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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide including sub-Saharan Africa. The GALAD score, derived from Gender, Age, Lens culinaris agglutinin-reactive fraction of alpha fetoprotein, Alpha fetoprotein, and Des-carboxy-prothrombin, has high accuracy in diagnosing HCC in Asia, Europe, and North America; however, it has not been validated in an African cohort. The aim of this study was to assess the performance of the GALAD score in the diagnosis of HCC in sub-Saharan Africa. Clinical data from patients with cirrhosis (n = 93) or HCC (n = 78) from outpatient hepatology clinics at three teaching hospitals in Ghana were abstracted, and serum samples were analyzed. A logistic regression model predicting HCC status based on the GALAD score was constructed to obtain the ROC curve for GALAD. The AUC with 95% confidence interval (CI) was calculated. The median GALAD score was higher among patients with HCC versus cirrhosis controls (8.0 vs. -4.1, P < 0.01). The AUC of the GALAD score for HCC detection was 0.86 (95% CI, 0.79-0.92). At a cut-off value of -0.37, the GALAD score had a sensitivity of 0.81 and a specificity of 0.86. The AUC (95% CI) was 0.87 (0.80-0.95) and 0.81 (0.67-0.94) in hepatitis B virus-positive and hepatitis B virus-negative patients, respectively. The GALAD score has a high accuracy for HCC detection. It has great potential to improve HCC surveillance in sub-Saharan Africa where imaging resources are limited. Significance: The GALAD score or its relevant modifications have the potential to aid in improving HCC surveillance efforts in low-resource settings in sub-Saharan Africa. This could enhance early detection rates of HCC and potentially improve survival rates in resource-limited settings., (©2024 The Authors; Published by the American Association for Cancer Research.)

GalNAc-modified ferrous sulfide nanoparticles have been developed to conduct chemodynamic and gas therapy for fighting against orthotopic hepatocellular carcinoma. This nanomedicine owns good liver targeting ability, which takes full advantage of the tumor microenvironment to ensure the therapy effect and improve the safety.

Background: Various epigenetic regulations systematically govern gene expression in cells involving various biological processes. Dysregulation of the epigenome leads to aberrant transcriptional programs and subsequently results in diseases, such as cancer. Therefore, comprehensive profiling epigenomics is essential for exploring the mechanisms underlying gene expression regulation during development and disease., Methods: In this study, we developed single-cell chromatin proteins and accessibility tagmentation (scCPA-Tag), a multi-modal single-cell epigenetic profile capturing technique based on barcoded Tn5 transposases and a droplet microfluidics platform. scCPA-Tag enables the simultaneous capture of DNA profiles of histone modification and chromatin accessibility in the same cell., Results: By applying scCPA-Tag to K562 cells and a hepatocellular carcinoma (HCC) sample, we found that the silence of several chromatin-accessible genes can be attributed to lysine-27-trimethylation of the histone H3 tail (H3K27me3) modification. We characterized the epigenetic features of the tumour cells and different immune cell types in the HCC tumour tissue by scCPA-Tag. Besides, a tumour cell subtype (C2) with more aggressive features was identified and characterized by high chromatin accessibility and a lower abundance of H3K27me3 on tumour-promoting genes., Conclusions: Our multi-modal scCPA-Tag provides a comprehensive approach for exploring the epigenetic landscapes of heterogeneous cell types and revealing the mechanisms of gene expression regulation during developmental and pathological processes at the single-cell level., Highlights: scCPA-Tag offers a highly efficient and high throughput technique to simultaneously profile histone modification and chromatin accessibility within a single cell. scCPA-Tag enables to uncover multiple epigenetic modification features of cellular compositions within tumor tissues. scCPA-Tag facilitates the exploration of the epigenetic landscapes of heterogeneous cell types and provides the mechanisms governing gene expression regulation., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Objective: Few studies have examined the outcomes of radiofrequency ablation (RFA) for liver tumors in patients on hemodialysis. This study aimed to investigate short-term outcomes following RFA for liver tumors in patients on hemodialysis., Methods: Data of patients ≥ 20 years old diagnosed with liver tumors who underwent RFA were extracted from the Nationwide Inpatient Sample (NIS) database 2005-2020. The study population was divided into two groups: patients on hemodialysis and those not on hemodialysis. Propensity score matching (PSM) was employed to address baseline differences. Associations between hemodialysis and in-hospital outcomes, including prolonged length of stay (LOS), in-hospital mortality, unfavorable discharge, and complications were determined using logistic regression analyses., Results: After applying the inclusion and exclusion criteria, a total of 12,749 patients constituted the study population, with 550 remaining after 1:4 PSM (110 on hemodialysis and 440 without hemodialysis). After adjustment in the multivariable analyses, patients on maintenance hemodialysis showed significantly higher risks of prolonged LOS (adjusted odds ratio [aOR] = 2.88, 95 % confidence interval [CI]: 1.78-4.65), in-hospital mortality (aOR=31.90, 95 % CI: 17.68-57.58), unfavorable discharge (aOR=3.79, 95 % CI: 2.05-7.01), at least one complications (aOR=3.68, 95 % CI: 2.49-5.44), and greater total hospital costs (adjusted Beta [aBeta] = 126.75, 95 % CI: 113.68-139.82)., Conclusions: Patients on hemodialysis undergoing RFA for liver tumors have greater risks of adverse short-term outcomes including in-hospital mortality, prolonged LOS, complications, and unfavorable discharge. Careful consideration and close monitoring are warranted for patients on hemodialysis when planning for RFA.3., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A nano-immunomodulator modified with N -acetylgalactosamine (GalNAc) on calcium carbonate (CaCO 3 ) was prepared for targeted and responsive immunotherapy. And the immunologic adjuvant (CpG ODNs) and doxorubicin (DOX) were released to synergistically improve immune response for treating orthotopic liver cancer.

