Hepatocellular Carcinoma Patients Research Articles

Predictive Prognostic Model for Hepatocellular Carcinoma Based on Seven Genes Participating in Arachidonic Acid Metabolism.

The occult onset and rapid progression of hepatocellular carcinoma (HCC) lead to an unsatisfactory overall survival (OS) rate. Established prognostic predictive models based on tumor-node-metastasis staging and predictive factors do not report satisfactory predictive efficacy. Arachidonic acid plays pivotal roles in biological processes including inflammation, regeneration, immune modulation, and tumorigenesis. We, therefore, constructed a prognostic predictive model based on seven genes linked to arachidonic acid metabolism, using samples of HCC patients from databases to analyze the genomic profiles. We also assessed the predictive stability of the constructed model. Sample data of 365 patients diagnosed with HCC were extracted from The Cancer Genome Atlas (TCGA, training set) and HCCDB18, GSE14520, and GSE76427 databases (validation sets). Patient samples were clustered using ConsensusClusterPlus analysis based on the expression levels of 12 genes involved in arachidonic acid metabolism that were significantly associated with HCC prognosis. Differentially expressed genes (DEGs) within different clusters were distinguished and compared using WebGestaltR. Immunohistochemistry (IHC) analysis was performed using a human HCC tissue microarray (TMA). Tumor immune microenvironment assessment was performed using ESTIMATE, ssGSEA, and TIDE. Samples of patients with HCC were classified into three clusters, with significant differences in OS. Cluster 2 showed the best prognosis, whereas cluster 1 presented the worst. The three clusters showed significant differences in immune infiltration. We then performed Cox and LASSO regression analyses, which revealed CYP2C9, G6PD, CDC20, SPP1, PON1, TRNP1, and ADH4 as prognosis-related hub genes, making it a simplified prognostic model. TMA analysis for the seven target genes showed similar results of regression analyses. The high-risk group showed a significantly worse prognosis and reduced immunotherapy efficacy. Our model showed stable prognostic predictive efficacy. This seven-gene-based model showed stable outcomes in predicting HCC prognosis as well as responses to immunotherapy.

Apolipoprotein A1-encoding recombinant adenovirus remodels cholesterol metabolism in tumors and the tumor microenvironment to inhibit hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor requiring effective treatments. Oncolytic viruses induce anti-tumor responses but have limited efficacy. Apolipoprotein A1 (ApoA1) inhibits inflammation, modulates immunity, and promotes anti-oxidation. This study aims to construct an oncolytic adenovirus (Ad5)-ApoA1 for superior anti-tumor effects.We analyzed ApoA1 expression in tumors and its prognostic significance using public databases. Subsequently, we engineered a recombinant oncolytic adenovirus Ad5-ApoA1 and assessed its replication and oncolytic efficacy in vitro and in nude mice. The impact of Ad5-ApoA1 on the tumor microenvironment of HCC was evaluated through flow cytometry, transcriptome sequencing, single-cell sequencing, and other methodologies. Additionally, mechanisms of immune microenvironment modulation by Ad5-ApoA1 were explored. ApoA1 expression was down-regulated with HCC progression and significantly positively correlated with the prognosis of HCC patients. Ad5-ApoA1 exhibited robust oncolytic activity but showed no therapeutic effect on nude mice. However, it significantly inhibited HCC growth and prolonged the survival period of both healthy-immune and humanized immune-reconstituted NCG mice. Furthermore, Ad5-ApoA1 significantly promoted the expression of IFN-γ and GzmB in CD8+ T cells while inhibiting the expression of PD-1 and LAG-3. Notably, the cholesterol content in the CD8+ T cells studied was significantly correlated with the expression of PD-1 and LAG-3, with ApoA1 promoting cholesterol efflux and reducing cholesterol levels. Ad5-ApoA1 activates CD8+ T cells by promoting large-scale viral replication. High levels of ApoA1 protein expression promote cholesterol efflux, inhibit CD8+ T cell depletion, and reduce inflammatory factors, ultimately leading to superior therapeutic effects on hepatocellular carcinoma.

