 90%, specificity of 85%, and an accuracy of 91%. Evaluation of the diagnostic significance of MAGED-1 demonstrated an AUC value of 0.726, with a sensitivity of 63.6% and a specificity of 73.5%. In conclusion, MAGED-1 might be a specific and sensitive biomarker for HCC, potentially improving the malignancy diagnosis and prognosis.

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.

Deubiquitinases play essential roles in hepatocellular carcinoma (HCC) progression, however, the role of ubiquitin-specific peptidase 21 (USP21) in HCC development remains unclear. The present work aims to analyze the effect of USP21 on tumor property of HCC cells and the underlying mechanism. mRNA expression levels of USP21 and H2BFS were analyzed by quantitative real-time polymerase chain reaction. Protein expression of USP21, E-cadherin, N-cadherin, Vimentin, H2BFS and methyltransferase 3 (METTL3) was assessed by western blotting assay or immunohistochemistry assay. Clonogenicity assay was used to analyze cell proliferation. Flow cytometry assay was performed to quantify apoptotic rate of cells. Wound-healing assay and transwell assay were conducted to analyze cell migration and invasion, respectively. Xenograft mouse model assay was performed to determine the effect of USP21 knockdown on tumor formation. m6A RNA immunoprecipitation assay (MeRIP) was used to analyze the effect of METTL3 silencing on methylated level of USP21. USP21 expression was upregulated in HCC tissues and cells when compared with control groups. USP21 silencing inhibited proliferation, migration and invasion and induced apoptosis of HCC cells, accompanied by the increased E-cadherin protein expression and decreased N-cadherin and Vimentin protein expression. Moreover, USP21 knockdown delayed tumor formation in vivo. USP21 stabilized H2BFS by deubiquitination, and H2BFS overexpression attenuated USP21 silencing-induced effects in HCC cells. Further, METTL3-mediated m6A methylation of USP21. METTL3-mediated m6A methylation of USP21 promoted HCC progression by stabilizing H2BFS through deubiquitination.

This study aimed to evaluate the cost-effectiveness (CE) of 4 hepatocellular carcinoma (HCC) surveillance strategies in the United Kingdom, the GAAD algorithm, which combines Gender (biological sex) and Age with Elecsys® biomarker assays, alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (previously Des-γ-carboxy prothrombin); ultrasound (US); US + AFP and GAAD + US.

A de novo microsimulation state-transition Markov model was developed in Microsoft Excel® from the perspective of the United Kingdom National Health Service to calculate life-years, quality-adjusted life-years (QALYs), costs, incremental CE ratios, and net monetary benefits. Parameters were sourced from peer-reviewed published literature, national guidelines, and public cost databases. Sensitivity and scenario analyses were performed to evaluate the impact of parameter and structural uncertainty on the results.

In a simulated cohort of 100 000 patients, discounted costs and QALYs per patient were £8663 and 6·066 for US, £9095 and 6·076 for US + AFP, £8719 and 6·078 for GAAD alone, and £9114 and 6·086 for GAAD + US. At a CE threshold of £20 000/QALY, GAAD was the most cost-effective strategy; however, although most costly, GAAD + US was the most clinically effective. Sensitivity and scenario analyses indicated that HCC incidence along with costs associated with diagnostic performance influence CE.

Considering the cost of US and low incidence of HCC in the United Kingdom, this study suggests that GAAD alone or in combination with US are cost-effective surveillance strategies compared with US and US + AFP. Although GAAD + US showed the highest QALY increase, GAAD alone is considered preferable regarding CE; however, better performance estimates for GAAD + US are needed to confirm.

Epithelial-mesenchymal transition (EMT) is central to HCC metastasis, in which RNA-binding proteins (RBPs) play a key role.

To explore the role of RBPs in metastasis of hepatocellular carcinoma (HCC), whole transcriptome sequencing was conducted to identify differential RBPs between HCC with metastasis and HCC without metastasis. The influence of RBPs on metastasis of HCC was verified by in vitro and in vivo experiments. The interaction of RBPs with non-coding RNAs was evaluated by RNA immunoprecipitation and pull-down assays. RNA sequencing, whole-genome sequencing, and alternative splicing analysis were further performed to clarify post-transcriptional regulation mechanisms.

Whole transcriptome sequencing results showed that expression of thioredoxin (Trx) was significantly upregulated in HCC patients with metastasis. Trx was also found to be associated with poor prognosis in HCC patients. Overexpression of Trx could promote migration and invasion of HCC cells in vitro and increase the rate of lung metastasis of HCC cells in vivo. Moreover, binding assays showed that Trx could bind to LINC00152. As a result, LINC00152 was verified to determine the pro-metastasis function of Trx by knockdown assay. Furthermore, we revealed that Trx could regulate metastasis-associated alternative splicing program. Specifically, angiopoietin 1 (ANGPT1) was the splicing target; the splicing isoform switching of ANGPT1 could activate the PI3K-Akt pathway, upregulate EMT-associated proteins, and promote migration and invasion of HCC cells.

