Prognostic Factor For Hepatocellular Carcinoma Patients Research Articles

TMX2 potentiates cell viability of hepatocellular carcinoma by promoting autophagy and mitophagy

ABSTRACT The dysregulation of membrane protein expression has been implicated in tumorigenesis and progression, including hepatocellular carcinoma (HCC). In this study, we aimed to identify membrane proteins that modulate HCC viability. To achieve this, we performed a CRISPR activation screen targeting human genes encoding membrane-associated proteins, revealing TMX2 as a potential driver of HCC cell viability. Gain- and loss-of-function experiments demonstrated that TMX2 promoted growth and tumorigenesis of HCC. Clinically, TMX2 was an independent prognostic factor for HCC patients. It was significantly upregulated in HCC tissues and associated with poor prognosis of HCC patients. Mechanistically, TMX2 was demonstrated to promote macroautophagy/autophagy by facilitating KPNB1 nuclear export and TFEB nuclear import. In addition, TMX2 interacted with VDAC2 and VADC3, assisting in the recruitment of PRKN to defective mitochondria to promote cytoprotective mitophagy during oxidative stress. Most interestingly, HCC cells responded to oxidative stress by upregulating TMX2 expression and cell autophagy. Knockdown of TMX2 enhanced the anti-tumor effect of lenvatinib. In conclusion, our findings emphasize the pivotal role of TMX2 in driving the HCC cell viability by promoting both autophagy and mitophagy. These results suggest that TMX2 May serve as a prognostic marker and promising therapeutic target for HCC treatment.

Prognostic Factors after Hepatectomy for Hepatocellular Carcinoma—The Importance of Pathological Immunophenotyping, the Steatohepatitic Subtype and the Impact of the Hepatic Pedicle Clamping

Introduction: Hepatectomy (HP) is, along with liver transplantation, the only potentially curative treatment for Hepatocellular Carcinoma (HCC). The high prevalence of Metabolic Syndrome (MS) may be causing a shift in the HCC spectrum. Hepatic Pedicle Clamping (HPC), used to reduce perioperative bleeding during HP, has been theorized to increase the risk of recurrence. Cytokeratin 19 (CK19) and glypican-3 (GLP-3) have been identified as markers of worse prognosis in HCC. Materials and Methods: A clinical and pathological review of 59 patients undergoing HP for HCC between 2005 and 2013 was performed. Chronic liver disease was observed in 53 patients (89.8%), with cirrhosis in 54.2% [most frequent etiologies: ethylism (47.5%), HCV (25.4%) and HBV (11.9%)]. MS was in 36% of patients. In addition, 95% of patients had Child–Pugh class A and 5% class B, and there was a median MELD of 8 (6–18). A single nodule was observed in 46 patients (78%) with an average size of 5.4 cm. Microscopic vascular invasion (MiVI) was in 49% of patients and macroscopic (MaVI) in 17. HPC was in 43 patients (74.1%). Statistical analysis was performed with SPSS™ 21.0. Survival tests (Kaplan–Meier, log-rank and Cox regression). Statistical significance was with p < 0.05. Results: Major morbidity in 22% of patients. Mortality in 5.1%. Median overall survival (OS) of 71 months and median disease-free survival (DFS) of 37. In a multivariate analysis: MaVI (p = 0.001), MiVI (p = 0.005) and HCV infection (p = 0.002) were associated with worse OS; MS was associated with better OS (p = 0.001); MaVI (p = 0.000), MiVI (p = 0.035) and HPC (p = 0.012) were associated with worse DFS. CK19+/GLP-3− (p = 0.007) and CK19−/GLP-3+ (p = 0.029) patients were associated with worse DFS and CK19−/GLP-3− (p = 0.031) with better DFS. Discussion/Conclusions: HPC was an independent factor of worse DFS. The ischemia-reperfusion injury (IRI) produced by HPC could promote a more angiogenic and angioinvasive phenotype of tumor cells, resulting in higher recurrence. HCV etiology was associated with worse OS. MS was associated with better OS, highlighting the importance of a hepatectomy in these cases. The combined detection of CK19 and GLP-3 was an independent prognostic factor in HCC patients allowing for the identification of more aggressive tumors.