Systemic chemotherapy improves outcome of hepatocellular carcinoma patients treated with transarterial chemoembolization

Systemic chemotherapy improves outcome of hepatocellular carcinoma patients treated with transarterial chemoembolization

ZNF143-mediated upregulation of MEX3C promotes hepatocellular carcinoma progression

BackgroundMicrovascular invasion is strongly associated with aggressive tumor behavior and recurrence in hepatocellular carcinoma (HCC) patients. Zinc finger protein 143(ZNF143) is a transcription factor involved in a wide variety of physiological and developmental processes. This study primarily focuses on the exact biological role and mechanism of ZNF143 in HCC migration and invasion. MethodsThe expression and prognosis of ZNF143 in HCC patients were analyzed. The levels of ZNF143, mex-3 RNA binding family member C (MEX3C) were quantified by western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell migration ability was detected by wound- healing assay. Matrigel transwell assay was conducted to evaluate the invasion of HCC cells. The differential expression genes of ZNF143 overexpression and knockdown were screened by mRNA profiling analysis. Dual luciferase assay was performed to determine the promoter activity of MEX3C. The enrichment of ZNF143 at MEX3C promoter was determined by chromatin immunoprecipitation (ChIP). ResultsZNF143 is overexpressed in HCC tissues and that its overexpression is correlated with poorer prognosis, especially in HCC patients with higher tumor grades and microvascular invasion. Gain- and loss-of function experiments showed that ZNF143 promotes migration and invasion in HCC cells. mRNA profiling showed that ZNF143 significantly upregulates MEX3C. ZNF143 was positively correlated with MEX3C expression in HCC tissue. ZNF143 activates MEX3C transcription by directly binding to its promoter. MEX3C knockdown inhibited migration and invasion induced by ZNF143 overexpression in HCC cells. ConclusionZNF143 promotes HCC cell migration and invasion by binding to MEX3C promoter and activating its expression.

Significance of anatomical resection and wide surgical margin for HCC patients with MVI undergoing laparoscopic hepatectomy: A multicenter study

ObjectiveTo investigate the impact of surgical resection margin and hepatic resection type on prognosis and compare their prognostic significance on patients with hepatocellular carcinoma (HCC) with or without microvascular invasion (MVI) who underwent laparoscopic liver resection (LLR). MethodsA retrospective analysis was conducted on 320 patients with HCC who underwent LLR. According to the grading of MVI, patients were classified as M0, M1 and M2. Patients were divided into the anatomical resection (AR) and nonanatomical resection (NAR) groups according to the hepatic resection type. Survival and Cox regression analyses were performed to explore the effects of AR and NAR, wide and narrow resection margin on overall survival (OS) and time to recurrence (TTR). ResultsIn the whole cohort, narrow resection margin was an independent risk factor for OS and TTR, whereas NAR was not. Subgroup analysis showed that narrow resection margin and NAR were both independent risk factors for OS and TTR in HCC patients with MVI. The 5-year OS and TTR rates of the two groups (NAR-wide resection margin and AR-narrow resection margin) with M1 were 85.3 % versus 62 % and 34.4 % versus 60.2 %. Similarly, the 5-year OS and TTR rates of the two groups (NAR-wide resection margin and AR-narrow resection margin) with M2 were 80.2 % versus 47.9 % and 30.8 % versus 64.8 %. ConclusionsAnatomical hepatectomy and wide resection margin were independent protective factors for HCC patients with MVI receiving LLR. Nonetheless, wide resection margin had a greater impact on prognosis than anatomical hepatectomy.

Úloha imunoterapie pri liečbe hepatocelulárneho karcinómu

Hepatocellular carcinoma (HCC) represents the most common primary liver malignancy, accounting for approximately 75–80% of all liver cancer cases. The global incidence of hepatocellular carcinoma is increasing due to rising rates of underlying diseases, creating a significant cancer burden and a significant clinical challenge due to its often late presentation and limited effective treatment options. Immune checkpoint inhibitors have revolutionized the treatment approach in various malignancies. In the treatment of advanced hepatocellular carcinoma, immunotherapy has proven to be more effective than tyrosine kinase inhibitors, which have been a treatment option for a decade. Clinical trials such as the HIMALAYA and IMbrave150 have demonstrated significant survival benefits, showing superior efficacy compared to sorafenib. Despite these promising results, not all HCC patients respond to immunotherapy equally. There is a need to search for reliable prognostic and predictive biomarkers that can help predict which patients are most likely to benefit from immunotherapy, thereby personalizing treatment and improving outcomes. The purpose of this article is to provide a summary of clinical trials on immunotherapy for various stages of hepatocellular carcinoma.