O-linked-β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a strong correlation between anoikis resistance and tumor progression, invasion, and metastasis. Nevertheless, the classification of anoikis in HCC and the investigation of novel biological target mechanisms in this context continue to pose challenges, requiring further exploration., Methods: Combined with HCC samples from TCGA, GEO and ICGC databases, cluster analysis was conducted on anoikis genes, revealing novel patterns among different subtypes. Significant gene analysis of different gene subtypes was performed using WCGNA. The anoikis prognostic risk model was established by Lasso-Cox. Go, KEGG, and GSEA were applied to investigate pathway enrichment primarily observed in risk groups. We compared the disparities in immune infiltration, TMB, tumor microenvironment (TME), and drug sensitivity between the two risk groups. RT-qPCR and Western blotting were performed to validate the expression levels of SLCO4C1 in HCC. The biological functions of SLCO4C1 in HCC cells were assessed through various experiments, including CCK8 assay, colony formation assay, invasion migration assay, wound healing assay, and flow cytometry analysis., Results: HCC was divided into 2 anoikis subtypes, and the subtypeB had a better prognosis. An anoikis prognostic model based on 12 (COPZ2, ACTG2, IFI27, SPP1, EPO, SLCO4C1, RAB26, STC2, RAC3, NQO1, MYCN, HSPA1B) risk genes is important for survival and prognosis. Significant differences were observed in immune cell infiltration, TME, and drug sensitivity analysis between the risk groups. SLCO4C1 was downregulated in HCC. SLCO4C1 downregulation promoted the proliferation, invasion, migration, and apoptosis of HCC cells. The tumor-suppressive role of SLCO4C1 in HCC has been confirmed., Conclusions: Our study presents a novel anoikis classification method for HCC that reveals the association between anoikis features and HCC. The anoikis feature is a critical biomarker bridging tumor cell death and tumor immunity. In this study, we provided the first evidence of SLCO4C1 functioning as a tumor suppressor in HCC.

Considering the high fatality of hepatocellular carcinoma (HCC), current prognostic systems are insufficient to accurately forecast HCC patients' outcomes. In our study, nine anoikis‑related genes (PTRH2, ITGAV, ANXA5, BIRC5, BDNF, BSG, DAP3, SKP2, and EGF) were determined to establish a risk scoring model using LASSO regression, which could be validated in ICGC dataset. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curve analysis confirmed the risk score possessed an accurate predictive value for the prognosis of HCC patients. The high-risk group showed a higher infiltration of aDCs, macrophages, T-follicular helper cells, and Th2 cells. Besides, PD-L1 was significantly higher in the high-risk group compared to the low-risk group. Several anoikis‑related genes, such as ANX5, ITGAV, BDNF and SKP2, were associated with drug sensitivity in HCC. Finally, we identified BIRC5 and SKP2 as hub genes among the nine model genes using WGCNA analysis. BIRC5 and SKP2 were over-expressed in HCC tissues, and their over-expression was associated with poor prognosis, no matter in our cohort by immunohistochemical staining or in the TCGA cohort by mRNA-Seq. In our cohort, BIRC5 expression was highly associated with the T stage, pathologic stage, histologic grade and AFP of HCC patients. In general, our anoikis-related risk model can enhance the ability to predict the survival outcomes of HCC patients and provide a feasible therapeutic strategy for immunotherapy and drug resistance in HCC. BIRC5 and SKP2 are hub genes of anoikis‑related genes in HCC., (© 2023. Springer Nature Limited.)

