Liver Hepatocellular Carcinoma Research Articles

Value of TMEM115 as a Potential Prognostic Biomarker in Liver Hepatocellular Carcinoma

Transmembrane protein 115 (TMEM115) is a membrane protein; considering the potential of membrane proteins as biomarkers for various pathological conditions, we aimed to examine the value of TMEM115 as a potential biomarker for improving the prognosis and treatment of liver hepatocellular carcinoma (LIHC) in this study. Online databases including the Tumor Immune Estimation Resource, UALCAN, Gene Expression Profiling Interactive Analysis version 2, OSlihc, and human Protein Atlas were used. The analysis suggested that TMEM115 expression in LIHC was higher compared to normal tissues; further, TMEM115 expression was confirmed to be related with poor prognosis in LIHC. Higher protein expression levels of TMEM115 were observed in LIHC tissues than in normal tissues. Tumor infiltration by immune cells was confirmed to be correlated with the expression of TMEM115. High TMEM115 expression and immune cell infiltration were further related to poor prognosis in LIHC. We also confirmed a correlation between TMEM115 and TP53 mutations. In conclusion, we confirmed that TMEM115 expression is correlated with tumor-infiltrating immune cells and poor prognosis in LIHC and that TMEM115 shows potential as a prognostic biomarker in LIHC.

METTL3 facilitates stemness properties and tumorigenicity of cancer stem cells in hepatocellular carcinoma through the SOCS3/JAK2/STAT3 signaling pathway.

Liver cancer stem cells (LCSCs) contribute to tumor recurrence and cancer cell proliferation in patients with hepatocellular carcinoma (HCC). METTL3-catalyzed m6A modification is relevant to the cancer stem cell (CSC) phenotype, including LCSCs. LCSCs were isolated from MHCC-97H and HepG2 cells through flow cytometry. UALCAN data were used to analyze the expression of METTL3 in liver hepatocellular carcinoma (LIHC) tissues. Loss- and gain-of-function experiments were utilized to assess the biological effects of METTL3 and SOCS3 on the proliferation and stemness phenotypes in vitro and in vivo. The mechanisms underlying the impact of METTL3 were explored using qPCR, MeRIP-qPCR, dual-luciferase reporter, and western blot assays. METTL3 was significantly upregulated in LIHC tissues according to the UALCAN database. METTL3 was highly expressed in LIHC and was significantly correlated with individual cancer stage, tumor grade and lymph node metastasis. Patients with low METTL3 expression had a longer overall survival time based on the data from UALCAN. In addition, the level of METTL3 was enhanced in LCSCs and decreased in non-LCSCs compared to HCC cells. Moreover, overexpression of METTL3 stimulated the proliferation and stemness of LCSCs in vitro and in vivo, while loss of METTL3 impeded it. Bioinformatics analysis combined with validation experiments determined that m6A was modified by METTL3-targeting SOCS3 mRNA. METTL3 had side effects regarding the stability of SOCS3 mRNA. SOCS3 overexpression impaired and SOCS3 depletion facilitated the development of LCSCs via the JAK2/STAT3 pathway. Furthermore, METTL3 depletion suppressed proliferation and stemness in LCSCs, which was restored by SOCS3 knockdown or colivelin treatment. We discovered that METTL3 facilitated the stemness and tumorigenicity of LCSCs by modifying SOCS3 mRNA with m6A.

NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe

Hepatocellular carcinoma (HCC) is the sixth most common malignancy globally and ranks third in terms of both mortality and incidence rates. Surgical resection holds potential as a curative approach for HCC. However, the residual disease contributes to a high 5-year recurrence rate of 70%. Due to their excellent specificity and optical properties, fluorescence-targeted probes are deemed effective auxiliary tools for addressing residual lesions, enabling precise surgical diagnosis and treatment. Research indicates histone deacetylase 6 (HDAC6) overexpression in HCC cells, making it a potential imaging biomarker. This study designed a targeted small-molecule fluorescent probe, SeCF3-IRDye800cw (SeCF3-IRD800), operating within the Second near-infrared window (NIR-II, 1000-1700nm). The study confirms the biocompatibility of SeCF3-IRD800 and proceeds to demonstrate its applications in imaging invivo, fluorescence-guided surgery (FGS) for liver cancer, liver fibrosis imaging, and clinical samples incubation, thereby preliminarily validating its utility in liver cancer. SeCF3-IRD800 was synthesized by combining the near-infrared fluorescent dye IRDye800cw-NHS with an improved HDAC6 inhibitor. Initially, a HepG2-Luc subcutaneous tumor model (n=12) was constructed to investigate the metabolic differences between SeCF3-IRD800 and ICG invivo. Subsequently, HepG2-Luc (n=12) and HCCLM3-Luc (n=6) subcutaneous xenograft mouse models were used to assess invivo targeting by SeCF3-IRD800. The HepG2-Luc orthotopic liver cancer model (n=6) was employed to showcase the application of SeCF3-IRD800 in FGS. Liver fibrosis (n=6) and HepG2-Luc orthotopic (n=6) model imaging results were used to evaluate the impact of different pathological backgrounds on SeCF3-IRD800 imaging. Three groups of fresh HCC and normal liver samples from patients with liver cancer were utilized for SeCF3-IRD800 incubation exvivo, while preclinical experiments illustrated its potential for clinical application. The HDAC6 inhibitor 6 (SeCF3) modified with trifluoromethyl was labeled with IRDy800CW-NHS to synthesize the small-molecule targeted probe SeCF3-IRD800, with NIR-II fluorescence signals. SeCF3-IRD800 was rapidly metabolized by the kidneys and exhibited excellent biocompatibility. Invivo validation demonstrated that SeCF3-IRD800 achieved optimal imaging within 8h, displaying high tumor fluorescence intensity (7658.41±933.34) and high tumor-to-background ratio (5.20±1.04). Imaging experiments with various expression levels revealed its capacity for HDAC6-specific targeting across multiple HCC tumor models, suitable for NIR-II intraoperative imaging. Fluorescence-guided surgery experiments were found feasible and capable of detecting sub-visible 2mm tumor lesions under white light, aiding surgical decision-making. Further imaging of liver fibrosis mice showed that SeCF3-IRD800's imaging efficacy remained unaffected by liver pathological conditions. Correlations were observed between HDAC6 expression levels and corresponding fluorescence intensity (R2=0.8124) among normal liver, liver fibrosis, and HCC tissues. SeCF3-IRD800 identified HDAC6-positive samples from patients with HCC, holding advantages for perspective intraoperative identification in liver cancer. Thus, the rapidly metabolized HDAC6-targeted small-molecule NIR-II fluorescence probe SeCF3-IRD800 holds significant clinical translational value. The successful application of NIR-II fluorescence-guided surgery in liver cancer indicates that SeCF3-IRD800 has great potential to improve the clinical diagnosis and treatment of liver cancer, and could be used as an auxiliary tool for surgical treatment of liver cancer without being affected by liver pathology. This paper is supported by the National Natural Science Foundation of China (NSFC) (92,059,207, 62,027,901, 81,930,053, 81,227,901, 82,272,105, U21A20386 and 81,971,773), CAS Youth Interdisciplinary Team (JCTD-2021-08), the Zhuhai High-level Health Personnel Team Project (Zhuhai HLHPTP201703), and Guangdong Basic and Applied Basic Research Foundation under Grant No. 2022A1515011244.

Retracted: Cuproptosis-Related Genes CDK1 and COA6 Involved in the Prognosis Prediction of Liver Hepatocellular Carcinoma

Retracted: Cuproptosis-Related Genes CDK1 and COA6 Involved in the Prognosis Prediction of Liver Hepatocellular Carcinoma

Liver stiffness as a cornerstone in heart disease risk assessment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) typically presents with hepatic fibrosis in advanced disease, resulting in increased liver stiffness. A subset of patients further develops liver cirrhosis and hepatocellular carcinoma. Cardiovascular disease is a common comorbidity in patients with MASLD and its prevalence is increasing in parallel. Recent evidence suggests that especially liver stiffness, whether or not existing against a background of MASLD, is associated with heart diseases. We conducted a narrative review on the role of liver stiffness in the prediction of highly prevalent heart diseases including heart failure, cardiac arrhythmias (in particular atrial fibrillation), coronary heart disease, and aortic valve sclerosis. Research papers were retrieved from major scientific databases (PubMed, Web of Science) until September 2023 using 'liver stiffness' and 'liver fibrosis' as keywords along with the latter cardiac conditions. Increased liver stiffness, determined by vibration-controlled transient elastography or hepatic fibrosis as predicted by biomarker panels, are associated with a variety of cardiovascular diseases, including heart failure, atrial fibrillation, and coronary heart disease. Elevated liver stiffness in patients with metabolic liver disease should lead to considerations of cardiac workup including N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide determination, electrocardiography, and coronary computed tomography angiography. In addition, patients with MASLD would benefit from heart disease case-finding strategies in which liver stiffness measurements can play a key role. In conclusion, increased liver stiffness should be a trigger to consider a cardiac workup in metabolically compromised patients.