Unlocking vinpocetine's oncostatic potential in early-stage hepatocellular carcinoma: A new approach to oncogenic modulation by a nootropic drug.

The development of new drugs for the inhibition of hepatocellular carcinoma (HCC) development and progression is a critical and urgent need. The median survival rate for HCC patients remains disappointingly low. Vinpocetine is a safe nootropic agent that is often used to enhance cognitive function. The impact of vinpocetine on HCC development and progression has not been fully explored. Our main objective was to investigate the possible inhibitory role of vinpocetine in rats exposed to diethylnitrosamine. We observed that vinpocetine increased the survival rate of these rats and improved the ultrastructure of their livers. Additionally, vinpocetine reduced the liver weight index, mitigated liver oxidative stress, and improved liver function. In both in vitro and in vivo settings, vinpocetine demonstrated antiproliferative and apoptotic properties. It downregulated the expression of CCND1 and Ki-67 while exhibiting anti-BCL-2 effects and enhancing the levels of Bax and cleaved caspase-3. Vinpocetine also successfully deactivated NF-κB, STAT3, and HIF-1α, along with their associated transcription proteins, thereby exerting anti-inflammatory and anti-angiogenic role. Furthermore, vinpocetine showed promise in reducing the levels of ICAM-1 and TGF-β1 indicating its potential role in tissue remodeling. These findings strongly suggest that vinpocetine holds promise as a hepatoprotective agent by targeting a range of oncogenic proteins simultaneously. However, further approaches are needed to validate and establish causal links between our observed effects allowing for a more in-depth exploration of the mechanisms underlying vinpocetine's effects and identifying pivotal determinants of outcomes.

Role and therapeutic potential of E3s in the tumor microenvironment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a high-incidence, poor-prognosis malignancy worldwide, requiring new strategies for treatment. Ubiquitination, especially ubiquitination through E3 ubiquitin ligases, plays an indispensable role in the development and progression of HCC. E3 ubiquitin ligases are crucial enzymes in ubiquitination, controlling the degradation of specific substrate proteins and influencing various cellular functions, such as tumor cell proliferation, apoptosis, migration, and immune evasion. In this review, we systematically summarize the mechanisms of E3 ubiquitin ligases in HCC, with a focus on the significance of RING, HECT, and RBR types in HCC progression. The review also looks at the potential for targeting E3 ligases to modulate the tumor microenvironment (TME) and increase immunotherapy efficacy. Future studies will optimize HCC treatment by formulating specific inhibitors or approaches that will be based on gene therapy targeting E3 ligases in order to overcome resistance issues with present treatments and create optimism in the journey of treatment for HCC patients.

Stage dependent microbial dynamics in hepatocellular carcinoma and adjacent normal liver tissues

The interactive pathway of the gut-liver axis underscores the significance of microbiome modulation in the pathogenesis and progression of various liver diseases, including hepatocellular carcinoma (HCC). This study aims to investigate the disparities in the composition and functionality of the hepatic microbiota between tumor tissues and adjacent normal liver tissues, and their implications in the etiology of HCC. We conducted a comparative analysis of the hepatic microbiome between adjacent normal liver tissues and tumor tissues from HCC patients. Samples were categorized according to the modified Union for International Cancer Control (mUICC) staging system into Non-tumor, mUICC stage I, mUICC stage II, and mUICC stage III groups. Microbial richness and community composition were analyzed, and phylogenetic profiles were examined to identify significantly altered microbial taxa among the groups. Predicted metabolic pathways were analyzed using PICRUSt2. Our analysis did not reveal significant differences in microbial richness and community composition with the development of HCC. However, phylogenetic profiling identified significantly altered microbial taxa among the groups. Sphingobium, known for degrading polychlorinated biphenyls (PCBs), exhibited a significantly negative correlation with clinical indices in HCC patients. Conversely, Sphingomonas, a gut bacterium associated with various liver diseases, showed a positive correlation. Predicted metabolic pathways suggested a correlation between atrazine degradation and valine, leucine, and isoleucine biosynthesis with mUICC stage and tumor size. Our results underscore the critical link between hepatic microbial composition and function and the HCC tumor stage, suggesting a potentially pivotal role in the development of HCC. These findings highlight the importance of targeting the hepatic microbiome for therapeutic strategies in HCC.

