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Medicine Dec 2023The molecular mechanisms of hepatocellular carcinoma (HCC) are still not well understood. Gene microarray analysis showed that the expression of Intelectin-1 (ITLN-1) in...
The molecular mechanisms of hepatocellular carcinoma (HCC) are still not well understood. Gene microarray analysis showed that the expression of Intelectin-1 (ITLN-1) in tumor-adjacent normal liver tissue was 454.8 times higher than in the corresponding cancer tissue. ITLN-1 is a secreted soluble glycoprotein which has been reported to be associated with the occurrence and development of various tumor types. However, the prognostic significance of ITLN-1 in HCC remain unclear. Real-time fluorescence quantitative polymerase chain reaction was used to investigate 149 liver cancer cases for ITLN-1 mRNA expression. Immunohistochemistry and western blot analysis were used to ascertain protein expression of ITLN-1 in cancer and para-carcinomatous tissue, and further to evaluate the correlation between ITLN-1 mRNA expression and surgical prognosis after liver resection. The ITLN-1 mRNA and protein levels were significantly higher in adjacent normal liver tissues than HCC tissues. Real-time fluorescence quantitative polymerase chain reaction showed that the ITLN-1 expression was decreased in 78.5% (117/149) of HCC tissues compared with their corresponding adjacent liver tissues. Moreover, its low expression was significantly correlated with increased tumor size, tumor differentiation degree, degree of liver cirrhosis, capsule integrity, vascular invasion and tumor recurrence. Patients with high ITLN-1 expression had significantly better overall and recurrence-free survival after curative liver resection. Multivariate cox regression analysis showed that ITLN-1 was an independent predictor of surgical outcomes in HCC patients. The present study suggested that low ITLN-1 expression was associated with poor clinical outcome for HCC patients, indicating a novel biomarker for prognosis evaluation and a potential therapeutic target for HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Biomarkers, Tumor; Neoplasm Recurrence, Local; RNA, Messenger; Real-Time Polymerase Chain Reaction
PubMed: 38050235
DOI: 10.1097/MD.0000000000036474 -
Academic Radiology Sep 2023The objective of this study is to accurately and timely assess the efficacy of patients with hepatocellular carcinoma (HCC) after the initial transarterial...
Efficacy and Interpretability Analysis of Noninvasive Imaging Based on Computed Tomography in Patients with Hepatocellular Carcinoma After Initial Transarterial Chemoembolization.
RATIONALE AND OBJECTIVES
The objective of this study is to accurately and timely assess the efficacy of patients with hepatocellular carcinoma (HCC) after the initial transarterial chemoembolization (TACE).
MATERIALS AND METHODS
This retrospective study consisted of 279 patients with HCC in Center 1, who were split into training and validation cohorts in the ratio of 4:1, and 72 patients in Center 2 as an external testing cohort. Radiomics signatures both in the arterial phase and venous phase of contrast-enhanced computed tomography images were selected by univariate analysis, correlation analysis, and least absolute shrinkage and selection operator regression to build the predicting models. The clinical model and combined model were constructed by independent risk factors after univariate and multivariate logistic regression analysis. The biological interpretability of radiomics signatures correlating transcriptome sequencing data was explored using publicly available data sets.
RESULTS
A total of 31 radiomics signatures in the arterial phase and 13 radiomics signatures in the venous phase were selected to construct Radscore_arterial and Radscore_venous, respectively, which were independent risk factors. After constructing the combined model, the area under the receiver operating characteristic curve in three cohorts was 0.865, 0.800, and 0.745, respectively. Through correlation analysis, 11 radiomics signatures in the arterial phase and 4 radiomics signatures in the venous phase were associated with 8 and 5 gene modules, respectively (All P < .05), which enriched some pathways closely related to tumor development and proliferation.
CONCLUSION
Noninvasive imaging has considerable value in predicting the efficacy of patients with HCC after initial TACE. The biological interpretability of the radiological signatures can be mapped at the micro level.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Retrospective Studies; Chemoembolization, Therapeutic; Tomography, X-Ray Computed
PubMed: 37393179
DOI: 10.1016/j.acra.2023.05.027 -
Cell Reports. Medicine May 2024Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration....
Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Macrophages; Immunotherapy; Animals; Tumor Microenvironment; Mice; Drug Resistance, Neoplasm; Male; Female; Cell Line, Tumor; Neoplasm Invasiveness; Immune Checkpoint Inhibitors; Middle Aged; T-Lymphocytes, Cytotoxic; Tumor-Associated Macrophages
PubMed: 38614095
DOI: 10.1016/j.xcrm.2024.101505 -
Asian Pacific Journal of Cancer... Dec 2023Angiogenesis contributes to hepatocellular carcinoma (HCC) progression by promoting tumor growth and metastasis. Netrin-4 (NTN4) is a secreted glycoprotein that has been...
BACKGROUND
Angiogenesis contributes to hepatocellular carcinoma (HCC) progression by promoting tumor growth and metastasis. Netrin-4 (NTN4) is a secreted glycoprotein that has been reported to control angiogenesis and preserve endothelial homeostasis. Macrovascular invasion of the portal vein, referred to as portal vein invasion (PVI) is associated with poor prognosis in HCC patients. In this work, we sought to understand more about the systemic and hepatic level expression of NTN4 and its receptors in HCC patients with and without portal vein invasion.