The relationship between tumor-infiltrating neutrophils and clinical outcomes in patients with resectable hepatocellular carcinoma

BackgroundThe impact of tumor-infiltrating neutrophils (TINs) on clinical outcomes has been reported in various cancer types, but their role in hepatocellular carcinoma (HCC) has not been fully evaluated. The aim of this study was to investigate the prognostic values for TINs in HCC patients undergoing curative resection.MethodsWe assessed immune markers (CD3, CD4, CD8, CD66b) using immunohistochemistry in 115 patients who underwent curative resection for HCC. We analyzed the prognostic values for tumor-infiltrating immune cells, including neutrophils, and other clinicopathological factors.ResultsIn the Multivariate Cox analysis of overall survival (OS), alpha-fetoprotein (AFP) ≥ 100 ng/mL (hazard ratio (HR), 2.74, 95% confidence interval (CI), 1.17–6.44; P = 0.021) and Barcelona Clinic Liver Cancer (BCLC) B/C stage (HR, 3.98, 95% CI, 1.68–9.43; P = 0.020) were found to be independent poor prognostic factors in HCC patients undergoing resection. The presence of CD66b+TINs was observed in 66 (57.4%) patients. However, CD66b+TINs were not associated with recurrence-free survival and OS.ConclusionsOur study identified low CD66b+TINs in resectable HCC, and CD66b+ TINs did not have a significant role for the clinical outcomes of patients undergoing curative resection. The results suggest that TINs may play a role in more advanced stages of HCC.

Impact of ACSL4 on the prognosis of hepatocellular carcinoma: Association with cancer-associated fibroblasts and the tumour immune microenvironment.

Recently, the association between hepatocellular carcinoma (HCC) and ferroptosis has been the focus of much attention. The expression of long chain fatty acyl-CoA ligase 4 (ACSL4), a marker of ferroptosis, in tumour tissue is related to better prognosis in various cancers. In HCC, ACSL4 expression indicates poor prognosis and is related to high malignancy. However, the mechanism remains to be fully understood. We retrospectively enrolled 358 patients with HCC who had undergone hepatic resection. Immunohistochemistry (IHC) for ACSL4 was performed. Factors associated with ASCL4 expression were investigated by spatial transcriptome analysis, and the relationships were investigated by IHC. The association between ACSL4 and the tumour immune microenvironment was examined in a public dataset and investigated by IHC. Patients were divided into ACSL4-positive (n = 72, 20.1%) and ACSL4-negative (n = 286, 79.9%) groups. ACSL4 positivity was significantly correlated with higher α-fetoprotein (p = .0180) and more histological liver fibrosis (p = .0014). In multivariate analysis, ACSL4 positivity was an independent prognostic factor (p < .0001). Spatial transcriptome analysis showed a positive correlation between ACSL4 and cancer-associated fibroblasts; this relationship was confirmed by IHC. Evaluation of a public dataset showed the correlation between ACSL4 and exhausted tumour immune microenvironment; this relationship was also confirmed by IHC. ACSL4 is a prognostic factor in HCC patients and its expression was associated with cancer-associated fibroblasts and anti-tumour immunity.

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

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

The significance of HAUS1 and its relationship with immune microenvironment in hepatocellular carcinoma.

Background: HAUS Augmin-like complex subunit 1(HAUS1), as a controlling gene, which affected the production of spindle was firstly discovered in Drosophila cells. Although HAUS1 has been intensively studied, but its significance and relationship with the immune microenvironment in Hepatocellular carcinoma (HCC) remain unclear. Materials and Methods: All data of HCC in this paper were obtained from The Cancer Genome Atlas(TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO) and the Human Protein Atlas(HPA) database. The role and potential value of HAUS1 in the tumorigenesis and development of HCC were studied by applying plenty of bioinformatics analysis methods. Knocked down the expression of HAUS1 through siRNA and further investigated the function of HAUS1 in HCC Results: HAUS1 was highly expressed in HCC, which led to a poor prognosis. ROC curve analysis showed that HAUS1 had a excellent diagnostic value. It was also associated with clinical stage, pathological grade and AFP of HCC. Univariate and multivariate COX regression analysis showed that HAUS1 was an independent prognostic factor for HCC patients. HAUS1 was associated with immune cells infiltrate and immune checkpoints in HCC, and it could generate significative therapeutic results when combined with anti-CTLA4 and anti-CD274 treatment. In vitro experiments, HAUS1 was found to promote the proliferation, invasion and metastasis, participated in cell cycle regulation and inhibited apoptosis of HCC. Conclusion: These results suggested that HAUS1 might serve as a potential therapeutic target, as well as a diagnostic, prognostic, and survival biomarker for HCC.