Role of Serum Alpha-fetoprotein in Assessing the Resectability of Hepatocellular Carcinoma

Background: Serum AFP is a well-established tumor marker of hepatocellular carcinoma (HCC) which has already proved its acceptability in confirming the diagnosis and predicting the prognosis of HCC. Objective: The current study is aimed to evaluate the role of serum alpha-fetoprotein in assessing the resectability of HCC. Methods: This was a single-center, cross-sectional study done from September 2020 to August 2021 at the department of Hepatobiliary, pancreatic, and liver transplantation surgery at BSMMU. A total of 27 HCC patients who met the inclusion criteria were enrolled in the study. Clinical, laboratory, and imaging findings were obtained using a standardized data collecting sheet with the patients' informed agreement. AFP was measured by automated chemiluminescence analyzer (LIAISON XL, DiaSorin, Italy) in the Department of Biochemistry & Molecular Biology, BSMMU. Based on the ROC curve of this study, the patients were divided into group 1 with AFP levels 38.45 ng/ml and group 2 with AFP levels >38.45 ng/ml. According to the resectable criteria (TNM stage: I, II, BCLC stage: 0, A, B, CTP grade: A, B, ECOG PS: 0) established for the study, each AFP group was further subdivided into resectable and unresectable subgroups. Finally, the parameters (tumor size, number, location, CTP grade, fibrosis score, performance status, HBV positive, HBV DNA, BCLC and TNM stage) of the resectable and unresectable patients in each AFP group were evaluated. Statistical analyses were performed using SPSS version 22. Quantitative variables were expressed as mean±standard deviation and examined using an unpaired t-test. The qualitative data were represented by frequencies and percentages, and the Chi-Square test and Fisher exact test (where applicable) were used to determine any correlation. The statistical tests were conducted with a 95% confidence interval, and P0.05 was deemed statistically significant. Results: In this study, thirty seven percent (37%) patients ...........

Predictive value of early-stage postoperative albumin-bilirubin grade on the overall survival of hepatocellular carcinoma patients undergoing resection.

The albumin-bilirubin (ALBI) and ΔALBI grades have attracted substantial attention for their ability to predict the overall survival (OS) of patients with hepatocellular carcinoma (HCC). This retrospective study aimed to evaluate the predictive value of the ALBI grade at different time points for the OS of patients with HCC who underwent surgical resection. The clinical data of patients with HCC who underwent radical resection in our hospital were collected and analyzed. The survival rate was analyzed using the Kaplan-Meier method and log-rank test. The risk factors influencing OS were identified via univariate and multivariate Cox regression analyses. A total of 104 patients with HCC were included in this study. The 1-, 3-, and 5-year OS rates of these patients were 91.3%, 64.0%, and 60.2%, respectively. The OS rates were significantly higher in patients with early-stage postoperative ALBI grade 2 than in those with grade 3 (P < 0.001); however, the preoperative ALBI grade, later-stage postoperative ALBI grade, ΔALBI grade (early stage), or ΔALBI grade (later stage) did not affect the OS rate. Furthermore, resection of ≥3 Couinaud liver segments [hazard ratio (HR) = 4.74; 95% confidence interval (CI), 2.32-9.67; P < 0.001], occurrence of postoperative complications (HR = 2.95; 95% CI, 1.38-6.31; P = 0.005), and early-stage postoperative ALBI grade 3 (HR = 2.50; 95% CI, 1.18-5.31; P = 0.02) were identified as independent risk factors for the OS of patients with HCC. Early-stage postoperative ALBI grade can be used to predict the OS of patients with HCC who have undergone radical hepatectomy. Early-stage postoperative ALBI grade 3, resection of ≥3 Couinaud liver segments, and occurrence of postoperative complications are independent risk factors affecting the OS of these patients.

