Napabucasin deactivates STAT3 and promotes mitoxantrone-mediated cGAS-STING activation for hepatocellular carcinoma chemo-immunotherapy.

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

Triterpenes from Ganoderma lucidum inhibit hepatocellular carcinoma by regulating enhancer-associated lncRNA in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum) has been widely used as adjuvant of anti-tumor therapy for variety tumors. The bioactive ingredients of G. lucidum mainly include triterpenes, such as Ganoderic acid A, Ganoderic acid B, Ganoderenic acid A, Ganoderenic acid B, Ganoderenic acid D, and Ganoderic acid X. However, the effects and underlying mechanisms of G. lucidum are often challenging in hepatocellular carcinoma (HCC) treatment. AIM OF THE STUDY: To explore the potential role and mechanism of enhancer-associated lncRNAs (en-lncRNAs) in G. lucidum treated HCC through the in vivo and in vitro experiments. MATERIALS AND METHODS: Hepa1-6-bearing C57 BL/6 mice model were established to evaluate the therapeutic efficacy of G. lucidum treated HCC. Ki67 and TUNEL staining were used to detect the tumor cell proliferation and apoptosis in vivo. The Mouse lncRNA 4*180K array was implemented to identify the differentially expressed (DE) lncRNAs and mRNAs of G. lucidum treated tumor mice. The constructed lncRNA-mRNA co-expression network and bioinformatics analysis were used to selected core en-lncRNAs and its neighboring genes. The UPLC-MS method was used to identify the triterpenes of G. lucidum, and the in vitro experiments were used to verify which triterpene monomers regulated en-lncRNAs in tumor cells. Finally, a stable knockdown/overexpression cell lines were used to confirm the relationship between en-lncRNA and neighboring gene. RESULTS: Ki67 and TUNEL staining demonstrated G. lucidum significantly inhibited tumor growth, suppressed cell proliferation and induced apoptosis in vivo. Transcriptomic analysis revealed the existence of 126 DE lncRNAs high correlated with 454 co-expressed mRNAs in G. lucidum treated tumor mice. Based on lncRNA-mRNA network and qRT-PCR validation, 6 core lncRNAs were selected and considered high correlated with G. lucidum treatment. Bioinformatics analysis revealed FR036820 and FR121302 might act as enhancers, and qRT-PCR results suggested FR121302 might enhance Popdc2 mRNA level in HCC. Furthermore, 6 main triterpene monomers of G. lucidum were identified by UPLC-MS method, and in vitro experiments showed FR121302 and Popdc2 were significantly suppressed by Ganoderenic acid A and Ganoderenic acid B, respectively. The knock/overexpression results demonstrated that FR121302 activating and enhancing Popdc2 expression levels, and Ganoderenic acid A and Ganoderenic acid B dramatically suppressed FR121302 and decreased Popdc2 level in Hepa1-6 cells. CONCLUSIONS: Enhancer-associated lncRNA plays a crucial role as an enhancer during hepatocarcinogenesis, and triterpenes of G. lucidum significantly inhibited tumor cell proliferation and induced apoptosis by regulating en-lncRNAs. Our study demonstrated Ganoderenic acid A and Ganoderenic acid B suppressed en-lncRNA FR121302 may be one of the critical strategies of G. lucidum inhibit hepatocellular carcinoma growth.

The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma.

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.

Enhancing cancer immunotherapy using cordycepin and Cordyceps militaris extract to sensitize cancer cells and modulate immune responses.

Integrating immunotherapy with natural compounds holds promise in enhancing the immune system's ability to eliminate cancer cells. Cordyceps militaris, a traditional Chinese medicine, emerges as a promising candidate in this regard. This study investigates the effects of cordycepin and C. militaris ethanolic extract (Cm-EE) on sensitizing cancer cells and regulating immune responses against breast cancer (BC) and hepatocellular carcinoma (HCC) cells. Cordycepin, pentostatin and adenosine were identified in Cm-EE. Cordycepin treatment decreased HLA-ABC-positive cells in pre-treated cancer cells, while Cm-EE increased NKG2D ligand and death receptor expression. Additionally, cordycepin enhanced NKG2D receptor and death ligand expression on CD3-negative effector immune cells, particularly on natural killer (NK) cells, while Cm-EE pre-treatment stimulated IL-2, IL-6, and IL-10 production. Co-culturing cancer cells with effector immune cells during cordycepin or Cm-EE incubation resulted in elevated cancer cell death. These findings highlight the potential of cordycepin and Cm-EE in improving the efficacy of cancer immunotherapy for BC and HCC.