Prognostic Significance of C-Reactive Protein in Lenvatinib-Treated Unresectable Hepatocellular Carcinoma: A Multi-Institutional Study.

Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). However, the significance of the serum CRP level, specifically in HCC patients treated with lenvatinib, remains unclear. We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. Clinical characteristics were assessed to identify clinical associations between serum CRP and HCC prognosis. The median overall serum CRP level was 0.29 mg/dL. The cohort was divided into two groups: the low-CRP group with a serum CRP < 0.5 mg/dL and the high-CRP group with a serum CRP ≥ 0.5 mg/dL. The low-CRP group exhibited significantly longer overall survival (OS) than the high-CRP group (22.9 vs. 7.8 months, p < 0.001). No significant difference was observed for progression-free survival (PFS) between the high- and low-CRP groups (9.8 vs. 8.4 months, p = 0.411), while time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). The discontinuation rate due to poor performance status was significantly higher in the high-CRP group (p < 0.001). A baseline serum CRP level exceeding 0.5 mg/dL was identified as an unfavorable prognostic factor in HCC patients receiving lenvatinib treatment.

An integrative analysis reveals the prognostic value and potential functions of MTMR2 in hepatocellular carcinoma

Abnormal expression of myotubularin-related protein 2 (MTMR2) has been identified in certain types of cancer, leading to varying effects on tumor genesis and progression. However, the various biological significances of MTMR2 in hepatocellular carcinoma (HCC) have not been systematically and comprehensively studied. The aim of this study was to explore the role of MTMR2 in HCC. We obtained the raw data from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Afterward, we analyzed the data using R and cBioPortal. We investigated the connection between MTMR2 and its expression, prognosis, clinical significance, methylation, genetic alterations, tumor microenvironment (TME), tumor mutation burden (TMB), and drug reactivity in HCC patients. MTMR2 expression levels in HCC cells were validated through western blotting and RT-qPCR. MTMR2 exhibits high levels of expression across a wide range of cancer types, including HCC. MTMR2 is diagnostically valuable in detecting HCC, with its up-regulated expression often being indicative of poor prognosis among HCC patients. The in vitro experiments confirmed elevated MTMR2 expression in HepG2, HUH-7, and MHCC-97H cells. Univariate and multivariate Cox analysis demonstrated that MTMR2 was an independent prognostic factor in HCC patients. The cg20195272 site has the highest degree of methylation in MTMR2, and it is positively correlated with MTMR2 expression. Patients with high levels of methylation at the cg20195272 site show poor prognosis. Analysis of the TME indicates that high expression of MTMR2 is associated with elevated ESTIMATE score and that MTMR2 expression correlates positively with infiltration by resting memory CD4 T cells, activated dendritic cells, as well as several immune checkpoints. There is a negative correlation between MTMR2 expression and TMB, and drug sensitivity analyses have shown that higher MTMR2 expression is associated with lower IC50 values. This study indicates that increased expression of MTMR2 may play a crucial role in the occurrence, progression, diagnosis, prognostic prediction and drug therapy of HCC.

E2F1-mediated Up-regulation of NCAPG Promotes Hepatocellular Carcinoma Development by Inhibiting Pyroptosis.

As a subunit of the condensin complex, NCAPG has an important role in maintaining chromosome condensation, but its biological function and regulatory mechanism in hepatocellular carcinoma (HCC) remains undefined. The prognostic ability of NCAPG in HCC patients was examined by univariate and multivariate Cox regression analysis. ROC curves were plotted to compare the predictive ability of NCAPG and AFP. Double luciferase reporter system, and ChIP were used to investigate transcriptional potential of E2F1 to NCAPG. Pyroptosis was observed by scanning electron microscopy. Protein expression of NCAPG, E2F1, and major proteins constituting NLRP3 inflammasome was determined by western blotting and ELISA. An in vivo tumor formation assay was conducted to verify the in vitro results. Up-regulated NCAPG was identified in HCC tissues compared with adjacent tissue and high NCAPG was positively correlated with poor prognosis. Serum NCAPG mRNA level was a prognostic factor in HCC patients and also a diagnostic factor with higher predictive ability compared with AFP [AUROC 0.766 (95% CI: 0.650-0.881) vs. 0.649 (95% CI 0.506-0.793)]. HBx transfection resulted in concomitant up-regulation of E2F1 and NCAPG. E2F1 significantly increased the activity of luciferase reporter fused with NCAPG reporter, and the interaction of E2F1 and NCAPG gene was confirmed by ChIP. Silencing of E2F1 resulted in significant down-regulation of NCAPG. Knockdown of NCAPG promote pyroptosis mediated by NLRP3 inflammasome activation in multiple HCC cell lines and also suppressed tumorigenesis in vitro. We identified a novel role of NCAPG in the regulation of NLRP3 inflammasome-mediated pyroptosis, which was regulated by its upstream transactivator, E2F1. The role of E2F1-NCAPG-NLRP3 regulation of pyroptosis network may be a potential target in HCC treatment.