METHODS
A total of 154 patients with HCC, and 90 healthy volunteers were recruited in this case-control study. Patients with HCC were further subdivided into those with portal vein invasion (PVI) (n=68), and those without portal vein invasion (NPVI) (n=86). Clinical characteristics and liver function parameters were recorded among the study subjects PVI and NPVI. The serum levels of NTN4 (pg/ml) were estimated by ELISA. HCC tissues and normal non-tumorous liver tissues (controls) were collected for gene expression analysis of NTN4 and its receptors.
RESULTS
ALT, ALP, and GGT levels were significantly elevated in the serum of HCC patients with PVI compared to NPVI and control subjects. Systemic NTN4 was significantly reduced in both PVI and NPVI patients compared to control subjects. At the tissue level, the hepatic NTN4 followed a similar trend with significantly lower mRNA expression in both patients with PVI and NPVI compared to control subjects.
CONCLUSIONS
Systemic and hepatic NTN4 levels were reduced in both PVI and NPVI subjects. The hepatic expression of NTN4 receptors Neogenin and UNC5B were markedly elevated in patients with HCC with PVI compared to NPVI. Future experimental studies might shed the role of NTN4 and its receptors in the development of PVI in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Case-Control Studies; Liver Neoplasms; Neoplasm Invasiveness; Netrin Receptors; Netrins; Portal Vein
PubMed: 38156865
DOI: 10.31557/APJCP.2023.24.12.4285 -
Journal of Hepatology Mar 2024The diagnosis and management of hepatocellular carcinoma (HCC) have improved significantly in recent years. With the introduction of immunotherapy-based combination... (Review)
Review
The diagnosis and management of hepatocellular carcinoma (HCC) have improved significantly in recent years. With the introduction of immunotherapy-based combination therapy, there has been a notable expansion in treatment options for patients with unresectable HCC. Simultaneously, innovative molecular tests for early detection and management of HCC are emerging. This progress prompts a key question: as liquid biopsy techniques rise in prominence, will they replace traditional tissue biopsies, or will both techniques remain relevant? Given the ongoing challenges of early HCC detection, including issues with ultrasound sensitivity, accessibility, and patient adherence to surveillance, the evolution of diagnostic techniques is more relevant than ever. Furthermore, the accurate stratification of HCC is limited by the absence of reliable biomarkers which can predict response to therapies. While the advantages of molecular diagnostics are evident, their potential has not yet been fully harnessed, largely because tissue biopsies are not routinely performed for HCC. Liquid biopsies, analysing components such as circulating tumour cells, DNA, and extracellular vesicles, provide a promising alternative, though they are still associated with challenges related to sensitivity, cost, and accessibility. The early results from multi-analyte liquid biopsy panels are promising and suggest they could play a transformative role in HCC detection and management; however, comprehensive clinical validation is still ongoing. In this review, we explore the challenges and potential of both tissue and liquid biopsy, highlighting that these diagnostic methods, while distinct in their approaches, are set to jointly reshape the future of HCC management.
Topics: Humans; Biomarkers, Tumor; Carcinoma, Hepatocellular; Liquid Biopsy; Liver Neoplasms; Neoplastic Cells, Circulating
PubMed: 38104635
DOI: 10.1016/j.jhep.2023.11.030 -
BMC Medical Imaging Jul 2023The indocyanine green retention rate at 15 min (ICG-R15) is a useful tool to evaluate the functional liver reserve before hepatectomy for liver cancer. Taking ICG-R15...
OBJECTIVE
The indocyanine green retention rate at 15 min (ICG-R15) is a useful tool to evaluate the functional liver reserve before hepatectomy for liver cancer. Taking ICG-R15 as criteria, we investigated the ability of a machine learning (ML)-based radiomics model produced by Gd-EOB-DTPA-enhanced hepatic magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) image in evaluating functional liver reserve of hepatocellular carcinoma (HCC) patients.
METHODS
A total of 190 HCC patients with CT, among whom 112 also with MR, were retrospectively enrolled and randomly classified into a training dataset (CT: n = 133, MR: n = 78) and a test dataset (CT: n = 57, MR: n = 34). Then, radiomics features from Gd-EOB-DTPA MRI and CT images were extracted. The features associated with the ICG-R15 classification were selected. Five ML classifiers were used for the ML-model investigation. The accuracy (ACC) and the area under curve (AUC) of receiver operating characteristic (ROC) with 95% confidence intervals (CI) were utilized for ML-model performance evaluation.