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study.

BACKGROUND: Tri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules. METHODS: This real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups. RESULTS: The median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74-37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85-18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848-2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574-2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively. CONCLUSION: Our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Frontline evaluation: Atezolizumab-bevacizumab versus lenvatinib for BCLC stage B hepatocellular carcinoma exceeding the up-to-seven criteria.

INTRODUCTION: This study aimed to evaluate the efficacy and safety of atezolizumab combined with bevacizumab (Atez/Bev) compared to lenvatinib (LEN) as first-line systemic therapy for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) exceeding the up-to-seven criteria threshold, who are typically unsuitable for transarterial chemoembolization (TACE). METHODS: A retrospective analysis was conducted on 49 consecutive patients with HCC treated at Tokyo Metropolitan Komagome Hospital between May 2018 and October 2023. The patients were divided into two groups: the Atez/Bev group (21 patients) and the LEN group (28 patients). Eligibility criteria included Child-Pugh A classification, no prior systemic therapy, and ineligibility for resection, ablation, or transplantation. Treatment outcomes were assessed through periodic imaging and laboratory tests, evaluating OS, PFS, ORR, and disease control rate (DCR). RESULTS: Both groups demonstrated comparable baseline characteristics, with a median follow-up of 15.4 months. No significant difference was observed in OS between the Atez/Bev and LEN groups (median OS: 19.80 vs. 22.20 months, p = 0.763). The median PFS was 10.23 months for Atez/Bev and 7.20 months for LEN (p = 0.343). There were no statistically significant differences in ORR or DCR between the two groups. Common adverse events included elevated AST and ALT levels, with no significant difference in the overall rate of adverse events between the groups. CONCLUSIONS: Atez/Bev and LEN demonstrated comparable efficacy and safety as first-line systemic treatments for patients with BCLC stage B HCC exceeding the up-to-seven criteria. Both therapeutic options are viable for this population, though further large-scale prospective studies are required to confirm these findings.

ZNF740 facilitates the malignant progression of hepatocellular carcinoma via the METTL3/HIF­1A signaling axis.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer­related death, and efficient treatments to facilitate recovery and enhance long­term outcomes are lacking. Zinc finger proteins (ZNFs), known as the largest group of transcription factors, have gained interest for their roles in HCC by stimulating the transcription of well­known tumor­causing genes. However, the specific roles and molecular mechanisms of ZNF740 in HCC remain unknown. The present study performed bioinformatics analysis and RNA­sequencing analysis of differentially expressed genes in HCC, detected ZNF740 expression levels in HCC using reverse transcription­quantitative PCR, western blotting and immunohistochemistry, and explored the effects of ZNF740 on the progression of liver cancer in vitro and in vivo using cellular functionality assays and cell­derived xenografts. In addition, a dual­luciferase reporter assay was performed to analyze the binding of ZNF740 with the METTL3 promoter. Furthermore, cell functionality experiments were performed to analyze whether ZNF740 promotes the proliferation of liver cancer cells in a METTL3­dependent manner. Bioinformatics and immunoprecipitation assays were further used to analyze the molecular mechanism of ZNF740 in liver cancer. The present study demonstrated that ZNF740 expression was upregulated in HCC. Mechanistically, overexpressed ZNF740 interacted with the methyltransferase­like 3 (METTL3) promoter and increased METTL3 expression, leading to the stabilization of hypoxia­inducible factor­1A (HIF1A) mRNA in an N6­methyladenosine/YTH N6­methyladenosine RNA­binding protein 1­dependent manner. Eventually, the ZNF740/METTL3/HIF1A signaling axis may facilitate the proliferation, invasion and metastasis of liver cancer via METTL3/HIF­1A signaling. The present findings revealed the important role of ZNF740 and suggested a potential therapeutic approach that might improve clinical therapies for liver cancer.

Efficacy and safety of transarterial chemoembolization plus lenvatinib combined with PD-1 inhibitors versus transarterial chemoembolization plus lenvatinib for unresectable hepatocellular carcinoma: a meta-analysis.