Beauvericin is a world-spread mycotoxin isolated from the traditional Chinese medicine, Bombyx batryticatus (BB), which has been widely used to treat various neoplastic diseases. This study investigated the anti-hepatocellular carcinoma (HCC) activity of beauvericin and its potential mechanism. In this study, H22-bearing mice were intraperitoneally injected with 3, 5, 7 mg/kg of beauvericin once per-week over a three-week period. TUNEL staining determined the extent of tumor apoptosis induced by beauvericin. ELISA kits detected the level of IL-2, Perforin, and TNF-α, IFN-γ level in the serum. H22 hepatoma cells were exposed to beauvericin (5, 10, and 20 μmol/L) to investigate the underlying pathway. CCK-8 assay was used to observe the influence of beauvericin on the growth of H22 cells. Flow cytometry was used to detect the cell apoptosis and ROS level. Western blotting was performed to detect apoptotic and PI3K/AKT pathway protein production. The results showed that beauvericin could remarkably inhibit the growth of HCC in mice, combined with elevated TNF-α and IL-2. In vitro, beauvericin significantly promoted the generation of ROS, up-regulated Bax/Bcl-2 ratio and cleaved caspase-9, cleaved caspase-3 levels, down-regulated p-PI3K/PI3K ratio, p-AKT/AKT ratio, promoted the apoptosis of H22 cells, and inhibited the growth of H22 cells. Remarkably, treatment with PI3K/AKT activator (740Y-P and SC79) could prevent beauvericin-induced H22 cell apoptosis. These findings collectively indicate that beauvericin inhibits HCC growth by inducing apoptosis via the PI3K/AKT pathway., Competing Interests: Declaration of competing interest None of the authors has any conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Various studies have reported cell-free RNAs (cfRNAs) as noninvasive biomarkers for detecting hepatocellular carcinoma (HCC). However, they have not been independently validated, and some results are contradictory. We provided a comprehensive evaluation of various types of cfRNA biomarkers and a full mining of the biomarker potential of new features of cfRNA., Methods: We first systematically reviewed reported cfRNA biomarkers and calculated dysregulated post-transcriptional events and cfRNA fragments. In 3 independent multicentre cohorts, we further selected 6 cfRNAs using RT-qPCR, built a panel called HCCMDP with AFP using machine learning, and internally and externally validated HCCMDP's performance., Findings: We identified 23 cfRNA biomarker candidates from a systematic review and analysis of 5 cfRNA-seq datasets. Notably, we defined the cfRNA domain to describe cfRNA fragments systematically. In the verification cohort (n = 183), cfRNA fragments were more likely to be verified, while circRNA and chimeric RNA candidates were neither abundant nor stable as qPCR-based biomarkers. In the algorithm development cohort (n = 287), we build and test the panel HCCMDP with 6 cfRNA markers and AFP. In the independent validation cohort (n = 171), HCCMDP can distinguish HCC patients from control groups (all: AUC = 0.925; CHB: AUC = 0.909; LC: AUC = 0.916), and performs well in distinguishing early-stage HCC patients (all: AUC = 0.936; CHB: AUC = 0.917; LC: AUC = 0.928)., Interpretation: This study comprehensively evaluated full-spectrum cfRNA biomarker types for HCC detection, highlighted the cfRNA fragment as a promising biomarker type in HCC detection, and provided a panel HCCMDP., Funding: National Natural Science Foundation of China, and The National Key Basic Research Program (973 program)., Competing Interests: Declaration of interests The authors declare no potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

A new mode of cell death, disulfidptosis, has been discovered. Clinical prognostic significance of disulfidptosis related pattern in hepatocellular carcinoma(HCC). In this study, a risk score model was established based on disulfidptosis model to analyze the role of risk score in clinical prognosis, immune cell infiltration, drug sensitivity and immunotherapy response. Disulfidptosis subtype were constructed based on the transcriptional profiles of 15 disulfidptosis-related genes(DRGs). All 601 samples were defined as high risk group(HRG) and low risk group(LRG) based on the disulfidptosis risk score. Drug sensitivity and response to immunotherapy were calculated by immunophenotypic score(IPS), tumor prediction, tumor immune dysfunction and rejection(TIDE). RT-qPCR was used to determine the mRNA level of disulfidptosis prognostic gene. Risk groups was identified as potential predictors of immune cell infiltration, drug sensitivity, and immunotherapy responsiveness. HRG may benefit from immunotherapy. Classification is very effective in predicting the prognosis and therapeutic effect of patients, and provides a reference for accurate individualized treatment. This study suggests that new biomarkers related to Disulfidptosis can be used in clinical diagnosis of liver cancer to predict prognosis and treatment targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: As a critical component of the autophagic machinery, autophagy-related gene 5 (ATG5) is essential for autophagosome formation. Autophagy participates in the transformation and progression of various malignant tumors, but the role of ATG5 in hepatocellular carcinoma (HCC) remains to be illustrated. In this study we aimed to investigate the prognostic significance of ATG5 in HCC., Methods: ATG5 expression was evaluated in 89 pairs of HCC tissues and adjacent non-tumor tissues. The relationship between ATG5 expression and patients' clinicopathological characteristics and prognosis were evaluated. Moreover, subgroup analyses were performed regarding patients' age and number of tumors. Nomograms estimating overall survival (OS) and disease-free survival (DFS) were conducted., Results: ATG5 expression was increased in HCC specimens rather than adjacent non-tumor tissues. The upregulated ATG5 expression was positively associated with serum α-fetoprotein (AFP) level. Moreover, cases with a strong ATG5 expression had a poorer disease-free survival (DFS) and overall survival (OS) than those with a weak ATG5 expression. Multivariate analysis showed that a strong expression of ATG5 was related to a poor OS and DFS in patients with HCC. Further analysis indicated that cases with a higher ATG5 expression had a poorer OS and DFS in the young patients (≤55 years) and those with solitary tumor. The nomogram suggested that there was a coherence between nomogram prediction and the actual situation of patient survival related to ATG5., Conclusion: ATG5 promotes tumor progression in HCC, making it a potential biomarker in the diagnosis and a therapeutic target of HCC., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