Targeting of CD25+ Activated T Cells in Gvhd-Associated Marrow Suppression and Cytopenias

Introduction: Secondary cytopenias occurring after hematopoietic cell transplant (HCT) are an observed complication of graft-versus-host disease (GVHD). Causes include peripheral immune mediated destruction (hemolytic anemia or thrombocytopenia), usually associated with autoantibody production, and peripheral destruction associated with microangiopathy (TMA). However, cases have been observed where marrow production of the affected lineage is abnormal. Immune-mediated cases are treated with increased immunosuppression, e.g., steroids or calcineurin inhibitors (CNI), and TMA with complement inhibition. To better understand the mechanisms and treatment of hypoproductive cytopenias in GVHD, we combined analyses of hematopoietic stem and progenitor cells (HSPC) and peripheral blood and marrow activated T cells. We describe 3 cases of GVHD-associated cytopenias marked by HSPC depletion and presence of CD25 (IL-2R alpha subunit)-positive activated T cells in the marrow that responded to combinations of immunosuppression containing basiliximab (basil) anti-CD25 monoclonal antibody blockade. Methods/Results: We describe combined HSPC and T cell analyses in 3 patients (P) with severe GVHD-associated cytopenias. P1 was at 5 years post-HCT for acute lymphoblastic leukemia, P2 at 2 years post-HCT for severe aplastic anemia (SAA), and P3 at 1.5 months post-liver transplant for alcohol use disorder-associated cirrhosis and hepatocellular carcinoma ( Table 1). Because of refractory cytopenias, all were being considered for HCT. However, marrow analyses revealed that each had normal frequencies of phenotypic HSC, with variable decreases in cellularity and frequencies of committed progenitors ( Table 2). Chimerism analyses showed that 100% of CD34+ cells in P1 and P2 were of donor origin, and in P3 of host origin. All 3 marrows had activated CD3+ T cells per expression of CD69 and/or CD38, and frequency of CD25 on >10% of T cells. In addition, P1 had evidence of IgG bound to committed progenitor populations. The treatment strategy was to block IL-2 signaling with basil (induction of 20 mg on day 1, 4, 7, 14, 21, 28, followed by alternate week and then monthly dosing for 2-9 months), combined with suppression of IL-2 production with steroid and/or CNI. After induction, repeat analyses of the blood and marrow T-cells confirmed complete blockade of CD25. Therapy was also individualized for specific clinical conditions or as noted on marrow evaluation. P1 received prednisone, CNI, and rituximab for a presumed anti-HSPC autoantibody. At 9 months he was weaned off all therapy and remains on no immunosuppressive treatment 2 years later. P2 did not receive CNI due to chronic renal failure but received steroids and later sirolimus. At ~18 months, his cytopenias recurred, but subsequently responded to basil re-induction and steroids. P3 has received prednisone, CNI, and sirolimus indefinitely for prevention of liver rejection and/or hepatocellular carcinoma relapse. P1 had no viral reactivation; P2 had CMV pneumonia with his second course responsive to antiviral therapy, completion of basil, and tapering of steroids; and P3 had CMV reactivation responsive to antiviral therapy and EBV viremia. P3 has a recent diagnosis of EBV+ intrahepatic B cell lymphoma. In all cases, blood counts normalized except P2 who has anemia due to CKD. Discussion: HSPC analyses in these patients with GVHD and cytopenias demonstrate that peripheral changes are not due to loss of HSC, but instead to quantitative and/or qualitative defects in committed progenitor populations, likely mediated by activated CD25+ T cells. In addition, the presence of IgG on HSPCs in P1 demonstrates a novel role for antibody-mediated humoral suppression in some cases. The presence of HSC indicates that there may be no need for re-transplant. Previous studies of SAA have shown activated T cells to be drivers of aplasia and is the basis for immune suppressive therapy (anti-thymocyte globulin and CNI). Our analyses of patients with GVHD-associated cytopenias demonstrates that targeting of IL-2 signaling via combined CD25 receptor blockade and pharmacologic inhibition of IL-2 production can correct the marrow defects and cytopenias, albeit with need for attention to viral infections. Targeting CD25 in patients with evidence of CD25+ activated T cells is a rational approach to the difficult problem of GVHD-associated marrow suppression and cytopenias.

Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma

Methyltransferase-like 3 (METTL3) is the key subunit of methyltransferase complex responsible for catalyzing N6-methyladenosine (m6A) modification on mRNA, which is the most prevalent post-transcriptional modification in eukaryotes. In this study, we utilized online databases to analyze the association between METTL3 expression and various aspects of tumorigenesis, including gene methylation, immunity, and prognosis. Our investigation revealed that METTL3 serves as a prognostic marker and therapeutic target for liver hepatocellular carcinoma (LIHC). Through experimental studies, we observed frequent upregulation of METTL3 in LIHC tumor tissue and cells. Subsequent inhibition of METTL3 using a novel small molecule inhibitor, STM2457, significantly impeded tumor growth in LIHC cell lines, spheroids, and xenograft tumor model. Further, transcriptome and m6A sequencing of xenograft bodies unveiled that inhibition of METTL3-m6A altered genes enriched in SMAD and MAPK signaling pathways that are critical for tumorigenesis. These findings suggest that targeting METTL3 represents a promising therapeutic strategy for LIHC.

The expression of VEGF and cyclin D1/EGFR in common primary liver carcinomas in Egypt: an immunohistochemical study.

The most common types of primary malignant liver tumours are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Treatment options for patients who are inoperable/advanced, or recurring are challenging. Cyclin D1, epidermal growth factor (EGFR) and vascular endothelial growth factor (VEGR) are common carcinogenic proteins that have potential therapeutic targets in various cancers. They have been implicated in the development of HCC and CCA. In this study, we aimed to evaluate the oncogenic function expression of cyclin D1, EGFR and VEGF in HCC and CCA of Egyptian patients. This could help to validate their therapeutic potential. Tumour cases were selected from 82 cases of primary liver carcinomas, with 58 cases being from HCC and 24 cases from CCA compared to 51 non-tumour adjacent liver cases and 18 from normal liver tissue. The immunohistochemical study of cyclin D1, EGFR and VEGR was conducted. Cyclin D1, EGFR and VEGF are overexpressed in HCC and CCA as compared to the control group (p < 0.001). Cyclin D1 was related to well-differentiated grade and early pathologic stage in HCC (p = 0.016 and p = 0.042, respectively). The well-differentiated grade showed significantly higher VEGF levels (p = 0.04). In the CCA group, however, EGFR was strongly related to high tumour size (p = 0.047). EGFR and VEGF were overexpressed in HCC raised in the non-cirrhotic liver compared to those developed in post-hepatitic liver cirrhosis (p = 0.003 and p = 0.014). Cyclin D1, EGFR and VEGF shared significant overexpression in HCC and CCA. EGFR and VEGF may play an oncogenic function in the development of HCC in non-cirrhotic liver. Furthermore, cyclin D1 and VEGF may play a good prognostic function in HCC, but EGFR may play a bad prognostic role in CCA.

GPNMB+ Gal-3+ hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis.

Hepatocellular carcinoma (HCC) formation is a multi-step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single-cell transcriptome sequencing was applied to profile rat models of toxin-induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta ), Epcam+ population with differentiation potential (EP+Diff ) and immunosuppressive malignant transformation subset (MTImmu ). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu . Importantly, GPNMB+ Gal-3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+ Gal-3+ MTImmu cells. Enrichment of the GPNMB+ Gal-3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single-cell HCC progression atlas and uncovered GPNMB+ Gal-3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.

Identification and validation of palmitoylation metabolism-related signature for liver hepatocellular carcinoma

BackgroundProtein S-palmitoylation is a reversible posttranslational modification widely involved in tumor progression. Nevertheless, the function of palmitoylation metabolism in prognosis and tumor microenvironment characteristics in liver hepatocellular carcinoma (LIHC) patients is not fully understood. MethodsmRNA and clinical data of LIHC patients were obtained from the TCGA and ICGC databases. Consensus clustering was used to construct palmitoylation metabolism-related clusters. Univariate Cox and Lasso regression analyses were employed to establish a palmitoylation metabolism-related signature (PMS). ssGSEA was applied to evaluate the immune cell score in each LIHC sample. Functional enrichments were accessed through GO, KEGG and GSVA. Drug sensitivity data were downloaded from the GDSC database. ResultsThree palmitoylation metabolism-related clusters with different prognostic and immune infiltration characteristics were constructed in LIHC. We identified PMS with distinct survival, clinical, and tumor immune microenvironment characteristics. The high PMS group had a poorer prognosis, higher infiltration of immunosuppressive cells and higher expression of immune checkpoints. ZDHHC20 exerted a tumor-promoting role in LIHC and was significantly associated with immunosuppressive cells and immunosuppressive checkpoints. Additionally, in HepG-2 and SMCC-7721 cells, si-ZDHHC20 boosted apoptosis but decreased proliferation and migration when compared to si-NC. ConclusionOur research revealed that PMS may accurately predict the prognosis and immune characteristics of LIHC patients. ZDHHC20 has significant clinical and immune relevance in LIHC and may contribute to the formulation of new targets for LIHC immunotherapy.

