Hepatocellular Carcinoma Metastasis Research Articles

Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a mitochondrial isoenzyme, supports the growth of cancer cells under glucose deficiency conditions in vitro. This study investigated the role and potential mechanism of PCK2 in the occurrence and development of Hepatocellular carcinoma (HCC). The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other databases distinguish the expression of PCK2 and verified by qRT-PCR and Western blotting. Kaplan–Meier was conducted to assess PCK2 survival in HCC. The potential biological function of PCK2 was verified by enrichment analysis and gene set enrichment analysis (GSEA). The correlation between PCK2 expression and immune invasion and checkpoint was found by utilizing Tumor Immune Estimation Resource (TIMER). Lastly, the effects of PCK2 on the proliferation and metastasis of hepatocellular carcinoma cells were evaluated by cell tests, and the expressions of Epithelial mesenchymal transformation (EMT) and apoptosis related proteins were detected. PCK2 is down-regulated in HCC, indicating a poor prognosis. PCK2 gene mutation accounted for 1.3% of HCC. Functional enrichment analysis indicated the potential of PCK2 as a metabolism-related therapeutic target. Subsequently, we identified several signaling pathways related to the biological function of PCK2. The involvement of PCK2 in immune regulation was verified and key immune checkpoints were predicted. Ultimately, after PCK2 knockdown, cell proliferation and migration were significantly increased, and N-cadherin and vimentin expression were increased. PCK2 has been implicated in immune regulation, proliferation, and metastasis of hepatocellular carcinoma, and is emerging as a novel predictive biomarker and metabolic-related clinical target.

Marantic Endocarditis Associated with Metastatic Fibrolamellar Hepatocellular Carcinoma in a Young Adult: About a Case

We describe the case of a 21-year-old patient presenting with marantic endocarditis of the aortic valve occurring in the context of underlying metastatic fibrolamellar hepatocellular carcinoma. The patient was admitted due to a pulmonary embolism complicating deep vein thrombosis in the right lower limb. Upon admission, the patient was hemodynamically stable and afebrile, with a poor general condition. Physical examination revealed a painful swelling in the right lower limb extending up to the thigh, hepatomegaly suggestive of a tumor, and moderate ascites. Cardiac auscultation did not reveal any murmurs or abnormal sounds. Laboratory tests showed a non-specific inflammatory syndrome, and blood cultures were negative. The electrocardiogram indicated regular sinus tachycardia. Echocardiography revealed a mobile, hyperechoic mass located on the ventricular aspect of the aortic valve, without regurgitation or stenosis. The patient was started on heparin therapy. Unfortunately, the patient passed away at home two weeks later, and no autopsy was performed.

Aspirin suppresses hepatocellular carcinoma progression by inhibiting platelet activity.

Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. Platelets (PLTs) are known to play a key role in the maintenance of liver homeostasis and the pathophysiological processes of a variety of liver diseases. Aspirin is the most classic antiplatelet agent. However, the molecular mechanism of platelet action and whether aspirin can affect HCC progression by inhibiting platelet activity need further study. To explore the impact of the antiplatelet effect of aspirin on the development of HCC. Platelet-rich plasma, platelet plasma, pure platelet, and platelet lysate were prepared, and a coculture model of PLTs and HCC cells was established. CCK-8 analysis, apoptosis analysis, Transwell analysis, and real-time polymerase chain reaction (RT-PCR) were used to analyze the effects of PLTs on the growth, metastasis, and inflammatory microenvironment of HCC. RT-PCR and Western blot were used to detect the effects of platelet activation on tumor-related signaling pathways. Aspirin was used to block the activation and aggregation of PLTs both in vitro and in vivo, and the effect of PLTs on the progression of HCC was detected. PLTs significantly promoted the growth, invasion, epithelial-mesenchymal transition, and formation of an inflammatory microenvironment in HCC cells. Activated PLTs promoted HCC progression by activating the mitogen-activated protein kinase/protein kinase B/signal transducer and activator of transcription three (MAPK/ AKT/STAT3) signaling axis. Additionally, aspirin inhibited HCC progression in vitro and in vivo by inhibiting platelet activation. PLTs play an important role in the pathogenesis of HCC, and aspirin can affect HCC progression by inhibiting platelet activity. These results suggest that antiplatelet therapy has promising application prospects in the treatment and combined treatment of HCC.