Background: Locoregional treatment combined with systemic therapy is expected to play a synergistic anticancer role. We conducted this systemic meta-analysis to examine the efficacy and safety of transarterial chemoembolization (TACE) plus lenvatinib with or without programmed cell death protein-1 (PD-1) inhibitors (TLP group) compared with TACE + lenvatinib (TL group) for unresectable hepatocellular carcinoma (uHCC). Methods: From the inception date to April 2024, the data from PubMed, EMBASE, the Cochrane Library, Ovid, Web of Science, and Clinical Trials. gov were used for meta-analysis. All clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). The hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CI) were used to measure the pooled effect. Results: This study included 10 retrospective cohort studies, including 1128 patients. The OS (HR=0.51; 95% CI: 0.43-0.60, P < 0.05), PFS (HR=0.52; 95% CI: 0.45-0.61, P < 0.05), ORR (RR = 1.58; 95% CI: 1.37-1.83; P < 0.05) and DCR (RR = 1.31; 95% CI: 1.20-1.43; P < 0.05) were significantly higher in TLP group than in the TL group. The incidence of AEs was acceptable. Prognostic factor analysis identified that ECOG PS (1/0), Child-Pugh class (B/A), BCLC stage (C/B) and main portal vein invasion (yes/no) were independent prognostic factors for OS. BCLC stage (C/B) and main portal vein invasion (yes/no) were independent prognostic factors for PFS. Conclusion: The TLP group had better efficacy for uHCC than that of the TL group, with acceptable safety. Systematic review registration: PROSPERO, identifier (CRD42023420093).

Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and ranks as the third leading cause of cancer-related mortality globally. The liver performs a wide range of tasks and is the primary organ responsible for metabolizing harmful substances and foreign compounds. Oxidative stress has a crucial role in growth and improvement of hepatocellular carcinoma (HCC). Nuclear factor erythroid 2 (1)-related factor 2 (Nrf2) is an element that regulates transcription located in the cytoplasm. It controls the balance of redox reactions by stimulating the expression of many genes that depend on antioxidant response elements. Nrf2 has contrasting functions in the normal, healthy liver and HCC. In the normal liver, Nrf2 provides advantageous benefits, while in HCC it promotes harmful effects that support the growth and survival of HCC. Continuous activation of Nrf2 has been detected in HCC and promotes its advancement and aggressiveness. In addition, Activation of Nrf2 may lead to immune evasion, weakening the immune cells' ability to attack tumors and thereby promoting tumor development. Furthermore, chemoresistance in HCC, which is considered a form of stress response to chemotherapy medications, significantly impedes the effectiveness of HCC treatment. Stress management is typically accomplished by activating specific signal pathways and chemical variables. One important element in the creation of chemoresistance in HCC is nuclear factor-E2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the activation and production of a group of genes that encode proteins responsible for protecting cells from damage. This occurs through the Nrf2/ARE pathway, which is a crucial mechanism for combating oxidative stress within cells.

A nomogram model for early recurrence of HBV-related hepatocellular carcinomas after radical hepatectomy.

Background: To identify the risk factors and construct a predictive model for early recurrence of hepatitis B virus(HBV-)- related hepatocellular carcinomas(HCCs) after radical resection. Data and methods: A total of 465 HBV-related HCC patients underwent radical resections between January 1, 2012 and August 31, 2018.Their data were collected through the inpatient information management system of the First Affiliated Hospital of University of Science and Technology of China. Survival and subgroup analyses of early recurrence among male and female patients were performed using Kaplan-Meier curves. The independent risk factors associated with early postoperative tumor recurrence were analyzed using multivariate Cox proportional hazards regression model. Based on these independent risk factors, a risk function model for early recurrence was fitted, and a column chart for the prediction model was drawn for internal and external validation. Results: A total of 181 patients developed early recurrences, including 156 males and 25 females. There was no difference in the early recurrence rates between males and females. Tumor diameters>5cm, microvascular invasion and albumin level<35 g/L were independent risk factors for early recurrence. A nomogram for the early recurrence prediction model was drawn; the areas under the curve for the model and for external verification were 0.638 and 0.655, respectively. Conclusion: Tumor diameter>5 cm, microvascular invasion, and albumin level<35 g/L were independent risk factors for early recurrence. The prediction model based on three clinical indicators could predict early recurrence, with good discrimination, calibration, and extrapolation.

Enhanced efficacy of combined VEGFR peptide-drug conjugate and anti-PD-1 antibody in treating hepatocellular carcinoma.