Potential functions and causal associations of VPS29 in hepatocellular carcinoma: a bioinformatic and Mendelian randomization study.

Vacuolar protein sorting-associated protein 29 (VPS29) plays a certain role in cancer, but its biological significance in hepatocellular carcinoma (HCC) has not been studied. We utilized bioinformatics and Mendelian randomization (MR) analysis to explore the potential function of the VPS29 gene in HCC, as well as the causal relationship between VPS29 protein and HCC. We downloaded the raw data from TCGA, GEO, and IEU OpenGWAS databases. We used R software for data processing and analysis to explore the relationship between the VPS29 gene and the expression, prognosis, clinical features, methylation, immune microenvironment, tumor mutation burden, and drug sensitivity in HCC patients. Additionally, a two-sample Mendelian randomization analysis was conducted to investigate the causal relationship between the VPS29 protein and HCC. VPS29 was found to be overexpressed in various types of cancer, including HCC, and its elevated expression often predicts poor prognosis in HCC patients. Univariate and multivariate Cox analysis demonstrated that VPS29 was an independent prognostic factor in HCC patients. The ROC curve indicated that VPS29 has a high diagnostic value in HCC. There were differential expressions of VPS29 in various clinical feature subgroups. The expression of VPS29 was negatively correlated with methylation levels, and multiple methylation sites were identified in the promoter region, including cg20877181, cg03867797, cg10025392, cg21605021, which were associated with poorer overall survival (OS) at low methylation levels. VPS29 was associated with immune cell infiltration disorders, including CD8+ T cells, Eosinophils, Neutrophils, Tcm, NK CD56bright cells, TFH, Th2 cells, Th17 cells, etc. Drug sensitivity analysis showed that VPS29 could be indicative of treatment response to 10 common antineoplastic drugs in different expression subgroups. Inverse variance weighted (IVW) analysis revealed a significant increase in HCC risk associated with VPS29 [odds ratio (OR): 1.440; 95% confidence interval (CI): 1.195-1.736], and sensitivity analysis showed no heterogeneity or pleiotropy. VPS29 is a risk factor for the occurrence and progression of HCC and may serve as a molecular biomarker for the diagnosis and prognosis of HCC.