Gene Expression Reprogramming by Citrate Supplementation Reduces HepG2 Cell Migration and Invasion.

Citrate, which is obtained from oxaloacetate and acetyl-CoA by citrate synthase in mitochondria, plays a key role in both normal and cancer cell metabolism. In this work, we investigated the effect of 10 mM extracellular citrate supplementation on HepG2 cells. Gene expression reprogramming was evaluated by whole transcriptome analysis using gene set enrichment analysis (GSEA). The transcriptomic data were validated through analyzing changes in the mRNA levels of selected genes by qRT-PCR. Citrate-treated cells exhibited the statistically significant dysregulation of 3551 genes; 851 genes were upregulated and 822 genes were downregulated. GSEA identified 40 pathways affected by differentially expressed mRNAs. The most affected biological processes were related to lipid and RNA metabolism. Several genes of the cytochrome P450 family were upregulated in treated cells compared to controls, including the CYP3A5 gene, a tumor suppressor in hepatocellular carcinoma (HCC) that plays an important protective role in HCC metastasis. The citrate-induced dysregulation of cytochromes could both improve the effectiveness of chemotherapeutics used in combination and reduce the aggressiveness of tumors by diminishing cell migration and invasion.

SMP30 Interacts with ROCK1 to Inhibit HCC Invasiveness by Effecting the Epithelial-Mesenchymal Transition.

The senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases with age, and is closely associated with hepatocellular carcinoma (HCC) development. The primary goal of this study was to examine the mechanistic effect of SMP30 on HCC migration and invasion. Bioinformatic and immunohistochemical approaches were used to examine the expression of SMP30 in HCC tissues and its relationship to patient survival. We investigated the effects of SMP30 expression on HCC cell proliferation, migration, invasion, and cell cycle dynamics. cDNA microarray technology was used to determine the gene expression profile of SK-Hep-1 cells following recombinant SMP30 overexpression to identify genes downstream of SMP30 that regulate HCC cell migration and invasion. We identified SMP30 interacting proteins by affinity purification-mass spectrometry (AP-MS) and co-immunoprecipitation/western blotting (COIP-WB). SMP30 expression was lower in HCC tissues compared with normal liver tissues, and its expression positively correlated with overall survival in HCC patients. Additionally, SMP30 overexpression effectively blocked the migratory and invasive properties of SK-Hep-1 cells, but did not affect either proliferation rates or cell cycle. cDNA microarray results confirmed that many of the differentially expressed genes identified are involved in the process of epithelial-mesenchymal transition (EMT). AP-MS and COIP-WB experiments confirmed that Rho-associated protein kinase 1 (ROCK1) interacts with SMP30 in SK-Hep-1 cells, and ROCK1 is known to intimately regulate the EMT process. SMP30 inhibits HCC metastasis by influencing the expression of EMT-related proteins after interacting with ROCK1.

MARCH5 promotes hepatocellular carcinoma progression by inducing p53 ubiquitination degradation

BackgroundHuman MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests that imbalances in mitochondrial dynamics are strongly associated with cancer. However, the expression, biological function and prognostic significance of MARCH5 in hepatocellular carcinoma (HCC) have not been determined.Materials and methodsThe mRNA and protein expression of MARCH5 in HCC cell lines and tumor tissues was assessed by real-time quantitative PCR, Western blot analysis and immunohistochemistry. The clinical prognostic significance of MARCH5 was evaluated in 135 HCC patients. Knockdown or overexpression of MARCH5 in HCC cells was determined by in vitro cell proliferation, migration and invasion assays, and in vivo tumor growth and metastasis assays. In addition, the intrinsic mechanisms by which MARCH5 regulates HCC cell growth and metastasis were explored.ResultsMARCH5 was significantly overexpressed in HCC cells and was closely associated with patients' poor postoperative prognosis. In vivo and in vitro experiments revealed that MARCH5 significantly promoted the increase and invasive and migratory ability of hepatocellular carcinoma cells, which was mainly due to the promotion of autophagy by MARCH5. Mechanistic studies revealed that MARCH5 promoted autophagy through ubiquitination degradation of p53 leading to malignant progression of hepatocellular carcinoma.ConclusionOur findings suggest that MARCH5 plays a critical oncogenic role in HCC cells, which provides experimental evidence for the use of MARCH5 as a potential target for HCC therapy.