METTL3 confers oxaliplatin resistance through the activation of G6PD-enhanced pentose phosphate pathway in hepatocellular carcinoma.

Oxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m6A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mechanistically, METTL3 was found to modify E3 ligase TRIM21 near the 3'UTR with N6-methyladenosine, leading to reduced RNA stability upon recognition by YTHDF2. TRIM21, in turn, facilitated the degradation of the rate-limiting enzyme of PPP, G6PD, through the ubiquitination-proteasome pathway. Importantly, high expression of METTL3 was significantly associated with adverse prognosis and oxaliplatin resistance in HCC patients. Notably, treatment with the specific METTL3 inhibitor, STM2457, significantly improved the efficacy of oxaliplatin. These findings underscore the critical role of the METTL3/TRIM21/G6PD axis in driving oxaliplatin resistance and present a promising strategy to overcome chemoresistance in HCC.

Perioperative Tislelizumab plus intensity modulated radiotherapy in resectable hepatocellular carcinoma with macrovascular invasion: a phase II trial

Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC.

WNT/β-catenin Signaling and CD8+ Tumor-infiltrating Lymphocytes in Tremelimumab Plus Durvalumab for Advanced Hepatocellular Carcinoma.

Tremelimumab plus durvalumab is an approved first-line therapy for advanced hepatocellular carcinoma (HCC). Previous studies identified WNT/β-catenin mutations or CD8+ tumor-infiltrating lymphocytes (TILs) as biomarkers that can predict responsiveness to immune checkpoint inhibitor therapy in HCC. However, biomarkers for effectiveness of tremelimumab plus durvalumab in HCC have not been reported. This study investigated whether evaluation of WNT/β-catenin signaling and CD8+ TILs by immunohistochemical staining of tumor biopsy tissues can predict the response to tremelimumab plus durvalumab in patients with HCC. Fifteen HCC patients who underwent tumor biopsies were classified into three groups based on WNT/β-catenin signal activation and CD8+ TIL infiltration. The clinical responses to treatment in the groups were evaluated. Four patients had HCC with WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration, four patients had HCC with WNT/β-catenin signal activation and low-level CD8+ TIL infiltration, and seven patients had WNT/β-catenin signal activation and high-level CD8+ TIL infiltration or WNT/β-catenin signal inactivation and low-level CD8+ TIL infiltration. A better response rate was observed in the WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration group, and a worse response rate was observed in the WNT/β-catenin signal activation and low-level CD8+ TIL infiltration group. Although the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/β-catenin signaling and CD8+ TIL infiltration.

Extracellular Vesicles May Predict Response to Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma.

Treatment with atezolizumab and bevacizumab has been approved as one of the standards of care for patients with advanced hepatocellular carcinoma (HCC). The median overall survival (OS) upon available treatments still remains below 2 years, urgently suggesting better stratification tools to identify ideal candidates for this treatment and potentially allowing personalized approaches. In this study, we evaluated the potential role of extracellular vesicles (EVs) as a novel biomarker in patients receiving atezolizumab and bevacizumab for HCC. We characterized EVs in 212 longitudinal serum samples from an observational cohort of 53 individuals with advanced HCC, who started therapy with atezolizumab plus bevacizumab at our center between January 2020 and March 2022. In our cohort, the overall efficacy of atezolizumab and bevacizumab was comparable to previously published phase III data. We detected significantly smaller EVs in treatment responders, while enlarged EVs were associated with significantly decreased efficacy of atezolizumab and bevacizumab in terms of OS. A decrease in vesicle size during immunotherapy was related to a longer progression-free survival (PFS). A univariate Cox regression analysis including various clinicopathological parameters (e.g., tumor stage, markers of inflammation, organ dysfunction, or tumor markers) revealed vesicle size as an independent prognostic marker in HCC patients receiving atezolizumab and bevacizumab. Moreover, higher vesicle concentrations and lower zeta potentials were identified as a positive prognostic factor throughout treatment. Distinct EV characteristics such as vesicle size, concentration, and zeta potential represent promising novel biomarkers in patients with advanced HCC receiving atezolizumab and bevacizumab, potentially helping to identify optimal candidates for checkpoint inhibitor-based treatments.

