Search

Background: The combination of Sorafenib and transcatheter arterial chemoembolization (TACE) exhibits limited efficacy in the treatment of certain advanced hepatocellular carcinomas (HCC), and the molecular mechanisms underlying resistance to this combination remain unclear., Objective: This study aims to underscore the distinctive contribution of GeoMx DSP technology in elucidating the molecular intricacies of HCC resistance to the Sorafenib and TACE combination., Methods: Patients with advanced HCC during the waiting period before liver transplantation were classified into sensitive and resistant groups based on their response to Sorafenib and TACE combination therapy. Employing GeoMx DSP technology for comprehensive gene expression profiling, we identified pivotal molecular targets linked to resistance against combination therapy., Results: The investigation scrutinized intra-tumoral and inter-individual variances, unveiling a spectrum of crucial molecular targets, such as PLG, PLVAP, immunoglobulin genes, ORM1, and NR4A1, among others. Additionally, we explored signaling pathways associated with treatment responsiveness, including the PPAR signaling pathway. Notably, we emphasized the significance of the immune microenvironment characterized by heightened SPP1 expression in HCC resistance to combination therapy. In the resistant group, SPP1 + tumor-associated macrophage (TAM) infiltration was notably pronounced (p = 0.037), while T-cell depletion showed a mitigated presence (p = 0.013)., Conclusion: The study reveals intra- and inter-individual heterogeneity in HCC that is differentially responsive to the combination of Sorafenib and TACE, highlighting multiple key molecular targets associated with treatment resistance. The immune microenvironment is important, and in particular, SPP1 + TAM infiltration may play a key role. Meanwhile, the introduction of immunotherapy in patients resistant to combination therapy may lead to positive results., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Background and Aims: The practice of intraoperative blood salvage and autotransfusion (IBSA) during deceased donor liver transplantation for hepatocellular carcinoma (HCC) can potentially reduce the need for allogeneic blood transfusion. However, implementing IBSA remains debatable due to concerns about its possible detrimental effects on oncologic recurrence., Methods: This study retrospectively enrolled nationwide recipients of deceased donor liver transplantation for HCC between 2015 and 2020. The focus was on comparing the cumulative recurrence rate and the recurrence-free survival rate. Propensity score matching was conducted repeatedly for further subgroup comparison. Recipients were categorized based on the Milan criteria, macrovascular invasion, and pretransplant α-Fetoprotein (AFP) level to identify subgroups at risk of HCC recurrence., Results: A total of 6196 and 329 patients were enrolled in the non-IBSA and IBSA groups in this study. Multivariable competing risk regression analysis identified IBSA as independent risk factors for HCC recurrence ( P <0.05). Postmatching, the cumulative recurrence rate and recurrence-free survival rate revealed no significant difference in the IBSA group and non-IBSA group (22.4 vs. 16.5%, P =0.12; 60.3 vs. 60.9%, P =0.74). Recipients beyond Milan criteria had higher, albeit not significant, risk of HCC recurrence if receiving IBSA (33.4 vs. 22.5%, P =0.14). For recipients with macrovascular invasion, the risk of HCC recurrence has no significant difference between the two groups (32.2 vs. 21.3%, P =0.231). For recipients with an AFP level <20 ng/ml, the risk of HCC recurrence was comparable in the IBSA group and the non-IBSA group (12.8 vs. 18.7%, P =0.99). Recipients with an AFP level ≥20 ng/ml, the risk of HCC recurrence was significantly higher in the IBSA group. For those with an AFP level ≥400 ng/ml, the impact of IBSA on the cumulative recurrence rate was even more pronounced (49.8 vs. 21.9%, P =0.011)., Conclusions: IBSA does not appear to be associated with worse outcomes for recipients with HCC exceeding the Milan criteria or with macrovascular invasion. IBSA could be confidently applied for recipients with a pretransplant AFP level <20 ng/ml. For recipients with AFP levels ≥20 ng/ml, undertaking IBSA would increase the risk of HCC recurrence., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Given that prognosis of hepatocellular carcinoma (HCC) differs dramatically, it is imperative to uncover effective and available prognostic biomarker(s). The intratumor microbiome plays a significant role in the response to tumor microenvironment, we aimed to identify an intratumor microbiome signature for predicting the prognosis of HCC patients accurately and investigate its possible mechanisms subsequently., Methods: The TCGA HCC microbiome data (TCGA-LIHC-microbiome) was downloaded from cBioPortal. To create an intratumor microbiome-related prognostic signature, univariate and multivariate Cox regression analyses were used to quantify the association of microbial abundance and patients' overall survival (OS), as well as their diseases specific survival (DSS). The performance of the scoring model was evaluated by the area under the ROC curve (AUC). Based on the microbiome-related signature, clinical factors, and multi-omics molecular subtypes on the basis of "icluster" algorithm, nomograms were established to predict OS and DSS. Patients were further clustered into three subtypes based on their microbiome-related characteristics by consensus clustering. Moreover, deconvolution algorithm, weighted correlation network analysis (WGCNA) and gene set variation analysis (GSVA) were used to investigate the potential mechanisms., Results: In TCGA LIHC microbiome data, the abundances of 166 genera among the total 1406 genera were considerably associated with HCC patients' OS. From that filtered dataset we identified a 27-microbe prognostic signature and developed a microbiome-related score (MRS) model. Compared with those in the relatively low-risk group, patients in higher-risk group own a much worse OS (P < 0.0001). Besides, the time-dependent ROC curves with MRS showed excellent predictive efficacy both in OS and DSS. Moreover, MRS is an independent prognostic factor for OS and DSS over clinical factors and multi-omics-based molecular subtypes. The integration of MRS into nomograms significantly improved the efficacy of prognosis prediction (1-year AUC:0.849, 3-year AUC: 0.825, 5-year AUC: 0.822). The analysis of microbiome-based subtypes on their immune characteristics and specific gene modules inferred that the intratumor microbiome may affect the HCC patients' prognosis via modulating the cancer stemness and immune response., Conclusion: MRS, a 27 intratumor microbiome-related prognostic model, was successfully established to predict HCC patients overall survive independently. And the possible underlying mechanisms were also investigated to provide a potential intervention strategy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