The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC

Accumulating evidence indicated that HHEX participated in the initiation and development of several cancers, but the potential roles and mechanisms of HHEX in hepatocellular carcinoma (HCC) were largely unclear. Cancer stem cells (CSCs) are responsible for cancer progression owing to their stemness characteristics. We reported that HHEX was a novel CSCs target for HCC. We found that HHEX was overexpressed in HCC tissues and high expression of HHEX was associated with poor survival. Subsequently, we found that HHEX promoted HCC cell proliferation, migration, and invasion. Moreover, bioinformatics analysis and experiments verified that HHEX promoted stem cell-like properties in HCC. Mechanistically, ABI2 serving as a co-activator of transcriptional factor HHEX upregulated SLC17A9 to promote HCC cancer stem cell-like properties and tumorigenesis. Collectively, the HHEX-mediated ABI2/SLC17A9 axis contributes to HCC growth and metastasis by maintaining the CSC population, suggesting that HHEX serves as a promising therapeutic target for HCC treatment.

Corrigendum to: TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma.

Corrigendum to: TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma.

Exposure of benzo[a]pyrene induces HCC exosome-circular RNA to activate lung fibroblasts and trigger organotropic metastasis.

Benzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P-induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer-stroma communications for a toxicologically associated microenvironment. Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404-100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre-education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P-exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull-down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the "on-off" interaction of circRNA-miRNA pairs. We further developed an adeno-associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA-miRNA cascade. Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404-100Bap Exo. In the exosome-educated in vivo model, fibrosis factors and pro-inflammatory molecules of are up-regulated when injected with exosomes. Compared to non-exposed 7404 cells, circ_0011496 was up-regulated following B[a]P treatment and was mainly packaged into 7404-100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR-486-5p in recipient fibroblasts. The down-regulation of miR-486-5p converted fibroblast to cancer-associated fibroblast via regulating the downstream of Twinfilin-1 (TWF1) and matrix metalloproteinase-9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer-stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre-metastatic niche formation. We demonstrated that B[a]P-induced tumor exosomes can deliver circ_0011496 to activate miR-486-5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.

GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

An open-label, multicenter study investigating RP2 oncolytic immunotherapy in combination with second-line systemic atezolizumab combined with bevacizumab in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.

TPS4191 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved as frontline therapy for advanced HCC, but only a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), GM-CSF, and an anti–CTLA-4 antibody-like molecule. The direct oncolytic effect coupled with immune stimulation by RP2 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP2 with Bev. This study will evaluate the safety and efficacy of RP2 combined with Atezo plus Bev as second-line systemic therapy for unresectable and advanced HCC (NCT05733598). Methods: This is an open-label, single arm, phase 2 trial. Up to 30 pts will be enrolled and receive RP2 in combination with Atezo plus Bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status of 0 to 1, and progression on 1 prior systemic treatment, which must have included a PD-1/PD-L1–directed agent. Key exclusion criteria include untreated/incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts will receive intratumoral RP2 Q2W for 4 doses, then Q3W for up to 4 doses. Bev will be given at 10 mg/kg Q2W starting with the first dose of RP2 then at 15 mg/kg Q3W starting with cycle 4; Atezo will be given at 840 mg Q2W for cycles 2 and 3, then at 1200 mg Q3W starting with cycle 4. Pts will receive treatment until confirmed progressive disease, loss of clinical benefit, or unacceptable toxicity. The primary endpoint is overall response rate (ORR), defined as the proportion of pts achieving a best overall response of complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as modified for this study. Secondary endpoints are safety, ORR using HCC-modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

201P Retrospective multicenter real-life study evaluating the efficacy of atezolizumab in combination with bevacizumab in metastatic hepatocellular carcinoma: HIREAL study

201P Retrospective multicenter real-life study evaluating the efficacy of atezolizumab in combination with bevacizumab in metastatic hepatocellular carcinoma: HIREAL study

DUET-01: A first-in-human, phase 1/2 study of BOXR1030 in patients with advanced glypican-3-positive solid tumors.