Characterizing the key genes of COVID-19 that regulate tumor immune microenvironment and prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a highly heterogeneous malignant tumor associated with a poor prognosis, is a common cause of cancer-related deaths worldwide, with a limited survival benefit for patients despite ongoing therapeutic breakthroughs. Coronavirus disease 2019 (COVID-19), a severe infectious disease caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is a global pandemic and a serious threat to human health. The increased susceptibility to SARS-CoV-2 infection and a poor prognosis in patients with cancer necessitate the exploration of the potential link between the two. No studies have investigated the relationship of COVID-19 genes with the prognosis and tumor development in patients with HCC. We screened prognosis-related COVID-19 genes in HCC, performed molecular typing, developed a stable and reliable COVID-19 genes signature for predicting survival, characterized the immune microenvironment in HCC patients, and explored new molecular therapeutic targets. Datasets of HCC patients, including RNA sequencing data and clinical information, were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Prognosis-related COVID-19 genes were identified by univariate Cox analysis. Molecular typing of HCC was performed using the consensus non-negative matrix factorization method (cNMF), followed by the analysis of survival, tumor microenvironment, and pathway enrichment for each subtype. Prognostic signatures were constructed using LASSO-Cox regression models, and receiver operating characteristic (ROC) curves were used to validate the predictive performance of the signature. The same approach was used for the test and external validation sets. Seven software packages were applied to determine the abundance of immune infiltration in HCC patients and investigate its relationship with the risk scores. Gene set enrichment analysis (GSEA) was used to explore the potential mechanisms by which the COVID-19 genes affect hepatocarcinogenesis and prognosis. Three types of machine learning methods were combined to identify the most critical genes in the signature and localize their expression at the single cell level. We identified 53 prognosis-related COVID-19 genes and classified HCC into two molecular subtypes (C1, C2) by using the NMF method. The prognosis of C2 was significantly better than that of C1, and the two subtypes differed remarkably in terms of the tumor immune microenvironment and biological functions. The 17 COVID-19 genes were screened using the LASSO regression method to develop a 17 COVID-19 genes signature, which demonstrated a good predictive performance for 1-, 2- and 3-year OS of patients with HCC. The risk score as an independent prognostic factor for HCC has better predictive accuracy than traditional clinical variables. Patients in the TCGA cohort were categorized by risk score into the high- and low-risk groups, with the high-risk group mainly enriched in the immune modulation-related pathways and the low-risk group mainly enriched in the metabolism-related pathways, suggesting that the COVID-19 genes may affect disease progression and prognosis by regulating the tumor immune microenvironment and metabolism in HCC. NOL10 was identified as the most critical gene in the signature and hypothesized to be a potential therapeutic target for HCC. Objectively, the COVID-19 genes signature developed in this study, as an independent prognostic factor in HCC patients, is closely associated with the prognosis and tumor immune microenvironment of HCC patients and indicates that they may regulate the development of HCC in multiple ways, providing us with new perspectives for understanding the molecular mechanisms of HCC and finding effective therapeutic targets.

Prognosis of Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization(MC-hccAI 001): Development and Validation of the ALFP Score.

Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage Hepatocellular carcinoma (HCC) patients. However, predicting the survival of HCC patients receiving TACE remains challenging. In this retrospective study, we analyzed a total of 1805 HCC patients who received TACE. The patients were randomly divided into a training set (n = 1264) and a validation set (n = 541). We examined various prognostic factors within the training set and developed a simple ALFP (ALBI grade, AFP, and Prothrombin time) score, which was subsequently validated using the independent validation set. Our multivariate analysis revealed that baseline ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s were independent unfavorable prognostic factors for HCC patients receiving TACE (p < 0.05). Based on these findings, we constructed the ALFP score, which assigns 1 point each for ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s. The score has a range of 0 to 3, and higher scores are associated with poorer outcomes. The median overall survival (OS) varied significantly among different ALFP score groups, both in the training set and the validation set (p < 0.001). We further examined the ALFP score in subgroups based on tumor diameter and the number of intrahepatic lesions. In each subgroup, higher ALFP scores were consistently associated with lower OS (p < 0.05). Our study confirms the prognostic value of the ALFP score in predicting the survival of HCC patients undergoing TACE. The score incorporates easily obtainable baseline parameters and provides a simple and practical tool for risk stratification and treatment decision-making in HCC patients.

Development and validation of a diagnostic and prognostic model for lung metastasis of hepatocellular carcinoma: a study based on the SEER database.

Lung metastasis (LM) is a common occurrence in patients with hepatocellular carcinoma (HCC), and it is associated with a poorer prognosis compared to HCC patients without LM. This study aimed to identify predictors and prognostic factors for LM in HCC patients as well as develop diagnostic and prognostic nomograms specifically tailored for LM in HCC patients. A retrospective analysis was conducted on HCC patients from the Surveillance, Epidemiology, and End Results (SEER) database, covering the period from 2010 to 2015. The study employed multivariate logistic regression analysis to identify risk factors associated with LM in HCC patients. Additionally, multivariate Cox proportional hazards regression analysis was utilized to investigate prognostic factors for HCC patients with LM. Subsequently, two nomograms were developed to predict the risk and prognosis of LM in HCC patients. The performance of the nomograms was evaluated through calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). This retrospective study included a total of 5,934 patients diagnosed with HCC, out of which 174 patients were diagnosed with LM. Through multivariate logistic regression analysis, several independent risk factors for LM in HCC patients were identified, including tumor grade, tumor size, American Joint Committee for Cancer (AJCC) T stage, and AJCC N stage. Furthermore, multivariate Cox analysis revealed that tumor grade, delayed treatment, surgery, and radiation were independent prognostic factors for HCC patients with LM. To assess the predictive power of the developed nomograms, calibration curves, receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA) were employed. The findings demonstrated that the nomograms exhibited satisfactory performance in both the training and validation sets. Additionally, the prognostic nomogram effectively stratified HCC patients with LM into low- and high-risk groups for mortality. These two nomograms optimally predicted the risk and prognosis of LM in HCC patients. Both nomograms have satisfactory performance. This would help clinicians to make accurate clinical decisions.