As one member of fatty acid binding proteins (FABPs), FABP5 makes a contribution in the occurrence and development of several tumor types, but existing analysis about FABP5 and FABP5-related molecular mechanism remains limited. Meanwhile, some tumor patients showed limited response rates to current immunotherapy, and more potential targets need to be explored for the improvement of immunotherapy. In this study, we made a pan-cancer analysis of FABP5 based on the clinical data from The Cancer Genome Atlas database for the first time. FABP5 overexpression was observed in many tumor types, and was statistically associated with poor prognosis of several tumor types. Additionally, we further explored FABP5-related miRNAs and corresponding lncRNAs. Then, miR-577-FABP5 regulatory network in kidney renal clear cell carcinoma as well as CD27-AS1/GUSBP11/SNHG16/TTC28-AS1-miR-22-3p-FABP5 competing endogenous RNA regulatory network in liver hepatocellular carcinoma were constructed. Meanwhile, Western Blot and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis were used to verify miR-22-3p-FABP5 relationship in LIHC cell lines. Moreover, the potential relationships of FABP5 with immune infiltration and six immune checkpoints (CD274, CTLA4, HAVCR2, LAG3, PDCD1 and TIGIT) were discovered. Our work not only deepens the understanding of FABP5's functions in multiple tumors and supplements existing FABP5-related mechanisms, but also provides more possibilities for immunotherapy., (© 2023. The Author(s).)

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), but its pathogenic mechanism remains to be explored. The RNA N 6 -methyladenosine (m 6 A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), plays a critical role in the HCC progression. However, the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive. Here, we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection. O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination. Mechanistically, YTHDF2 stabilized minichromosome maintenance protein 2 (MCM2) and MCM5 transcripts in an m 6 A-dependent manner, thus promoting cell cycle progression and HBV-related HCC tumorigenesis. Moreover, targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression. Taken together, our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m 6 A methylation and HCC progression. Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection., (© 2023. The Author(s).)

Estrogen receptor alpha (ESR1) has been implicated in the pathological process of Hepatitis B virus (HBV) infection and is probably an important determinant for gender differences. In this study, a total of 975 subjects including 368 healthy controls, 323 hepatocellular carcinoma (HCC) patients with HBsAg positive, and 284 HBV-infected subjects without HCC were included. Three single nucleotide polymorphisms of ESR1 (rs2234693, rs2077647, rs2228480) were detected to investigate the correlation between ESR1 polymorphisms and the susceptibility to HBV persistence and the clinical outcomes. The association of ESR1 polymorphisms with HCC prognosis was investigated in our cohort enrolling 376 HBV-HCC patients. The frequency of rs2234693 C allele was lower in chronic Hepatitis B (CHB) and liver cirrhosis (LC) than that in HCC patients in the males (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.41-0.96). rs2228480 A allele was associated with increased risk of LC (AOR = 2.20, 95% CI = 1.06-4.56) in HBV genotype C, and significantly decreased the risk of HCC recurrence (p = 0.010) and ESR1 mRNA level in tumor tissues (p = 0.032). Haplotype C-G-G was associated with significantly increased risk of HBV persistence (OR = 1.37, 95% CI = 1.08-1.73), while it was opposite for C-A-G and T-G-G (OR = 0.41, 95% CI = 0.27-0.62; OR = 0.53, 95% CI = 0.32-0.85, respectively). These results imply that combinations of these ESR1 polymorphisms may be valuable for the prediction of HBV persistence., (© 2023 Wiley Periodicals LLC.)