This study aimed to design a VEGFR-targeting peptide-drug conjugate with the ability to decrease tumor burden and suppress tumor angiogenesis, and to further evaluate the therapeutic effect of anti-PD-1 antibody in HCC therapy. A VEGFR-targeting peptide VEGF125 - 136 (QR) was conjugated with a lytic peptide (KLU) to form a peptide-drug conjugate QR-KLU. And the efficacy of QR-KLU in combination with anti-PD-1 antibody for HCC therapy in vivo and in vitro were evaluated. QR-KLU inhibited the proliferation and migration of mouse HCC cell line (Hepa1-6) cells under normoxic and hypoxic conditions in a dose-dependent manner. In the subcutaneous Hepa1-6 tumor model, QR-KLU combined with the anti-PD-1 antibody substantially inhibited tumor growth, promoted tumor necrosis, and prolonged the survival time of tumor-bearing mice. QR-KLU substantially inhibited hypoxia-induced expression of VEGF, promoted tumor vascular normalization, and increased cluster of differentiation 8+ (CD8+) T cell infiltration in the tumor. In addition, QR-KLU and anti-PD-1 antibody demonstrated a strong synergistic effect in promoting the activation of intratumoral CD8+ T cells, reducing the expression of immune-inhibitory factors, and increasing the expression of immune-stimulatory factors. This study proposed a novel approach for enhancing the efficacy of anti-PD-1 antibody using a VEGFR-targeting peptide-drug conjugate in HCC therapy.

Impact of prior SARS-CoV-2 infection on postoperative recovery in patients with hepatocellular carcinoma resection.

BACKGROUND: The impact of prior SARS-CoV-2 infection on postoperative recovery of patients who underwent liver resection for hepatocellular carcinoma (HCC) remains uncertain given the lack of sufficient evidence. AIM: To investigate the impact of prior SARS-CoV-2 infection on postoperative recovery of patients who underwent liver resection for hepatocellular carcinoma (HCC). METHODS: Patients who were pathologically diagnosed with HCC and underwent elective partial hepatectomy in Guangdong Provincial People's Hospital between January 2022 and April 2023 were enrolled in this retrospective cohort study. The patients were divided into two groups based on their history of SARS-CoV-2 infection. Rehabilitation parameters, including postoperative liver function, incidence of complications, and hospitalization expenses, were compared between the two groups. Propensity score matching (PSM) was performed to reduce confounding bias. RESULTS: We included 172 patients (58 with and 114 without prior SARS-CoV-2 infection) who underwent liver resection for HCC. No significant differences in the rehabilitation parameters were observed between the two groups. After PSM, 58 patients were selected from each group to form the new comparative groups. Similar results were obtained within the population after PSM. CONCLUSION: Prior SARS-CoV-2 infection does not appear to affect postoperative rehabilitation, including liver function, postoperative complications, or hospitalization expenses among patients with HCC after elective partial hepatectomy.

High ratio of resident to exhausted CD4 + T cells predicts favorable prognosis and potentially better immunotherapeutic efficacy in hepatocellular carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are significantly implicated in regulating the tumor immune microenvironment (TIME) and immunotherapeutic response. However, little is known about the impact of the resident and exhausted status of TILs in hepatocellular carcinoma (HCC). METHODS: Single-cell RNA sequencing data was applied to discover resident and exhausted signatures of TILs. Survival outcomes, biological function, immune infiltration, genomic variation, immunotherapeutic efficacy, and sorafenib response were further explored the clinical significance and molecular association of TILs in HCC. Moreover, a candidate gene with predictive capability for the dismal subtype was identified through univariate Cox regression analysis, survival analysis, and the BEST website. RESULTS: Single-cell analysis revealed that CD8 + T, CD4 + T, and NK cells were strongly associated with resident and exhausted patterns. Specific resident and exhausted signatures for each subpopulation were extracted in HCC. Further multivariate Cox analysis revealed that the ratio of resident to exhausted CD4 + T cells in TIME was an independent prognostic factor. After incorporating tumor purity with the ratio of resident to exhausted CD4 + T cells, we stratified HCC patients into three subtypes and found that (i) CD4 residencyhighexhaustionlow subtype was endowed with favorable prognosis, immune activation, and sensitivity to immunotherapy; (ii) CD4 exhaustionhighresidencylow subtype was characterized by genome instability and sensitivity to sorafenib; (iii) Immune-desert subtype was associated with malignant-related pathways and poor prognosis. Furthermore, spindle assembly abnormal protein 6 homolog (SASS6) was identified as a key gene, which accurately predicted the immune-desert subtype. Prognostic analysis as well as in vitro and in vivo experiments further demonstrated that SASS6 was closely associated with tumor prognosis, proliferation, and migration. CONCLUSIONS: The ratio of resident to exhausted CD4 + T cells shows promise as a potential biomarker for HCC prognosis and immunotherapy response and SASS6 may serve as a biomarker and therapeutic target for prognostic assessment of HCC.