MiRNAs in Alcohol-Related Liver Diseases and Hepatocellular Carcinoma: A Step toward New Therapeutic Approaches?

Alcohol-related Liver Disease (ALD) is the primary cause of chronic liver disorders and hepatocellular carcinoma (HCC) development in developed countries and thus represents a major public health concern. Unfortunately, few therapeutic options are available for ALD and HCC, except liver transplantation or tumor resection for HCC. Deciphering the molecular mechanisms underlying the development of these diseases is therefore of major importance to identify early biomarkers and to design efficient therapeutic options. Increasing evidence indicate that epigenetic alterations play a central role in the development of ALD and HCC. Among them, microRNA importantly contribute to the development of this disease by controlling the expression of several genes involved in hepatic metabolism, inflammation, fibrosis, and carcinogenesis at the post-transcriptional level. In this review, we discuss the current knowledge about miRNAs’ functions in the different stages of ALD and their role in the progression toward carcinogenesis. We highlight that each stage of ALD is associated with deregulated miRNAs involved in hepatic carcinogenesis, and thus represent HCC-priming miRNAs. By using in silico approaches, we have uncovered new miRNAs potentially involved in HCC. Finally, we discuss the therapeutic potential of targeting miRNAs for the treatment of these diseases.

Unraveling the molecular links between benzopyrene exposure, NASH, and HCC: an integrated bioinformatics and experimental study

Benzopyrene (B[a]P) is a well-known carcinogen that can induce chronic inflammation and fibrosis in the liver, leading to liver disease upon chronic exposure. Nonalcoholic steatohepatitis (NASH) is a chronic liver condition characterized by fat accumulation, inflammation, and fibrosis, often resulting in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the intricate connections between B[a]P exposure, NASH, and HCC. Through comprehensive bioinformatics analysis of publicly available gene expression profiles, we identified differentially expressed genes (DEGs) associated with B[a]P exposure, NASH, and liver cancer. Furthermore, network analysis revealed hub genes and protein–protein interactions, highlighting cellular metabolic dysfunction and disruption of DNA damage repair in the B[a]P-NASH-HCC process. Notably, HSPA1A and PPARGC1A emerged as significant genes in this pathway. To validate their involvement, we conducted qPCR analysis on cell lines and NASH mouse liver tissues and performed immunohistochemistry labeling in mouse and human HCC liver sections. These findings provide crucial insights into the potential regulatory mechanisms underlying benzopyrene-induced hepatotoxicity, shedding light on the pathogenesis of B[a]P-associated NASH and HCC. Moreover, our study suggests that HSPA1A and PPARGC1A could serve as promising therapeutic targets. Enhancing our understanding of their regulatory roles may facilitate the development of targeted therapies, leading to improved patient outcomes.

High CD49a+ NK cell infiltrate is associated with poor clinical outcomes in Hepatocellular Carcinoma

NK cells infiltrating Hepatocellular Carcinoma (HCC) may express residency markers such as Integrin Subunit Alpha 1 (CD49a) that have been associated with nurturing functions in the decidua, and characterized by the production of angiogenic factors as well as loss of cytotoxicity. CIBERSORT, a computational analysis method for quantifying cell fractions from bulk tissue gene expression profiles, was used to estimate the infiltrating immune cell composition of the tumor microenvironment from gene expression profiles of a large cohort of 225 HCCs in the public GEO database. Decidual-like CD49a+ NK cells, in addition to another 22 immune cell populations, were characterized and thoroughly investigated so that HCC cell heterogeneity in a large cohort of 225 HCCs from the public GEO database could be studied. An inverse correlation of the expression of CD49a+ NK-cells and CD8+ T-cells suggested a negative association with clinical outcomes. This result was confirmed in a further validation cohort of 100 HCC patients from The Cancer Genome Atlas, Liver Hepatocellular Carcinoma (TCGA-LIHC). Cox regression analysis did not identify CD49a+ cells as a variable independently associated with survival. However, a more abundant infiltrate of this subset was present in patients at a more advanced pathological and clinical HCC stage. In conclusion, we found that NK cells, with a decidual-like gene expression profile, are enriched in HCC, and their abundance increases not only in tumor size but also at advanced stages of the disease suggesting that these cells play a role in tumor growth. For this reason, these NK cells may represent a possible new target for immunotherapeutic approaches in HCC.