Identification of a novel signature based on macrophage-related marker genes to predict prognosis and immunotherapeutic effects in hepatocellular carcinoma.

Tumor-related macrophages (TAMs) have emerged as an essential part of the immune regulatory network in hepatocellular carcinoma (HCC). Constructing a TAM-related signature is significant for evaluating prognosis and immunotherapeutic response of HCC patients. Informative single-cell RNA sequencing (scRNA-seq) dataset was obtained from the Gene Expression Omnibus (GEO) database, and diverse cell subpopulations were identified by clustering dimension reduction. Moreover, we determined molecular subtypes with the best clustering efficacy by calculating the cumulative distribution function (CDF). The ESTIMATE method, CIBERSORT (cell-type identification by estimating relative subsets of RNA transcripts) algorithm and publicly available tumor immune dysfunction and exclusion (TIDE) tools were used to characterize the immune landscape and tumor immune escape status. A TAM-related gene risk model was constructed through Cox regression and verified in multiple datasets and dimensions. We also performed functional enrichment analysis to detect potential signaling pathways related to TAM marker genes. In total, 10 subpopulations and 165 TAM-related marker genes were obtained from the scRNA-seq dataset (GSE149614). After clustering 3 molecular subtypes based on TAM-related marker genes, we found significantly different prognostic survival and immune signatures among the three subtypes. Subsequently, a 9-gene predictive signature (TPP1, FTL, CXCL8, CD68, ATP6V1F, CSTB, YBX1, LGALS3, and APLP2) was identified as an independent prognostic factor for HCC patients. Those patients with high RiskScore had a lower survival rate and benefited less from immunotherapy than those with low RiskScore. Moreover, more samples of the Cluster C subtype were enriched in the high-risk group, with higher tumor immune escape incidence. We constructed a TAM-related signature with excellent efficacy for predicting prognostic survival and immunotherapeutic responses in HCC patients.

Identifying a novel cuproptosis-related necroptosis gene subtype-related signature for predicting the prognosis, tumor microenvironment, and immunotherapy of hepatocellular carcinoma.

Background: Cuproptosis and necroptosis represent two distinct programmed cell death modalities implicated in neoplastic progression; however, the role of combining cuproptosis and necroptosis in hepatocellular carcinoma (HCC) remains to be elucidated. Methods: A total of 29 cuproptosis-related necroptosis genes (CRNGs) were identified, followed by an extensive analysis of their mutational characteristics, expression patterns, prognostic implications, and associations with the tumor microenvironment (TME). Subsequently, a CRNG subtype-related signature was developed, and its value of prognostic prediction, TME, and therapeutic responses in HCC were thoroughly investigated. Last, quantitative real-time PCR and Western blotting were employed for investigating the signature gene expression in 15 paired clinical tissue samples. Results: Two distinct CRNG subtypes were discerned, demonstrating associations between CRNG expression patterns, clinicopathological attributes, prognosis, and the TME. A CRNG subtype-related prognostic signature, subjected to external validation, was constructed, serving as an independent prognostic factor for HCC patients, indicating poor prognosis for high-risk individuals. Concurrently, the signature's correlations with an immune-suppressive TME, mutational features, stemness properties, immune checkpoint genes, chemoresistance-associated genes, and drug sensitivity were observed, signifying its utility in predicting treatment responses. Subsequently, highly accurate and clinically convenient nomograms were developed, and the signature genes were validated via quantitative real-time PCR and Western blotting, further substantiating the stability and dependability of the CRNG subtype-related prognostic signature. Conclusion: Overall, this investigation presented an extensive panorama of CRNGs and developed the CRNG subtype-related prognostic signature, which holds potential for implementation in personalized treatment strategies and prognostic forecasting for HCC patients.

Effects of hypersplenism on the outcome of hepatectomy in hepatocellular carcinoma with hepatitis B virus related portal hypertension.