We found that Trx could interact with LINC00152 and promote HCC metastasis via regulating alternative splicing, indicating that Trx may serve as a novel therapeutic target for HCC treatment.

Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a rare and aggressive molecular subtype of hepatocellular carcinoma (HCC) associated with a poor prognosis. Unlike typical HCC, which commonly arises in the context of cirrhosis, MTM-HCC can develop in non-cirrhotic livers, presenting unique diagnostic and therapeutic challenges. This case report describes a 35-year-old male who presented with persistent epigastric pain, fatigue, and loss of appetite. Clinical examination revealed hepatomegaly, prompting advanced imaging and laboratory investigations. Imaging studies identified a large hepatic mass with portal vein thrombosis and metastatic lesions, while histopathological analysis confirmed the diagnosis of MTM-HCC. The patient initiated treatment with a combination of immune checkpoint inhibitors and anti-angiogenic agents, which represent the current standard for advanced HCC. Despite initial adherence, disease progression was observed after four cycles of therapy. The patient passed away less than two months after his last consultation. This clinical course highlights the aggressive nature of MTM-HCC and its limited responsiveness to existing therapeutic protocols. MTM-HCC is characterized by distinctive histological and molecular features that differentiate it from other HCC subtypes. These include specific genetic mutations and protein expression patterns that contribute to its aggressive behavior and poor prognosis. Advanced imaging modalities combined with histopathological analysis remain crucial for accurate diagnosis and classification. This case emphasizes the critical need for heightened clinical vigilance, particularly in younger patients with atypical presentations of liver disease. It also underscores the importance of developing more effective, tailored therapeutic strategies for MTM-HCC. Further research into its molecular characteristics and inclusion in clinical trials is essential to improving outcomes for patients with this challenging and understudied subtype of liver cancer.

Hepatocellular carcinoma (HCC) is often detected at advanced stages among patients with hepatitis B virus (HBV), underscoring the urgency for more precise surveillance tests. Here, we compare the clinical performance of the novel - GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], protein-induced by vitamin K absence-II [PIVKA-II]) and GALAD (gender [biological sex], age, AFP, Lens-culinaris AFP [AFP-L3]), PIVKA-II) algorithms to assess the utility of AFP-L3 for distinguishing HCC from benign chronic liver disease (CLD) in Chinese patients with predominantly chronic HBV infection. Eligible adults were enrolled, and biomarkers were measured using Elecsys (Cobas) or µTASWAKO assays. In total, 411 participants provided serum samples (HCC, n = 176 [early-stage, n = 110]; CLD, n = 136; specificity n = 101). HBV was the underlying disease etiology for most participants (HCC, 95%; benign CLD, 72%). For GAAD (Cobas), GALAD (Cobas), and GALAD (µTASWAKO), AUCs were 93.1% (95% CI: 90.0-96.2), 93.2% (90.0-96.3), and 92.7% (88.4-96.9) for early-stage, and 95.6% (93.6-97.6), 95.6% (93.6-97.7), and 95.8% (93.2-98.3) for all-stage HCC, versus CLD, respectively. Interestingly, both GAAD and GALAD algorithms demonstrated comparable diagnostic performance regardless of disease etiology (HBV vs. non-HBV), presence of cirrhosis, geographic region, and within pan-tumor specificity panels (p < 0.001), indicating AFP-L3 may have a negligible role in HCC surveillance.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and classifying the developmental stages of HCC can help with early prognosis and treatment. This study aimed to investigate diagnostic and prognostic molecular signatures underlying the progression of HCC, including tumor initiation and growth, and to classify its developmental stages based on gene expression levels. We integrated data from two cancer systems, including 78 patients with Edmondson-Steiner (ES) grade and 417 patients with TNM stage cancer. Functional profiling was performed using identified signatures. Using a multinomial logistic regression model (MLR), we classified controls, early-stage HCC, and advanced-stage HCC. The model was validated in three independent cohorts comprising 45 patients (neoplastic stage), 394 patients (ES grade), and 466 patients (TNM stage). Multivariate Cox regression was employed for HCC prognosis prediction. We identified 35 genes with gradual upregulation or downregulation in both ES grade and TNM stage patients during HCC progression. These genes are involved in cell division, chromosome segregation, and mitotic cytokinesis, promoting tumor cell proliferation through the mitotic cell cycle. The MLR model accurately differentiated controls, early-stage HCC, and advanced-stage HCC across multiple cancer systems, which was further validated in various independent cohorts. Survival analysis revealed a subset of five genes from TNM stage (HR: 3.27, p < 0.0001) and three genes from ES grade (HR: 7.56, p < 0.0001) that showed significant association with HCC prognosis. The identified molecular signature not only initiates tumorigenesis but also promotes HCC development. It has the potential to improve clinical diagnosis, prognosis, and therapeutic interventions for HCC. This study enhances our understanding of HCC progression and provides valuable insights for precision medicine approaches.