With the improvement of the average life expectancy and increasing incidence of obesity, the burden of liver disease is increasing. Liver disease is a serious threat to human health. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stem cells (MSCs) can be used as an alternative therapy for liver disease, especially liver cirrhosis, liver failure, and liver transplantation complications. However, MSCs may have potential tumorigenic effects. Exosomes derived from MSCs (MSC-Exos), as the important intercellular communication mode of MSCs, contain various proteins, nucleic acids, and DNA. MSC-Exos can be used as a delivery system to treat liver diseases through immune regulation, apoptosis inhibition, regeneration promotion, drug delivery, and other ways. Good histocompatibility and material exchangeability make MSC-Exos a new treatment for liver diseases. This review summarizes the latest research on MSC-Exos as delivery vehicles in different liver diseases, including liver injury, liver failure, liver fibrosis, hepatocellular carcinoma (HCC), and ischemia and reperfusion injury. In addition, we discuss the advantages, disadvantages, and clinical application prospects of MSC-Exos-based delivery vectors in the treatment of liver diseases., Competing Interests: The authors declare that they have no competing interests., (© 2023 Lu et al.)

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies; its recurrence is associated with high mortality and poor recurrence-free survival and is affected by multisystem and multilevel pathological changes. To identify the key proteins associated with tumor recurrence and the underlying mechanisms, proteomic profiling of tumor specimens from early recurrence and nonrecurrence patients was performed in this study. Proteomics was applied to identify differentially expressed proteins during the early recurrence of HCC after surgery. Osteosarcoma amplified-9 (OS-9) was discovered, and the correlation between OS-9 expression and the clinicopathological characteristics of patients was analyzed. Invasion and migration were examined in SMMC-7721 cells with and without OS-9 overexpression. Proteomics was performed once again using SMMC-7721 cells with OS-9 overexpression to further analyze the proteins with altered expression. OS-9 was overexpressed in the early recurrence group, and OS-9 overexpression was associated with high serum alpha-fetoprotein levels and poor recurrence-free survival in 196 patients with HCC. The invasion and migration abilities of SMMC-7721 cells were enhanced in the OS-9 overexpression group. Bioinformatic functional enrichment methods, including Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis, revealed that the hypoxia-inducible factor 1 (HIF-1) and tumor necrosis factor (TNF) signaling pathways were activated in the OS-9 overexpression group. The migration and invasion capacities of OS-9 overexpressed HCC cell line were weakened while treated with HIF-1α or TNF-α inhibitors. Conclusion: Our results suggest that the overexpression of OS-9 is related to HCC recurrence, thereby contributing to the migration and invasion capacities of HCC cell line by regulating the HIF-1 and TNF pathways., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Chloride intracellular channel 1 (CLIC1) is upregulated in hepatocellular carcinoma (HCC). The present study aimed to investigate the role of CLIC1 in HCC angiogenesis. Materials and Methods: Immunohistochemistry (IHC) was used to test the expression of CLIC1 and CD34 in 67 pairs of HCC and paracarcinoma tissues. The prognosis data of the patients were used to analyze the clinical relevance of CLIC1. We built a coculture system of HCC cells and endothelial cells to explore the migration of endothelial cells. Conditioned media (CMs) from HCC cells was then collected to assess endothelial cell migration. Experiments were then conducted to confirm the relationship between CLIC1 and angiogenesis in a subcutaneous tumor model. Results: CLIC1 expression was higher in HCC tumor tissues than in paracarcinoma tissues. Patients with increased CLIC1 expression showed a higher microvascular density (MVD; P  = .013). Kaplan-Meier curves indicated that patients with lower expression of CLIC1 had better overall survival ( P  < .001) and recurrence-free survival ( P  = .046). Vascular endothelial growth factor A (VEGFA) in CMs from CLIC1-knockdown cells was lower than in the control group, while VEGFA in CMs from CLIC1 overexpression cells was higher than in the control group. CMs from CLIC1 overexpression cell lines promote the in vitro migration of EA.hy926 cells. Meanwhile, adding Bevacizumab to CMs from CLIC1 overexpression cells significantly inhibited this migration. The growth of xenograft tumors derived from CLIC1-knockdown Huh7 cells was restrained compared with the control group ( P  < .001). IHC staining showed MVD was higher in tumors with CLIC1 overexpression. Conclusion: CLIC1 is a promising biomarker for predicting the prognosis of HCC patients, and expression of CLIC1 correlates with angiogenesis in HCC through regulating VEGFA.