Holmium-166 radioembolisation dosimetry in HCC.

To evaluate dosimetry, dose-response and dose-toxicity relationships for holmium-166 (166Ho) radioembolisation in patients with hepatocellular carcinoma (HCC). Thirty-one patients with hepatocellular carcinoma were included in the HEPAR Primary study (NCT03379844, registered on December 20th, 2017) and underwent 166Ho-microspheres radioembolisation. Linear mixed models assessed the association between tumour absorbed doses and response based on mRECIST both on tumour and patient level. Preliminary tumour absorbed dose thresholds were estimated based on predictive value. Linear regression models assessed the association between non-tumour absorbed dose and Common Terminology Criteria for Adverse Events version 4.03. Median tumour absorbed dose (tumour level) was 95.5 Gy (range 44-332 Gy). Median non-tumour absorbed dose based on whole liver volume was 19 Gy (range 3 - 48 Gy) and based on target liver volume was 30 Gy (range 13 - 54 Gy). There was a significant association between non-tumour absorbed dose and toxicity. Tumours with partial response/complete response (PR/CR, responders) received a 41% higher absorbed dose than tumours with progressive disease/stable disease (PD/SD, non-responders) (95%CI: 2%-93%, p = 0.04). A predictive value of 90% for tumour response was observed at a tumour absorbed dose threshold of 155 Gy, 100% predictive value was achieved at 184.5 Gy. This study confirms a positive relationship between tumour absorbed dose and response and between non-tumour absorbed dose and toxicity. Dose thresholds found in this study can serve as a basis for personalized dosimetry in HCC patients treated with 166Ho-microspheres.

Single-cell and bulk transcriptomic datasets enable the development of prognostic models based on dynamic changes in the tumor immune microenvironment in patients with hepatocellular carcinoma and portal vein tumor thrombus.

Hepatocellular carcinoma (HCC) patients exhibiting portal vein tumor thrombosis (PVTT) face a high risk of rapid malignant progression and poor outcomes, with this issue being compounded by a lack of effective treatment options. The integration of bulk RNA-sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) datasets focused on samples from HCC patients with PVTT has the potential to yield unprecedented insight into the dynamic changes in the tumor microenvironment (TME) and associated immunological characteristics in these patients, providing an invaluable tool for the reliable prediction of disease progression and treatment responses. scRNA-seq data from both primary tumor (PT) and PVTT cells were downloaded from the Gene Expression Omnibus (GEO) database, while the International Cancer Genome Consortium (ICGC) and Cancer Genome Atlas (TCGA) databases were used to access bulk RNA-seq datasets. scRNA-seq, clustering, GSVA enrichment, mutational profiling, and predictive immunotherapeutic treatment analyses were conducted using these data with the goal of systematically assessing the heterogeneity of PT and PVTT cells and establishing a model capable of predicting immunotherapeutic and prognostic outcomes in patients with HCC. These analyses revealed that PVTT cells exhibited patterns of tumor proliferation, stromal activation, and low levels of immune cell infiltration, presenting with immune desert and immune rejection-like phenotypes. PT cells, in contrast, were found to exhibit a pattern of immunoinflammatory activity. Core PVTT-associated genes were clustered into three patterns consistent with the tumor immune rejection and immune desert phenotypes. An established clustering model was capable of predicting tumor inflammatory stage, subtype, TME stromal activity, and patient outcomes. PVTT signature genes were further used to establish a risk model, with the risk scores derived from this model providing a tool to evaluate patient clinicopathological features including clinical stage, tumor differentiation, histological subtype, microsatellite instability status, and tumor mutational burden. These risk scores were also able to serve as an independent predictor of patient survival outcomes, responses to adjuvant chemotherapy, and responses to immunotherapy. In vitro experiments were used to partially validate the biological prediction results. These results offer new insight into the biological and immunological landscape of PVTT in HCC patients, By utilizing individual patient risk scores, providing an opportunity to guide more effective immunotherapeutic interventional efforts.

Carvacrol potentiates immunity and sorafenib anti-cancer efficacy by targeting HIF-1α/STAT3/ FGL1 pathway: in silico and in vivo study.