Although hepatectomy plus splenectomy is not regularly recommended for hepatocellular carcinoma (HCC) with portal hypertension related hypersplenism due to the high risk accompanied with surgical procedures for now. Many researchers still believe that hypersplenism is a controversial adverse prognostic factor for HCC patients. Thus, the primary objective of the study was to determine the effects of hypersplenism on the prognosis of these patients during and after hepatectomy. A total of 335 patients with HBV-related HCC who underwent surgical resection as primary intervention were included in this study and categorized into three groups. Group A consisted of 226 patients without hypersplenism, Group B included 77 patients with mild hypersplenism, and Group C contained 32 patients with severe hypersplenism. The influence of hypersplenism on the outcome during the perioperative and long-term follow-up periods was analyzed. The independent factors were identified using the Cox proportional hazards regression model. The presence of hypersplenism is associated with longer hospital stays, more postoperative blood transfusions, and higher complication rates. The overall survival (OS, P = 0.020) and disease-free survival (DFS, P = 0.005) were significantly decreased in Group B compared to those in Group A. Additionally, the OS (P = 0.014) and DFS (P = 0.005) were reduced in Group C compared to those in Group B. Severe hypersplenism was a significant independent prognostic variable for both OS and DFS. Severe hypersplenism prolonged the hospital stay, increased the rate of postoperative blood transfusion, and elevated the incidence of complications. Furthermore, hypersplenism predicted lower overall and disease-free survivals.

Comprehensive analysis of immunogenic cell death associated genes expression, tumor microenvironment, and prognosis in hepatocellular carcinoma.

Background: Immunogenic cell death (ICD) plays an important role in the development of cancers. This study attempted to explore the role of ICD in the prognosis of hepatocellular carcinoma (HCC). Methods: Gene expression and clinical data were downloaded from The Cancer Genome Alas and Gene Expression Omnibus dataset. The immune/stromal/Estimate scores of the tumor microenvironment (TME) were calculated by ESTIMATE and CIBERSORT algorithms. Kaplan-Meier analysis, functional enrichment analysis, least absolute shrinkage and selection operator (LASSO) analysis, and univariate and multivariate Cox regression analysis were used for prognostic gene screening and prognostic model construction. The correlation of immune cell infiltration and risk scores was analyzed as well. Molecular docking was used to explore the relevance of related genes to anti-cancer drugs. Results: Ten ICD associated differentially expressed genes in HCC were found, and all of them had good predictive ability for HCC. ICD gene high amount of expression group was associated with poor prognosis (p = 0.015). The TME, immune cell infiltration and gene expression were different between ICD high and low groups (all p < 0.05). Six ICD associated genes (BAX, CASP8, IFNB1, LY96, NT5E and PIK3CA) which could predict the survival status were identified and used to construct the prognostic model for HCC. A risk score was calculated and it could be used as an independent prognostic factor in HCC patients (p < 0.001). In addition, the risk score had a positive correlation with macrophage M0 (r = 0.33, p = 0.0086). Molecular docking indicated that sorafenib could bind strongly to the target protein, representing that sorafenib may exert anticancer effects through these six ICD associated genes. Conclusion: This study established a prognostic model including six ICD associated genes for HCC, which may deepen our understanding of ICD and guide therapy for HCC patients.

FOXP3 and SQSTM1/P62 correlate with prognosis and immune infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common highly malignant tumours worldwide. FOXP3 and SQSTM1/P62 have been shown to be abnormally expressed in tumour cells, but their function in different tumours remains controversial. The present study was designed to evaluate the expression of FOXP3 and P62 in HCC and their prognostic value as well as their relationship with immune infiltration in HCC patients. The Gene Expression Omnibus (GEO) database and TNMplot.com platform were used to analyse the expression of FOXP3 and P62. The Cancer Genome Atlas (TCGA) database and Kaplan-Meier plotter were used to assess the impacts of FOXP3 and P62 on clinical prognosis. In addition, TCGA database was also used to examine the correlation between the expression of FOXP3 and P62 and tumour immune infiltration using the CIBERSORT algorithm. Finally, immunohistochemistry (IHC) was used to determine expression levels of FOXP3 and P62 in 89 HCC and adjacent normal liver tissues, and their effects on clinicopathological features and prognosis were verified. FOXP3 expression was downregulated in HCC tissues, while P62 expression was upregulated. FOXP3 underexpression and P62 overexpression were closely related to decreased overall survival (OS) in HCC patients. Additionally, the abnormal expression of FOXP3 and P62 was closely related to the infiltration levels of 12 types of immune cells, including regulatory T cells (Tregs), M2 macrophages, M0 macrophages, and CD8 T cells. Notably, in the validation model, abnormal FOXP3 and P62 expression was significantly associated with adverse clinicopathological factors in HCC patients, including elevated α-fetoprotein (AFP) levels, poor tumour differentiation, and increased Ki67 levels. Furthermore, low FOXP3 and high P62 expression were independent risk factors for predicting OS prognosis in HCC patients. FOXP3 and P62 have been shown to be important prognostic factors in HCC patients and are associated with immune cell infiltration in HCC. These findings suggest that FOXP3 and P62 may be valuable prognostic biomarkers and potential therapeutic targets for HCC treatment.