Objective: Hepatoblastoma (HB) tumor rupture is a high-risk criterion in the International Childhood Liver Tumors Strategy Group (SIOPEL) 3/4 protocol. However, the causes and risk factors for HB rupture are still unknown, and whether tumor rupture is an independent risk factor for HB prognosis is still controversial. The purpose of this study was to retrospectively analyze the clinical characteristics of children with HB tumor rupture and to search for clinical risk factors to conduct early prediction and intervention., Methods: We conducted a retrospective study of 27 patients with HB rupture between July 2009 and July 2019. To further identify the risk factors for HB rupture, we included 97 nonruptured HB patients from January 2013 to January 2019. We searched for potentially useful characteristics for HB rupture by univariate and multivariate logistic regression analyses., Results: There were 27 patients with HB rupture, with the median age of 31 (12, 69) months. Nineteen cases (70.37%) were spontaneous tumor rupture, 1 case (3.70%) was posttraumatic rupture, 2 cases (7.41%) were tumor rupture after the biopsy, and 5 cases (18.52%) were tumor rupture after chemotherapy. After the tumor rupture, 4 patients died of hemorrhagic shock and multiple organ dysfunction syndrome (MODS), 4 patients refused further therapy and were discharged against medical advice, and the remaining 19 patients were stable after emergency treatment. After the treatment, 14 patients survived without disease, 2 patients died, and 3 patients were lost to follow-up. The median follow-up was 48 (33, 60) months, the 3-year overall survival (OS) was 54.7%. Compared with the non-tumor rupture group by multivariate logistic regression analysis, it was found that the maximum diameter of the primary tumor > 13.4 cm, and vascular invasion were independent risk factors for tumor rupture., Conclusion: HB rupture is rare, but it seriously threatens the life and health of children. In the acute phase of tumor rupture, surgery, rescue chemotherapy, transcatheter arterial embolization (TAE) and other supportive care can be adopted. Large tumors and vascular invasion are risk factors for HB rupture., Level of Evidence: Level IV., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A drug delivery system (DDS) based on gold-capped mesoporous silica nanoparticles (MSN) is fabricated for loading NOSH-aspirin, a nitric oxide (NO) and hydrogen sulfide (H 2 S) dual-donating cytotoxic molecule. The liver targeting and tumor microenvironment responsive properties of the nanosystem enable, for the first time, the concurrent delivery of NO and H 2 S from a DDS into hepatocellular carcinoma (HCC) cells. Combined gas-radiotherapy (GT-RT) from drug-loaded DDS (NOSH@MSN-Au-Gal) and X-ray irradiation shows highly synergistic anti-cancer activity against both normoxic and hypoxic HCC cells. Further studies revealed that the combined GT-RT not only retains the well-known anticancer mechanism of NO, H 2 S, and X-ray individually, but also alleviates HCC hypoxia via NO- and H 2 S- involved unique pathways. In mice, the GT-RT greatly slows the growth of both subcutaneous and orthotopic HCC tumors and shows high biocompatibility. The current work is expected to promote the clinical application of combined GT-RT as an effective cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: MicroRNA-421 (miR-421) has been implicated in hepatocellular carcinoma (HCC), but its potential mechanism in HCC remains unclear., Objectives: The study aimed to study the potential mechanism of miR-421 in HCC which is necessary., Methods: The downstream target genes of miR-421 were screened in HCC tissues and cells using miDIP, Targetscan, and starBase databases. Differential analysis, survival analysis, and Pearson correlation analysis were performed between miR-421 and its downstream target genes. Quantitative reverse transcription polymerase chain reaction and western blot were used to assay RNA and protein levels of 4-aminobutyrate aminotransferase (ABAT) and epithelial-mesenchymal transition (EMT)-related proteins. Cell-based assays, including CCK-8, wound healing, transwell, flow cytometry, and metabolic measurements, were implemented to assess proliferation, migration, invasion, cell cycle, and apoptosis of HCC cells with different treatments. Dual-luciferase assay was utilized to detect the targeting relationship between miR-421 and ABAT., Results: miR-421 level was elevated in HCC tissues and cells, and low miR-421 expression hindered phenotype progression of HCC cells. ABAT was identified as a direct target of miR-421 in HCC cells, and miR-421 could inhibit ABAT expression. Rescue assay revealed that miR-421 promoted HCC cell tumorigenesis progress and affected cell metabolic remodeling through down-regulating ABAT., Conclusion: The miR-421/ABAT regulatory axis promoted HCC cell tumorigenesis progress, highlighting its potential as a therapeutic target for HCC., (Copyright: © 2023 Permanyer.)