TPS2681 Background: Glypican-3 (GPC3) is a membrane-bound heparin sulfate proteoglycan involved in cell proliferation that is overexpressed in several tumor types. BOXR1030 is an autologous T-cell therapy that co-expresses a chimeric antigen receptor (CAR) targeting GPC3 on tumor cells and glutamic-oxaloacetic transaminase 2 (GOT2), a mitochondrial enzyme that plays an important role in maintaining mitochondrial function and improving T-cell functionality in the solid tumor microenvironment. In non-clinical studies, BOXR1030 showed GPC3-specific cytotoxicity, proliferation and cytokine release only in the presence of GPC3+ cells. Methods: DUET-01 (NCT05120271) is an open-label, dose escalation and expansion clinical trial to determine a safe dose of BOXR1030 in patients with advanced GPC3-positive solid tumors. Dose escalation will be guided by the occurrence of dose-limiting toxicities (DLTs) within 28 days of dosing. The Bayesian logistic regression model will be used on the accumulated DLT data to estimate the maximum tolerated dose (MTD). The Dose Escalation Committee will select the recommended phase 2 dose (RP2D) to be used in the expansion phase cohort(s) (10-20 subjects each) based on data accumulated in the dose escalation cohorts. Eligible subjects will undergo leukapheresis to obtain T cells for BOXR1030 manufacturing and will receive 3 days of lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 5 days prior to BOXR1030 administration. The starting dose is 0.3 × 106 BOXR1030 T cells/kg body weight. Antitumor activity will be assessed every 6 weeks after cell infusion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and RECIST for immune-based therapeutics (iRECIST). Six months after BOXR1030 administration, subjects will enter long-term follow-up for up to 15 years. Long-term follow-up assessments will focus on long-term safety and disease status. Main inclusion criteria are histologically confirmed advanced unresectable or metastatic hepatocellular carcinoma, squamous cell carcinoma of the lung, myxoid/round cell liposarcoma, or Merkel cell carcinoma; GPC3 overexpression by immunohistochemistry assay confirmed centrally on tumor specimen taken within 6 months prior to signing consent and after the initiation of the subject’s most recent systemic anticancer therapy; body weight of ≥ 50 kg (≥ 65 kg for dose level 1); and life expectancy > 16 weeks. The primary endpoints are the incidence of DLTs; determination of the MTD and RP2D; the type, frequency and severity of treatment-emergent adverse events; clinically significant abnormal safety laboratory findings and vital signs. Key secondary endpoints include efficacy parameters such as objective response rate, BOXR1030 T-cell expansion and persistence, and levels of inflammatory markers and cytokines. The first patient was treated with BOXR1030 in December 2022. Clinical trial information: NCT05120271 .

Phase 2/3 study of livmoniplimab in combination with budigalimab in patients with locally advanced or metastatic hepatocellular carcinoma.

TPS4190 Background: Most patients with hepatocellular carcinoma (HCC) present with advanced unresectable or metastatic disease and survival rates remain poor. While approved checkpoint inhibitor (CPI)-based combination regimens for HCC have shown improvements in overall survival (OS), not all patients respond to currently available CPI-based therapy, and new strategies to overcome CPI-resistance using novel combination therapies are urgently needed. HCC gene expression profile analysis points to TGF-β signaling as a possible mechanism of immune escape. The first-in-class humanized monoclonal antibody livmoniplimab (ABBV-151) was developed that specifically binds to the glycoprotein-A repetitions predominant-transforming growth factor (GARP–TGF)-β complex, blocking release of active TGF-β1 and promoting immunoreactivity. A phase 1 study in HCC showed an overall response rate (ORR) of 42% (5/12) when combining livmoniplimab with the programmed cell death 1 inhibitor budigalimab (ABBV-181). We describe herein a phase 2/3 study of livmoniplimab + budigalimab in patients with locally advanced or metastatic HCC. Methods: This multicenter, phase 2/3, randomized, open-label study (NCT06109272) will enroll patients (≥18 years) with advanced HCC (aHCC) who have not previously received systemic treatment and have Barcelona Clinic Liver Cancer stage B or C, not eligible for locoregional therapy, Child-Pugh class A or B7, and Eastern Cooperative Oncology Group performance status 0‒1. The study will have 2 stages. Stage 1 is a phase 2 dose-optimization lead-in, during which ~80 patients will be enrolled and randomized 1:1:2 to receive 1 of 2 doses of livmoniplimab in combination with budigalimab Q3W, or investigator’s choice of either atezolizumab + bevacizumab Q3W or single-dose tremelimumab + durvalumab Q4W per STRIDE regimen. The primary objective of stage 1 is to select the optimal livmoniplimab dose to use in combination with budigalimab. Efficacy, safety, pharmacokinetic (PK), and pharmacodynamic data will be combined with prior phase 1/2 study data to select the livmoniplimab dose for stage 2. Stage 2 is a phase 3 study in ~580 patients with aHCC. Patients will be randomized 1:1 to receive the optimized dose of livmoniplimab + budigalimab or single-dose tremelimumab (300 mg) + durvalumab (1500 mg) Q4W (STRIDE). The primary objective for stage 2 is to evaluate the efficacy of livmoniplimab + budigalimab as measured by median OS. Secondary objectives include assessment of safety, tolerability, immunogenicity, and PK, efficacy measured by median progression-free survival, ORR, and duration of response as well as the impact on patient-reported outcomes. Enrollment is planned in Europe, Asia, and USA, and is open as of Dec 2023. Clinical trial information: NCT06109272 .