Association between F-box-only protein 43 overexpression and hepatocellular carcinoma pathogenesis and prognosis.

Despite great advances in the prevention, diagnosis, treatment, and management regarding hepatocellular carcinoma (HCC), the overall prognosis of HCC remains unfavorable. The expression profile, prognostic role, and biological functions of F-box-only protein 43 (FBXO43) in HCC remain unclear. Here, we determine the expression profile and prognostic value of FBXO43 in patients with HCC. A total of 467 HCC patients and their clinicopathological data were collected from the Second Affiliated Hospital of Jiaxing University, the Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) databases. The expression profile, prognostic value, biological functions, and underlying mechanism of its involvement of FBXO43 were explored based on TCGA, Gene Expression Omnibus (GEO), LinkedOmics, and Cancer Dependency Map (DepMap). The expression of FBXO43 in 93 paired liver tissues was investigated via immunohistochemical staining, tissue microarray analysis, and Western blot. The prognostic value was assessed using survival analysis. FBXO43 RNA was upregulated in HCC liver tissues and was associated with an unfavorable prognosis (p < 0.05). Furthermore, FBXO43 protein was overexpressed in HCC liver tissues compared with that in paired normal liver tissues. Overexpression of FBXO43 protein was significantly associated with advanced TNM stage, large tumor size, lymphatic invasion, distant metastasis, earlier cancer recurrence, and decreased overall survival after radical surgery (p < 0.05). Cox regression analysis showed that FBXO43 had significant prognostic value in HCC. Importantly, FBXO43 and its co-expressed genes were mainly involved in cell cycle regulation, DNA replication, metabolic regulation, and so on. FBXO43 knockdown could significantly affect the HCC cell lines growth and proliferation. We first revealed that FBXO43 was overexpressed in liver HCC tissues at the RNA and protein levels and served as an independent prognostic factor for HCC patients. Therefore, FBXO43 is worth investigating as a potential HCC treatment target.

Prognostic value of combined pre- and postoperative albumin-to-alkaline phosphatase ratio for patients with hepatocellular carcinoma undergoing trans-catheter chemoembolisation

To reveal the prognostic value of the postoperative and dynamic albumin-to-alkaline phosphatase ratio (AAPR) in hepatocellular carcinoma (HCC) patients undergoing trans-catheter chemoembolisation (TACE). In total, 545 HCC patients undergoing initial TACE were enrolled into the study. The receiver operating characteristic (ROC) curve was plotted to determine the best cut-off for AAPR. Univariate and multivariate Cox regression analyses were used to confirm the independent prognostic effect of AAPR on overall survival (OS). The predictive performance of AAPR was assessed by ROC curves, concordance index (C-index), and Akaike information criterion (AIC), and was compared to existing liver function assessment systems. The optimal cut-off value for the AAPR was 0.26. Elevated AAPR (>0.26) was associated with a low risk of death after adjustment whether before (HR: 0.53; 95% CI: 0.4-0.69) or after (HR: 0.64; 95% CI: 0.43-0.95) TACE treatment. The combined pre- and postoperative AAPR showed much better performance in ROC curve (1-, 3-, and 5-year AUCs: 0.69, 0.71, 0.69), C-index (0.65; 95% CI: 0.59-0.72) and AIC analyses than pre-AAPR and post-AAPR alone or liver function assessment systems. This study demonstrated both preoperative and postoperative AAPR were independent prognostic factors for HCC patients undergoing TACE. In addition, the combined pre- and post-AAPR showed better predictive performance than pre-AAPR and post-AAPR alone or liver function assessment systems.