RESULTS
A total of 107 different radiomics features were extracted from MRI and CT, respectively. The features related to ICG-R15 which was classified into 10%, 20% and 30% were selected. In MRI groups, classifier XGBoost performed best with its AUC = 0.917 and ACC = 0.882 when the threshold was set as ICG-R15 = 10%. When ICG-R15 = 20%, classifier Random Forest performed best with AUC = 0.979 and ACC = 0.882. When ICG-R15 = 30%, classifier XGBoost performed best with AUC = 0.961 and ACC = 0.941. For CT groups, the classifier XGBoost performed best when ICG-R15 = 10% with AUC = 0.822 and ACC = 0.842. When ICG-R15 = 20%, classifier SVM performed best with AUC = 0.860 and ACC = 0.842. When ICG-R15 = 30%, classifier XGBoost performed best with AUC = 0.938 and ACC = 0.965.
CONCLUSIONS
Both the MRI- and CT-based machine learning models are proved to be valuable noninvasive methods for functional liver reserve evaluation.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Retrospective Studies; Liver Function Tests; Liver; Indocyanine Green; Tomography, X-Ray Computed; Magnetic Resonance Imaging; Machine Learning
PubMed: 37460944
DOI: 10.1186/s12880-023-01050-1 -
World Journal of Gastroenterology May 2024Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders...
Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians' approaches and patient outcomes.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Terminology as Topic; Risk Factors; Lipid Metabolism; Liver; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Cirrhosis; Bile Acids and Salts
PubMed: 38764762
DOI: 10.3748/wjg.v30.i18.2387 -
EBioMedicine Nov 2023The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However,...
BACKGROUND
The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However, this has posed significant challenges in preclinical research. Novel immunologically relevant models for PLC are urgently required to improve the translation from bench to bedside and back, explore and predict effective combinatorial therapies, aid novel drug discovery and develop personalised treatment modalities.
METHODS
We used human precision-cut tissue slices (PCTS) derived from resected tumours to create a patient-specific immunocompetent disease model that captures the multifaceted and intricate heterogeneity of the tumour and the tumour microenvironment. Tissue architecture, tumour viability and treatment response to single agent and combination therapies were assessed longitudinally over 8 days of ex vivo culture by histological analysis, detection of proliferation/cell death markers, ATP content via HPLC. Immune cell infiltrate was assessed using PCR and immunofluorescence. Checkpoint receptor expression was quantified via Quantigene RNA assay.
FINDINGS
After optimising the culture conditions, PCTS maintained the original tissue architecture, including tumour morphology, stroma and tumour-infiltrated leukocytes. Moreover, PCTS retained the tumour-specific immunophenotype over time, suggesting the utility of PCTS to investigate immunotherapeutic drug efficacy and identify non-responsiveness.
INTERPRETATION
Here we have characterised the PCTS model and demonstrated its effectiveness as a robust preclinical tool that will significantly support the development of successful (immuno)therapeutic strategies for PLC.
FUNDING
Foundation for Liver Research, London.
Topics: Humans; Liver Neoplasms; Tumor Microenvironment
PubMed: 37806285
DOI: 10.1016/j.ebiom.2023.104826 -
Molecular Cancer May 2024The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC...
BACKGROUND
The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development.
METHODS
Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms.
RESULTS
CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib.
CONCLUSION
This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.
Topics: Animals; Female; Humans; Male; Mice; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Ferroptosis; Gene Expression Regulation, Neoplastic; Liver Neoplasms; MicroRNAs; Neoplasm Proteins; RNA, Circular; Xenograft Model Antitumor Assays
PubMed: 38802795
DOI: 10.1186/s12943-024-02030-x -
The Turkish Journal of Gastroenterology... Dec 2023Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experience of 6 patients with liver transplantation for...
BACKGROUND/AIMS
Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experience of 6 patients with liver transplantation for hepatocellular carcinoma with background inherited metabolic disease.
MATERIALS AND METHODS
This is a single-center retrospective, descriptive study. Consecutive patients who underwent liver transplantation for hepatocellular carcinoma with background inherited metabolic disease were included in the study. The record of the patients was accessed, and the following data were extracted: sociodemographic variables, type of metabolic disease, date of liver transplantation, tumor characteristics, laboratory parameters, Model for End-Stage Liver Disease score, immediate- and long-term outcome after transplantation, disease-free survival, and overall survival. Data were analyzed using Statistical Package for the Social Sciences version 25.0.
RESULTS
Six patients received liver transplantation for hepatocellular carcinoma with background inherited metabolic liver disease. The median age was 4.5 years. The median Model for End-Stage Liver Disease score was 29.30. The median maximum tumor diameter was 2.15 cm. Three patients had multiple tumor nodules. Half of the patients had microvascular invasion. Four of the patients had a moderately differentiated tumor. Progressive familial intrahepatic cholestasis type II is the commonest inherited metabolic disease seen in 3 patients. Median follow-up is 46.1 months. Half of the patients are currently more than 5 years post liver transplantation with no features of recurrence. The estimated survival rates at 1, 3, and 5 years are 100%, 83.3%, and 83.3%, respectively.
CONCLUSION
Liver transplant for these categories of patients is associated with good disease-free and overall survival, even in the presence of some seemingly poor prognostic features.
Topics: Humans; Child, Preschool; Carcinoma, Hepatocellular; Liver Transplantation; Liver Neoplasms; End Stage Liver Disease; Retrospective Studies; Severity of Illness Index; Metabolic Diseases; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 37681267
DOI: 10.5152/tjg.2023.22679