HOXA9 promotes proliferation, metastasis and prevents apoptosis in hepatocellular carcinoma.

PURPOSE: This research aimed to evaluate the expression level of Homeobox A9 (HOXA9) and its role in tumorigenesis of hepatocellular carcinoma (HCC). METHODS: Bioinformatic analysis, qPCR and Western blot analysis of clinical samples were employed to evaluate mRNA and protein levels of HOXA9 in HCC patients and cell lines. In vitro cell proliferation, migration and invasion, cloning formation, xenograft tumor model, wound healing and apoptosis assays, RNA sequencing analysis of RPL38-silenced HCC-LM3 cells and qPCR, Western blot analysis were performed for validation. Analysis of HOXA9-related genes were conducted to identify their relationships between HOXA9. RESULTS: HOXA9 is dramatically upregulated in HCC. Upregulation of HOXA9 in HCC predicts poor survival of patients. Besides, HOXA9 promotes proliferation, metastasis and prevents apoptosis in HCC in vitro. In addition, HOXA9 controlled by Ribosomal protein RPL38 is upregulated in HCC. Bioinformatic analysis also indicated that HOXA9 is involved in the regulation of DNA methylation and immune infiltration in HCC. CONCLUSION: HOXA9 is dramatically upregulated in hepatocellular carcinoma and predicts poor prognosis. Besides, HOXA9 promoted proliferation and metastasis and prevented apoptosis in vitro, which is regulated by Ribosomal protein RPL38 in HCC.

Detection of hepatocellular carcinoma feeding vessels: MDCT angiography with 3D reconstruction versus digital subtraction angiography.

BACKGROUND: Accurate detection of Hepatocellular carcinoma (HCC) feeding vessels during transcatheter arterial chemoembolization (TACE) is important for an effective treatment, while limiting non-target embolization. This study aimed to investigate the feasibility and accuracy of pre-TACE three dimensional (3D) CT angiography for tumor-feeding vessels detection compared to DSA. METHODS: Sixty-nine consecutive patients referred for TACE from May 2022 to May 2023 were included. (3D) CT images were reconstructed from the pre-TACE diagnostic multiphasic contrast enhanced CT images and compared with non-selective digital subtraction angiography (DSA) images obtained during TACE for detection of HCC feeding vessels. A "Ground truth" made by consensus between observers after reviewing all available pre-TACE CT images, and DSA and CBCT images during TACE to detect the true feeding vessels was the gold standard. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), accuracy and ROC curve with AUC were calculated for each modality and compared. RESULTS: A total of 136 active HCCs were detected in the 69 consecutive patients included in the study. 185 feeding arteries were detected by 3D CT and DSA and included in the analysis. 3D CT detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV and accuracy of 91%, 71%, 98%, 36%, and 90%, respectively, with mean AUC = 0.81. DSA detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV, and accuracy of 80%, 58%, 96.5%, 16.5% and 78%, respectively, with mean AUC = 0.69. CONCLUSIONS: Pre-TACE 3D CT angiography has shown promise in improving the detection of HCC feeding vessels compared to DSA. However, further studies are required to confirm these findings across different clinical settings and patient populations. TRIAL REGISTRATION: This study was prospectively registered at Clinicaltrials.gov with ID NCT05304572; Date of registration: 2-4-2022.