EMT-related gene risk model establishment for prognosis and drug treatment efficiency prediction in hepatocellular carcinoma

This study was designed to evaluate the prognosis and pharmacological therapy sensitivity of epithelial mesenchymal transition-related genes (EMTRGs) that obtained from the EMTome database in hepatocellular carcinoma (HCC) using bioinformatical method. The expression status of EMTRGs were also investigated using the clinical information of HCC patients supported by TCGA database and the ICGC database to establish the TCGA cohort as the training set and the ICGC cohort as the validation set. Analyze the EMTRGs between HCC tissue and liver tissue in the TCGA cohort in the order of univariate COX regression, LASSO regression, and multivariate COX regression, and construct a risk model for EMTRGs. In addition, enrichment pathways, gene mutation status, immune infiltration, and response to drugs were also analyzed in the high-risk and low-risk groups of the TCGA cohort, and the protein expression status of EMTRGs was verified. The results showed a total of 286 differentially expressed EMTRGs in the TCGA cohort, and EZH2, S100A9, TNFRSF11B, SPINK5, and CCL21 were used for modeling. The TCGA cohort was found to have a worse outcome in the high-risk group of HCC patients, and the ICGC cohort confirmed this finding. In addition, EMTRGs risk score was shown to be an independent prognostic factor in both cohorts by univariate and multivariate COX regression. The results of GSEA analysis showed that most of the enriched pathways in the high-risk group were associated with tumor, and the pathways enriched in the low-risk group were mainly associated with metabolism. Patients in various risk groups had varying immunological conditions, and the high-risk group might benefit more from targeted treatments. To sum up, the EMTRGs risk model was developed to forecast the prognosis for HCC patients, and the model might be useful in assisting in the choice of treatment drugs for HCC patients.

Association of elevated autoantibody to high expression of GNAS in hepatocellular carcinoma

PurposeThis study was based on hepatocellular carcinoma (HCC) patients of early-stage to explore the diagnostic capability and possible production causes of anti-GNAS autoantibody. MethodsWe evaluated the frequency of anti-GNAS autoantibody in sera from patients with early-stage HCC by enzyme-linked immunosorbent assay (ELISA) and the expression of GNAS protein in early-stage HCC tissues by immunohistochemistry. Western blotting (WB) and real-time polymerase chain reaction (RT-PCR) were utilized to examine the expressions of GNAS protein and mRNA in cell lines. GEO and International Cancer Genome Consortium (ICGC) databases were inquired to explore mRNA expression and mutation of GNAS in HCC tissues. ResultsThe positive rates of anti-GNAS autoantibody in HCC patients at clinical stage I (78.1 %) and clinical stage II (57.1 %) were all significantly higher than that in healthy control (20 %). There was also a significant difference in GNAS protein expression between HCC and its adjacent normal liver tissues. The results from WB and RT-PCR showed a significant difference at the mRNA level but no statistical difference at the protein level between HCC and normal liver cell lines. The difference in mRNA level between HCC and adjacent normal liver tissues was verified to be significant. Furthermore, the ICGC database demonstrated a 10.6 % mutation frequency for GNAS in HCC patients. ConclusionThe coordination of elevated anti-GNAS autoantibody, high expression of GNAS in the mRNA and protein levels in HCC, and high frequency of GNAS mutation indicates that anti-GNAS autoantibody may be used as an early indicator of HCC.

Is the anterior approach recommended for liver resection of hepatocellular carcinoma? A systematic review and meta-analysis.

The anterior approach (AA) in liver resection has proven more effective with regard to short-term outcomes than the conventional approach (CA). However, its superiority over the CA concerning long-term outcomes remains unclear. This meta-analysis compared the short- and long-term outcomes of the AA and CA. Databases, including MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials, were searched to identify studies comparing the AA and CA for hepatocellular carcinoma (HCC) liver resection. The primary outcomes were the in-hospital mortality, in-hospital morbidity, disease-free survival (DFS), and overall survival (OS). Secondary outcomes were operative time, blood loss, blood transfusion, R0 rate, and length of hospital stay. Ten studies involving 1369 patients were included (AA, n = 595; CA, n = 774). Despite no significant differences in the in-hospital mortality or morbidity, the AA demonstrated a superior DFS (hazard ratio [HR], 0.63; 95% confidence interval [CI]: 0.51-0.77) and OS (HR, 0.56; 95% CI: 0.48-0.65) and was associated with a longer operative time, less blood loss, and less transfusion than the CA. No marked differences in other outcomes were noted. The AA for HCC liver resection helped reduce blood loss and need for transfusion, improving the DFS and OS.