Background: To evaluate the associations between pre-diagnostic levels of serum insulin, glucose and insulin resistance (HOMA-IR) and future risk of incident primary liver cancer (PLC) or chronic liver disease (CLD)-related mortality., Methods: We used a nested case-control design to evaluate subjects over 22 years of follow-up. Glucose, insulin, and three markers of hepatitis B virus (HBV) and hepatitis C virus were measured in fasting baseline serum from 119 incident PLCs, 157 CLD-death cases and 512 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression to estimate the associations between insulin, glucose, HOMA-IR and the risk of PLC or CLD death., Results: Compared with the lowest quartile of insulin, multivariable adjusted models showed that subjects in the highest quartile had elevated odds of developing PLC (OR Q4/Q1  = 2.42, 95% CI = 1.26-4.75, P trend  = 0.007), particularly in HBV-positive subjects (P interaction  = 0.040), and of CLD death (OR Q4/Q1  = 1.80, 95% CI = 1.02-3.21, P trend  = 0.018). For glucose, in the HBV-positive group, subjects in the fourth quartile had an increased risk of PLC (OR Q4/Q1  = 2.18, 95% CI = 1.07-4.60, P trend  = 0.009), and of CLD mortality (OR Q4/Q1  = 1.75, 95% CI = 0.95-3.28, P trend  = 0.019). Subjects with the highest HOMA-IR values had a threefold risk of developing PLC (OR Q4/Q1  = 2.94, 95% CI = 1.54-5.87, P trend  = 0.001), and a twofold risk of CLD death (OR Q4/Q1  = 2.20, 95% CI = 1.25-3.94, P trend  = 0.005)., Conclusions: We found that serum insulin and HOMA-IR could potentially be risk factors for PLC or CLD death., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance., Methods: PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing., Results: Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days, p = 2.28 × 10 -13 ). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness- and epithelial-mesenchymal transition (EMT)-related gene sets were found to be upregulated, whereas liver development- and liver specific molecule-related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis., Conclusions: HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC., (© 2022. Springer Nature Switzerland AG.)

Hepatocellular carcinoma (HCC) is a common high-mortality malignancy which still needs efficient treatments. HCC patients undergoing extrahepatic metastases are mostly with unsatisfactory prognosis. Therefore, specific attention has been paid to extrahepatic HCC metastasis. We integrated Sorafenib (Sor) and glucose oxidase (GOx) into a N-acetyl-galactosamine (GalNAc) modified zeolitic imidazolate framework (ZIF-8), designated as SG@GR-ZIF-8, for targeted bimodal therapies of chemotherapy and starvation therapy against HCC. The hepatic delivery of SG@GR-ZIF was mediated by the specific recognition of GalNAc residues with asialoglycoprotein (ASGPR) on the liver cell surface. Sor is a clinically approved anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. GOx can efficiently induce cell death and disturb malignant progression by suppressing glucose supply of cancer cells, which is highly associated with metabolic rewiring in metastasis. The nano-formulation exhibit significant anti-metastatic HCC activity against C5WN1 cells, a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In a subcutaneous C5WN1-tumor carrying mouse model, SG@GR-ZIF exhibits potent synergistic anti-tumor activity with a tumor inhibition rate of 89% and a prolonged survival status. The growth and pulmonary metastasis of HCC in an orthotopic mouse model of HCC was remarkably suppressed in SG@GR-ZIF treated group. The therapeutic strategy targeting energy supply combined with first-line treatment holds great promise for the future treatment of metastatic HCC. STATEMENT OF SIGNIFICANCE: SG@GR-ZIF, a N-acetyl-galactosamine modified metal-organic framework carrying Sorafenib and glucose oxidase, was fabricated for treating metastatic hepatocellular carcinoma (HCC). Sorafenib is an anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. Glucose oxidase blocks energy demand in HCC metastasis by depleting glucose. C5WN1 was used for therapeutic evaluations as a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In subcutaneous C5WN1-tumor bearing mice, SG@GR-ZIF exhibited a tumor inhibition rate of 89% and prolonged survival period. In orthotopic C5WN1-tumor carrying mice, the growth and pulmonary metastasis of hepatocarcinoma was remarkably suppressed by SG@GR-ZIF. Together, this study suggests the great potential of synergistic chemo/starvation therapy mediated by SG@GR-ZIF for treating metastatic HCC., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Signal transducer and activator of transcription 4 (STAT4) is closely related to liver diseases and affects the processes of inflammation and carcinogenesis by regulating immune responses. A single-nucleotide polymorphism rs7574865 (T > G) in STAT4 has been reported to be associated with the risk of hepatocellular carcinoma (HCC). In addition, hepatitis B virus (HBV) mutations are crucial risk factors for HBV-induced HCC. However, the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC remain unknown. Rs7574865 was genotyped in 846 healthy controls (HCs), 968 chronic hepatitis B (CHB) subjects, 316 liver cirrhosis (LC) subjects and 1021 HCC subjects using Sequenom MassArray. HBV mutations were detected via direct sequencing. Multivariate logistic regression analysis was used to evaluate the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC. We found that the rs7574865 TT genotype was significantly associated with HBeAg seroconversion (TT vs. GG, p = 0.012; TT vs. GT, p = 0.033). The rs7574865 GG genotype was significantly associated with increased risks of CHB (p = 0.048), LC (p = 0.005) and HCC (p < 0.001). The interaction term between rs7574865 and HBV C1913A significantly increased the risk of progression from CHB to HCC (p = 0.038), while the interaction term between rs7574865 and HBV T1674C significantly increased the risk of progression from LC to HCC (p = 0.023). STAT4 rs7574865 is significantly associated with the risks of CHB, LC and HCC. The interactions of rs7574865 with HBV C1913A and T1674C mutations significantly increase the risk of HCC, which have the potential to identify HBV-infected individuals who tend to progress from CHB or LC to HCC., (© 2022 Wiley Periodicals LLC.)