Comprehensive Analysis of the Mechanism of Anoikis in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC), ranking as the second-leading cause of global mortality among malignancies, poses a substantial burden on public health worldwide. Anoikis, a type of programmed cell death, serves as a barrier against the dissemination of cancer cells to distant organs, thereby constraining the progression of cancer. Nevertheless, the mechanism of genes related to anoikis in HCC is yet to be elucidated. Methods: This paper's data (TCGA-HCC) were retrieved from the database of the Cancer Genome Atlas (TCGA). Differential gene expression with prognostic implications for anoikis was identified by performing both the univariate Cox and differential expression analyses. Through unsupervised cluster analysis, we clustered the samples according to these DEGs. By employing the least absolute shrinkage and selection operator Cox regression analysis (CRA), a clinical predictive gene signature was generated from the DEGs. The Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of immune cell types. The external validation data (GSE76427) were procured from Gene Expression Omnibus (GEO) to verify the performance of the clinical prognosis gene signature. Western blotting and immunohistochemistry (IHC) analysis confirmed the expression of risk genes. Results: In total, 23 prognostic DEGs were identified. Based on these 23 DEGs, the samples were categorized into four distinct subgroups (clusters 1, 2, 3, and 4). In addition, a clinical predictive gene signature was constructed utilizing ETV4, PBK, and SLC2A1. The gene signature efficiently distinguished individuals into two risk groups, specifically low and high, demonstrating markedly higher survival rates in the former group. Significant correlations were observed between the expression of these risk genes and a variety of immune cells. Moreover, the outcomes from the validation cohort analysis aligned consistently with those obtained from the training cohort analysis. The results of Western blotting and IHC showed that ETV4, PBK, and SLC2A1 were upregulated in HCC samples. Conclusion: The outcomes of this paper underscore the effectiveness of the clinical prognostic gene signature, established utilizing anoikis-related genes, in accurately stratifying patients. This signature holds promise in advancing the development of personalized therapy for HCC.

The role of resection in hepatocellular carcinoma BCLC stage B: A multi-institutional patient-level meta-analysis and systematic review.

PURPOSE: The Barcelona Clinic Liver Cancer (BCLC) staging schema is widely used for hepatocellular carcinoma (HCC) treatment. In the updated recommendations, HCC BCLC stage B can become candidates for transplantation. In contrast, hepatectomy is currently not recommended. METHODS: This systematic review includes a multi-institutional meta-analysis of patient-level data. Survival, postoperative mortality, morbidity and patient selection criteria for liver resection and transplantation in BCLC stage B are explored. All clinical studies reporting HCC patients with BCLC stage B undergoing liver resection or transplantation were included. RESULTS: A total of 31 studies with 3163 patients were included. Patient level data was available for 580 patients from 9 studies (423 after resection and 157 after transplantation). The overall survival following resection was 50 months and recurrence-free survival was 15 months. Overall survival after transplantation was not reached and recurrence-free survival was 45 months. The major complication rate after resection was 0.11 (95%-CI, 0.0-0.17) with the 90-day mortality rate of 0.03 (95%-CI, 0.03-0.08). Child-Pugh A (93%), minor resection (60%), alpha protein level less than 400 (64%) were common in resected patients. Resected patients were mostly outside the Milan criteria (99%) with mean tumour number of 2.9. Studies reporting liver transplantation in BCLC stage B were scarce. CONCLUSION: Liver resection can be performed safely in selected patients with HCC BCLC stage B, particularly if patients present with preserved liver function. No conclusion can done on liver transplantation due to scarcity of reported studies.

Relationship between TIGIT expression on T cells and the prognosis of patients with hepatocellular carcinoma.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) combined with targeted therapy and immunotherapy can significantly improve the prognosis of patients with hepatocellular carcinoma (HCC). T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is a novel immunosuppressive molecule. This study aimed to analyze the clinical correlation between TIGIT expression on T cells and patients with HCC. METHODS: Clinical data from 140 patients with HCC were retrospectively collected, and TIGIT expression on T cells was examined in each patient. Patients were subsequently divided into high- and low-expression groups, and their prognosis was analyzed. RESULTS: Patients with a high TIGIT expression on their T cells at baseline had a larger tumor volume, later staging, higher proportion of regulatory T cells, higher blood concentrations of interleukin (IL)-6 and IL-10, and lower interferon-γ concentrations. Following TACE, CD155 concentration decreased; however, TACE did not affect TIGIT expression on T cells. Additionally, among patients receiving TACE combined with apatinib and camrelizumab treatment, patients with a high TIGIT expression on T cells had significantly shorter progression-free survival (PFS) and overall survival times than those of patients in the low-expression group. Patients receiving TACE combined with apatinib and camrelizumab treatment with higher TIGIT expression have shorter PFS time than those receiving TACE combined with apatinib treatment. CONCLUSIONS: Patients with HCC that have a high TIGIT expression on their T cells exhibited poorer baseline characteristics, immunosuppressive status, and prognosis after receiving TACE combined with apatinib and camrelizumab and maybe more suited to receive TACE combined with apatinib treatment instead.