Сhanges in the composition of gut microbiota in patients with chronic hepatitis С, non-alcoholic fatty liver disease at different stages of liver disease: a review

INTRODUCTION. The human gut microbiota is a set of microorganisms that are in symbiosis with the host organism. The predominance of bacteria of Bacteroidetes, Firmicutes, Actinobacteria types is a characteristic feature of human gut microbiota. However, the composition of the gut microbiota is subject to change under the influence of a number of factors. The influence of the gut-liver axis on the pathogenesis of many chronic liver diseases of various etiologies, both infectious and metabolic, has been proven. At the same time, in the analyzed literature, the data on the relationship between the nature of GM changes and the stage of liver damage are quite controversial.&#x0D; OBJECTIVE. Updating and systematization of ideas about the nature of changes in the composition of intestinal microbiota in chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD) at different stages of the disease.&#x0D; MATERIALS AND METHODS. We analyzed the scientific literature on GM changes in chronic liver diseases with regard to their etiology and disease stage, in particular in chronic viral hepatitis C and NAFLD. The search was conducted in PubMed, Google Scholar, and eLIBRARY databases for 2000-2023 using the following keywords: gut microbiota; microbiota in hepatitis C; microbiota in NAFLD; microbiota in liver fibrosis; liver fibrosis progression. Sixty scientific articles were analyzed and 42 sources were selected, of which more than 60% were published within the last five years.&#x0D; RESULTS. This review presents the results of original studies describing the main taxonomic differences between the microbiomes of healthy individuals and patients with CHC complicated by the formation of liver cirrhosis and hepatocellular carcinoma (HCC). Thus, patients with viral cirrhosis showed impoverishment of intestinal commensals Lachnospiraceae and Ruminococcaceae and significant enrichment of Streptococcaceae, Lactobacillaceae and Enterobacteriaceae. In patients with non-alcoholic steatohepatitis (NASH) and FII, enrichment of GM Phylum Bacteroides and Proteobacteria, Families Lachnospiraceae and Enterobacteriaceae, Genera Blautia and Escherichia, with a concomitant decrease of Prevotella was detected.&#x0D; DISCUSSION. The analysis of GM taxonomic units in the previously described studies did not reveal significant differences depending on the etiology of the underlying disease. However, a decrease in the representative of the phylum Firmicutes - Ruminococcaceae was observed in CHC in contrast to NAFLD. A more distinct relationship can be observed in the changes of intestinal microbiota in F(III-IV) irrespective of etiology. Thus, in advanced liver fibrosis and cirrhosis of both CHC and NAFLD etiologies, enrichment of GM has been described due to an increase in phylum Proteobacteria, in particular the genus Escherichia and phylum Firmicutes (Blautia, Veillonellaceae). In the studies analyzed, at F(III-IV), an enrichment of the microbiota is observed due to an increase in the phylum Bacteroidetes. Regarding the genus Prevotella, contradictory results were found. In addition, there are ambiguous data regarding the genera Lactobacillus, Ruminococcaceae and Bifidobacteria.&#x0D; CONCLUSION. Based on the results of the literature review, we obtained contradictory data on GM composition in patients with CHC and NAFLD. This may be due to the size of samples, heterogeneity of initial data during the selection of patients in the study. The relationship between the composition of microbiota and persistent inflammatory process, expressed liver fibrosis is observed. GM reflects not only functional disorders in chronic liver diseases of various etiologies, but can also serve as a diagnostic indicator of their progression.

HPB P11 Hepatic vein reconstruction during hepatectomy – a feasible and underused technique?

Abstract Background Hepatic vein involvement can be a contraindication to resection of liver tumours. This study aimed to assess the feasibility, long term outcomes and vein patency among patients who underwent hepatic vein reconstruction during liver resections for liver tumour(s). Methods Retrospective analysis of patients who underwent circumferential hepatic venous reconstruction identified from a prospectively maintained database. Standard volumetric analysis was performed using software to estimate volumetry with and without hepatic venous reconstruction. Long term vein patency was established using review of available radiology. Results 15 patients underwent 17 venous reconstructions for colorectal liver metastases (n=13), cholangiocarcinoma (n=1) and hepatocellular carcinoma (n=1). The median FLR without and with venous reconstruction were 32 (range 18.0-74.5) and 96% (range 26.9-97.7) respectively; the median increase in FLR was 34% per patient. Venous patency was 89% at a median follow-up of 25 months (Range 1-53) with 2 graft thrombosis. No patient developed PHLF. Conclusions Hepatic venous reconstruction during liver resection is safe and feasible. It has the potential to expand the scope of liver resection and preserve liver and venous drainage if needed in the future.