Hypoxia and tumor cell immunological escape greatly hinder the hepatocellular carcinoma (HCC) treatment efficiency. This study is designed to investigate the capability of carvacrol (CVR) to enhance sorafenib (SOR) anti-cancer efficacy and modulate anti-HCC immunity. CVR target and biological activities were predicted using Swiss Target Prediction website and PASS web server. UALCAN and LinkedOmics databases were used to examine hypoxia-inducible factor 1-alpha (HIF-1α) expression and the relationship between studied genes and tumor clinical features. Kaplan-Meier plotter (KM plotter) and TISIDB databases were used to illustrate correlation of HIF-1α with HCC prognosis and immune infiltration. The binding affinities of CVR to p300, KAT2B, CREBBP, and Hsp90 were demonstrated by molecular docking. In vivo analysis was performed in male Sprague-Dawley rats. The STAT3, JAK2, and fibrinogen-like protein 1 (FGL1) expressions were assessed by qRT-PCR. FGL1 was determined by ELISA. CD8+ T cell number was counted by flow cytometry. HIF-1α was determined by immunohistochemistry. CVR showed an HIF-1α inhibitory potential, which is highly expressed in HCC tissues. Also, elevated HIF-1α expression has been found to be correlated with clinicopathological characteristics, poor survival in HCC patients, and tumor immune cell infiltration. CVR/SOR enhanced liver functions and decreased AFP level. CVR/SOR hindered HCC progression by downregulating STAT3, JAK2, and FGL1. CVR/SOR induced tumor immunity via increasing CD8+ T cells. CVR/SOR is a powerful combination for tumor repression and enhancing SOR efficiency in HCC by modulating FGL1. Moreover, CVR/SOR might exert the aforementioned effects through HIF-1α/STAT3/FGL1 pathway.

Potential role of predictive models in assessment of liver inflammation in patients with hepatocellular carcinoma: a two-center cohort study

BackgroundHepatic inflammation in patients with hepatocellular carcinoma (HCC) remains unclear. This study aimed to construct a clinically expedient predictive model to grade hepatic inflammation in HCC patients.MethodsThis is a two-center retrospective cohort study of HCC patients comprising Derivation cohort and External Validation cohort of 1201 and 505 patients, respectively. Variables of liver inflammation identified through uni- and multi-variate logistic regression analyses were incorporated into predictive nomograms and applied to Derivation cohort, subject to internal and external validation.ResultsLiver fibrosis severity score, portal hypertension severity, and model for end-stage liver disease-sodium independently predicted hepatic inflammation grade. Performance for distinguishing G1 and non-G1 (≥ G2) patients was good with C-index of 0.810 and 0.817 in Derivation and External Validation cohort, respectively. The nomogram performed poorly to predict grade G2, G3 and G2 + G3, but performed well to predict G4.ConclusionsOur nomogram exhibited good performance for scaling hepatic inflammation (G1 and G4) in HCC, and could be employed as adjunctive diagnostic tools to guide HCC management strategy.

Expression of lipid-metabolism genes is correlated with immune microenvironment and predicts prognosis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This study was aimed to identify a lipid metabolism-related signature associated with the HCC microenvironment to improve the prognostic prediction of HCC patients. Clinical information and expression profile data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, including the GEO dataset GSE76427. The gene expression profile of lipid metabolism was downloaded from Molecular Signatures Database (MSigDB) database. The infiltrating immune cells were estimated by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE), MCP-counter, and TIMER algorithms. Functional analysis, including Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were performed to elucidate the underlying mechanisms. The prognostic risk model was performed by Least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis. Two distinct subgroups of survival were identified. Better prognosis was associated with high immune score, high abundance of immune infiltrating cells, and high immune status. GO and KEGG analysis showed that differentially expressed genes (DEGs) between the two subgroups were mainly enriched in immune related pathways. GSEA analysis suggested that the expression of lipid metabolism related genes (LMRGs) was related to dysregulation of immune in the high-risk group. Risk models and clinical features based on LMRGs predicted HCC prognosis. This study indicated that the lipid metabolism-related signature was important for the prognosis of HCC. The expression of LMRGs was related to the immune microenvironment of HCC patients and could be used to predict the prognosis of HCC.