Hepatitis B virus (HBV) infection is a main carcinogenic factor of hepatocellular carcinoma (HCC). TPX2 microtubule nucleation factor is recently recommended as a novel prognostic biomarker in HBV-infected HCC tissues. This study aimed to explore a TPX2-related ceRNA regulatory network in HBV-infected HCC and the potential impact on HCC prognosis. We comprehensively identified 541 differential expressed lncRNAs (DElncRNAs), 37 DEmiRNAs and 439 DEmRNAs from HBV-related TCGA-HCC cohorts in TPX2 low and TPX2 high groups. Based on their RNA-RNA interaction and expression analysis, four DElncRNAs (TRHDE-AS1, DLX6-AS1, SNHG14, HOXA11-AS), four DEmiRNAs (miR-23b, miR-320a, miR-589, miR-126) and five DEmRNAs (PKIA, PCDHA2, SHCBP1, PRSS16, KIF18A) in HCC tumor vs normal groups were subjected to the hub regulatory networks analysis and further prognostic value analysis. Importantly, the TRHDE-AS1/miR-23b/PKIA ceRNA network was associated with HCC prognosis. Furthermore, cellular location analysis and base-base interaction analysis indicated that the cytoplasmic lncRNA TRHDE-AS1 was regarded as a ceRNA to sponging miR-23b and then regulating PKIA. Interestingly, correlation analysis suggested the expression correlation between TRHDE-AS1 and PKIA in HCC. Finally, we further performed the methylation and immune infiltration analysis to explore the functional process of PKIA in HCC. We proposed a ceRNA regulatory network may help elucidate the mechanism by which TPX2 contributes to the prognosis of HBV-related HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wang, Chen, Yin, Mo, Sun, Yang, Zhang, Zhai, Li, Chen, Dai, Wang and Ma.)

Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies across the world. The annual incidence and death rates have increased at the highest rate of all cancers in recent years. Surgical resection is a potentially curative option for solitary HCC or unilobar disease without evidence of metastases or vascular invasion. This study focuses on the molecular differences between the HCC foci and paracancerous tissues and provides some valuable biomarkers based on the vibrational spectrum. Fourier transform infrared (FTIR) spectroscopy is a non-invasive and qualitative and semi-quantitative analysis technique that has been widely applied for the identification of macromolecular changes in biological tissues. In this study, the FTIR spectra of the HCC foci and the paracancerous tissues were recorded separately, and ten areas under the absorption peaks of all the specimens were calculated. The result demonstrates that the areas of protein-related absorption peaks at 1398 cm -1 , 1548 cm -1 , 1654 cm -1 and 3070 cm -1 may be the key indicators of the two different regions. After coupling with the classification algorithms of k -nearest neighbor (KNN), random forest (RF) and support vector machine (SVM), it was found that SVM with an RBF kernel performed best with the AUC (area under the ROC curve) reaching 0.997, and the performance was better than the feature based on the full spectrum. This reveals that the peak area-based FTIR spectra combined with the SVM algorithm may be a promising tool in identifying the HCC foci and the paracancerous tissues.