199P Result of atezolizumab plus bevacizumab for advanced or metastatic hepatocellular carcinoma in Vietnamese patients

199P Result of atezolizumab plus bevacizumab for advanced or metastatic hepatocellular carcinoma in Vietnamese patients

Preliminary data of a phase Ib/II trial evaluating the efficacy and safety of adebrelimab, camrelizumab plus apatinib as first-line therapy in patients with advanced hepatocellular carcinoma.

e16221 Background: The CARES-310 study has demonstrated that the combination of the anti-PD-1 antibody camrelizumab and the VEGFR2 tyrosine kinase inhibitor apatinib exhibits improved progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). We conducted this study to investigate whether the addition of the anti-PD-L1 antibody adebrelimab to camrelizumab and apatinib would further improve clinical outcomes. Methods: This is a prospective, phase 1b/2 clinical trial employing the i3 + 3 dose escalation design. Eligibility includes adults with unresectable or metastatic HCC, a ECOG PS of 0 or 1, a Child-Pugh score ≤ 7, and at least one measurable lesion per RECIST v 1.1. In phase 1b, patients (pts) received adebrelimab (10 mg/kg or 20 mg/kg, I.V., D1, Q3W), camrelizumab (200mg, I.V., D1, Q3W), and apatinib (250 mg orally daily). Phase 2 is a single arm, open-label trial in the first-line setting. The primary objective were dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended phase II dose (RP2D). With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 17 and 41 pts, respectively. Results: As of 4 February 2024, 6 HCC pts progressed after or were intolerant to first-line treatment (systemic therapy ± surgical resection) were treated in 1 dose cohorts. 1 DLT occurred (Grade 3 elevated blood bilirubin increased). The RP2D was adebrelimab (10 mg/kg), camrelizumab (200mg), and apatinib (250 mg). The most common drug-related AEs were Hypertension (83.3%) and Rash (50%); and Serum amylase increased, Itching, ALT/AST increased, and Hypothyroidism (each 33.3%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 1 pts (16.7%) discontinued due to drug-related AEs. Conclusions: The combination of Adebelimumab, Camrelizumab, and Apatinib demonstrated manageable safety for unresectable HCC. Enrollment in the phase II trial is ongoing and updated clinical data will be presented. Clinical trial information: NCT05924997 .

FAM188B promotes the growth, metastasis, and invasion of hepatocellular carcinoma by targeting the hnRNPA1/PKM2 axis