HPB P03 Stereoractic ablative radiotherapy provides a safe and feasible treatment alternative for non-surgical candidates with primary hepatocellular carcinoma

Abstract Background Stereotactic ablative radiotherapy (SABR) is a highly focused radiation treatment that delivers an intense dose of radiation to a tumour whilst limiting exposure of surrounding tissues. SABR has been associated with improvement in overall survival and local control in non-surgical candidates with primary hepatocellular carcinoma (HCC). The aim of this study was to evaluate the outcomes of HCC patients treated with SABR in a tertiary referral hepatobiliary centre. Methods A total of 33 patients (median age 72 years {range 47-85}, 79% male) who received SABR for primary HCC liver lesions over a 2-year period between July 2020 and August 2022 were retrospectively analysed. Patient, treatment and follow-up details were obtained from online patient records and imaging. Patients underwent SABR either due to co-morbidity precluding surgery (23/33), lack of suitable treatment alternatives (9/33) or due to patient choice (1/33). Five patients had previously undergone liver resection, eight transarterial chemoembolisation (TACE) and three microwave ablation (MWA). Results Table 1 shows patient demographics and treatment details of the study cohort. Overall survival was 79% at a median follow-up of 12 months (range 3-25). A total of seven patients died at a median of 8 months post SABR (range 4-18). Only 10/33 (30%) reported toxicity including gastrointestinal upset (n=5), fatigue (n=4) and localised rib discomfort (n=3). No Grade 3/4 toxicities were reported. Of those where radiological outcomes were available, two thirds (20/30) achieved local control at the treatment site while local disease progression occurred in 10/30 (33%). Overall, 6/20 (20%) of patients developed metastatic disease. Conclusions These data suggest SABR is a viable, well-tolerated and potentially effective treatment for HCC in patients unsuitable for surgical therapy. Longer-term follow-up data and prospective studies, including randomised trials, are required to assess survival benefit, and optimise patient selection and dose-fractionation regimens.

Development and validation of multi-omic prognostic signature of anoikis-related genes in liver hepatocellular carcinoma.

Liver hepatocellular carcinoma (LIHC) is characterized by high morbidity, rapid progression and early metastasis. Although many efforts have been made to improve the prognosis of LIHC, the situation is still dismal. Inability to initiate anoikis process is closely associated with cancer proliferation and metastasis, affecting patients' prognosis. In this study, a corresponding gene signature was constructed to comprehensively assess the prognostic value of anoikis-related genes (ARGs) in LIHC. Using TCGA-LIHC dataset, the mRNA levels of the differentially expressed ARGs in LIHC and normal tissues were compared by Student t test. And prognostic ARGs were identified through Cox regression analysis. Prognostic signature was established and then externally verified by ICGC-LIRI-JP dataset and GES14520 dataset via LASSO Cox regression model. Potential functions and mechanisms of ARGs in LIHC were evaluated by functional enrichment analyses. And the immune infiltration status in prognostic signature was analyzed by ESTIMATE algorithm and ssGSEA algorithm. Furthermore, ARGs expression in LIHC tissues was validated via qRT-PCR and IHC staining from the HPA website. A total of 97 differentially expressed ARGs were detected in LIHC tissues. Functional enrichment analysis revealed these genes were mainly involved in MAP kinase activity, apoptotic signaling pathway, anoikis and PI3K-Akt signaling pathway. Afterward, the prognostic signature consisting of BSG, ETV4, EZH2, NQO1, PLK1, PBK, and SPP1 had a moderate to high predictive accuracy and served as an independent prognostic indicator for LIHC. The prognostic signature was also applicable to patients with distinct clinical parameters in subgroup survival analysis. And it could reflect the specific immune microenvironment in LIHC, which indicated high-risk group tended to profit from ICI treatment. Moreover, qRT-PCR and IHC staining showed increasing expression of BSG, ETV4, EZH2, NQO1, PLK1, PBK and SPP1in LIHC tissues, which were consistent to the results from TCGA database. The current study developed a novel prognostic signature comprising of 7 ARGs, which could stratify the risk and effectively predict the prognosis of LIHC patients. Furthermore, it also offered a potential indicator for immunotherapy of LIHC.