Hepatocellular carcinoma (HCC), the leading cause of cancer-related deaths worldwide, is characterised by rapid growth and marked invasiveness. Accumulating evidence suggests that deubiquitinases play a pivotal role in HCC growth and metastasis. However, the expression of the deubiquitinase FAM188B and its biological functions in HCC remain unknown. The aim of our study was to investigate the potential role of FAM188B in HCC. The expression of FAM188B was significantly upregulated in liver cancer cells compared to normal liver cells, both at the transcriptional and translational levels. Similarly, FAM188B expression was higher in liver cancer tissues than in normal liver tissues. Bioinformatic analysis revealed that high FAM188B expression was associated with poor prognosis in patients with HCC. We further demonstrated that FAM188B knockdown inhibited cell proliferation, epithelial-mesenchymal transition, migration and invasion both in vitro and in vivo. Mechanistically, FAM188B knockdown significantly inhibited the hnRNPA1/PKM2 pathway in HCC cells. FAM188B may inhibit ubiquitin-mediated degradation of hnRNPA1 through deubiquitination. Notably, we observed that the inhibitory effects of FAM188B knockdown on HCC cell proliferation, migration and invasion were reversed when hnRNPA1 expression was restored. In conclusion, FAM188B promotes HCC progression by enhancing the deubiquitination of hnRNPA1 and subsequently activating the hnRNPA1/PKM2 pathway. Therefore, targeting FAM188B is a potential strategy for HCC therapy.

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.

Transcriptomic and genomic characteristics of intrahepatic metastases of primary liver cancer

BackgroundPatients with primary multifocal hepatocellular carcinoma (HCC) have a poor prognosis and often experience a high rate of treatment failure. Multifocal HCC is mainly caused by intrahepatic metastasis (IM), and though portal vein tumor thrombosis (PVTT) is considered a hallmark of IM, the molecular mechanism by which primary HCC cells invade the portal veins remains unclear. Therefore, it is necessary to recognize the early signs of metastasis of HCC to arrange better treatment for patients.ResultsTo determine the differential molecular features between primary HCC with and without phenotype of metastasis, we used the CIBERSORTx software to deconvolute cell types from bulk RNA-Seq based on a single-cell transcriptomic dataset. According to the relative abundance of tumorigenic and metastatic hepatoma cells, VEGFA+ macrophages, effector memory T cells, and natural killer cells, HCC samples were divided into five groups: Pro-T, Mix, Pro-Meta, NKC, and MemT, and the transcriptomic and genomic features of the first three groups were analyzed. We found that the Pro-T group appeared to retain native hepatic metabolic activity, whereas the Pro-Meta group underwent dedifferentiation. Genes highly expressed in the group Pro-Meta often signify a worse outcome.ConclusionsThe HCC cohort can be well-typed and prognosis predicted according to tumor microenvironment components. Primary hepatocellular carcinoma may have obtained corresponding molecular features before metastasis occurred.

CircDCAF8 promotes the progression of hepatocellular carcinoma through miR-217/NAP1L1 Axis, and induces angiogenesis and regorafenib resistance via exosome-mediated transfer

BackgroundCircular RNAs (circRNAs), which are a new type of single-stranded circular RNA, have significant involvement in progression of many diseases, including tumors. Currently, multiple circRNAs have been identified in hepatocellular carcinoma (HCC). Our study aims to investigate the function and mechanism of circDCAF8 in HCC.MethodsThe expression of circDCAF8 (hsa_circ_0014879) in HCC and para-carcinoma tissue samples was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The biological function of circDCAF8 in HCC was confirmed by experiments conducted both in vitro and in vivo. And the relationship between circDCAF8, miR-217 and NAP1L1 was predicted by database and verified using qRT-PCR, RNA-binding protein immunoprecipitation (RIP) and dual-luciferase reporter assays. Exosomes isolated from HCC cells were utilized to assess the connection of exosomal circDCAF8 with HCC angiogenesis and regorafenib resistance.ResultsCircDCAF8 is upregulated in HCC tissues and cell lines, and is linked to an unfavourable prognosis for HCC patients. Functionally, circDCAF8 was proved to facilitate proliferation, migration, invasion and Epithelial-Mesenchymal Transformation (EMT) in HCC cells. Animal examinations also validated the tumor-promoting characteristics of circDCAF8 on HCC. Besides, exosomal circDCAF8 promoted angiogenesis in HUVECs. Mechanistically, circDCAF8 interacted with miR-217 and NAP1L1 was a downstream protein of miR-217. CircDCAF8 promoted NAP1L1 expression by sponging miR-217. In addition, exosomes may transfer circDCAF8 from regorafenib-resistant HCC cells to sensitive cells, where it would confer a resistant phenotype.ConclusionCircDCAF8 facilitates HCC proliferation and metastasis via the miR-217/NAP1L1 axis. Meanwhile, circDCAF8 can promote angiogenesis and drive resistance to regorafenib, making it a viable therapeutic target for HCC patients.