Very limited treatment options are available to fight hepatocellular carcinoma (HCC), a serious global health concern with high morbidity and mortality. The integration of multiple therapies into one nanoplatform to exert synergistic therapeutic effects offers advantages over monotherapies. Here, we describe the construction of the nanoplatform Sor@GR-COF-366 for synergistic chemotherapy and photodynamic therapy (PDT) for HCC using a porphyrin-based covalent organic framework (COF-366) coated with N-acetyl-galactosamine (GalNAc) and rhodamine B (RhB), and loaded with the first-line agent, Sorafenib (Sor). The nanoplatform is targeted towards ASGPR-overexpressed HCC cells and liver tissues by GalNAc and observed by real-time imaging of RhB in vitro and in vivo. The nanoplatform Sor@GR-COF-366 exerts an enhanced synergistic tumor suppression effect in a subcutaneous HCC mouse model with a tumor inhibition rate (TGI) of 97% while significantly prolonging survival at very low toxicity. The potent synergistic therapeutic outcome is confirmed in an orthotopic mouse model of HCC with the TGI of 98% with a minimally invasive interventional PDT (IPDT). Sor@GR-COF-366 is a promising candidate to be combined with chemo-IPDT for the treatment of HCC. STATEMENT OF SIGNIFICANCE: This work describes the construction of covalent-organic frameworks (COFs) modified with glyco-moieties to serve as hepato-targeted multitherapy delivery systems. They combine minimally invasive interventional photodynamic therapy (IPDT) triggered synergism with chemotherapy treatment for hepatocellular carcinoma (HCC). With the aid of minimally invasive intervention, PDT can elicit potent anti-cancer activity for deep solid tumors. This platform shows strong therapeutic outcomes in both subcutaneous and orthotopic mouse models, which can significantly prolong survival. This work showed an effective combination of a biomedical nano-formulation with the clinical operational means in cancer treatment, which is greatly promising in clinical translation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Serum iron is associated with the risk of several diseases. However, limited prospective studies have been performed between serum iron and the subsequent risk of chronic liver disease (CLD) and primary liver cancer (PLC) incidence., Methods: We performed a nested case-control study using data from the Linxian Nutrition Intervention Trials among participants who developed PLC incidence or died from CLD over 22-years of follow-up. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the risk of PLC incidence or CLD death in different quintile of baseline serum iron using logistic regression., Results: Individuals with serum iron in the highest quintile, compared to those in the second quintile (the reference), had an increased risk of CLD mortality (OR=2.02, 95% CI=1.27-3.27, P trend =0.011). The association was stronger among HCV-positive participants (P interaction =0.005). For PLC incidence, the risk estimates were above one, but not statistically significant (all P > 0.05)., Conclusions: A significant positive association was found between serum iron and the risk of CLD-related mortality, especially in HCV-positive subjects. Our results suggest that serum iron plays a risk role in CLD death but not in PLC incidence., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68 Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10 -5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10 -6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUV max (median [range] 9.2 [4.9-28.4]), SUV mean 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Accumulating evidence has demonstrated that M2 macrophages contribute to the progression of hepatocellular carcinoma (HCC). Emodin is an anti-tumor agent and potentially regulates macrophage polarization. This study aims to explore the effect of emodin on M2 polarization in HCC and its underlying mechanism. After co-culture systems of M2 macrophages and HCC (HepG2 and Huh7) cells were established, it was shown that co-culture with M2 macrophages could promote both the proliferation and invasion of HepG2 and Huh7 cells. Emodin induces the transformation of M2 to M1 macrophages, thereby inhibiting the proliferation and invasion of HepG2 and Huh7 cells mediated by co-culturing with M2 macrophages. Based on bioinformatics analysis and in vitro validation, it was found that the effect of emodin on M2 polarization was regulated by the microRNA-26a (miR-26)/Transforming growth factor beta 1 (TGF-β1)/Protein kinase B (Akt) axis. In vivo analysis showed that co-culturing with M2 macrophages markedly facilitated the growth of HepG2 cells, which was significantly inhibited by emodin. Western blot analysis on xenografts confirmed that emodin could induce transformation of M2 to M1 macrophages and reverse the up-regulation of PCNA, TGF-β1, and p-Akt induced by M2 macrophages. In summary, our findings uncover a novel mechanism behind the anti-tumor effects of emodin that regulates M2 polarization via miR-26a/TGF-β1/Akt to suppress HCC growth.

Introduction: TRIpartite motif (TRIM) proteins are important members of the Really Interesting New Gene-finger-containing E3 ubiquitin-conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). However, the diverse expression patterns of TRIMs and their roles in prognosis and immune infiltrates in HCC have yet to be analyzed., Materials: Combined with previous research, we used an Oncomine database and the Human Protein Atlas to compare TRIM family genes' transcriptional levels between tumor samples and normal liver tissues, as verified by the Gene Expression Profiling Interactive Analysis database. We investigated the patient survival data of TRIMs from the Kaplan-Meier plotter database. Clinicopathologic characteristics associations and potential diagnostic and prognostic values were validated with clinical and expressional data collected from the cancer genome atlas., Results: We identified TRIM28, TRIM37, TRIM45, and TRIM59 as high-priority members of the TRIMs family that modulates HCC. Low expression of TRIM28 was associated with shorter overall survival (OS) than high expression (log-rank p = 0.009). The same trend was identified for TRIM37 (p = 0.001), TRIM45 (p = 0.013), and TRIM59 (p = 0.011). Multivariate analysis indicated that the level of TRIM37 was a significant independent prognostic factor for both OS (p = 0.043) and progression-free interval (p = 0.044). We performed expression and mutation analysis and functional pathways and tumor immune infiltration analysis of the changes in TRIM factors., Conclusion: These data suggested that TRIM28, TRIM37, TRIM45, and TRIM59 could serve as efficient prognostic biomarkers and therapeutic targets in HCC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. However, enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Here we conduct a genome-wide survey of HCC-susceptible enhancer variants through a three-stage association study in 11,958 individuals and identify rs73613962 (T > G) within the intronic region of PRMT7 at 16q22.1 as a susceptibility locus of HCC (OR = 1.41, P = 6.02 × 10 -10 ). An enhancer dual-luciferase assay indicates that the rs73613962-harboring region has allele-specific enhancer activity. CRISPR-Cas9/dCas9 experiments further support the enhancer activity of this region to regulate PRMT7 expression. Mechanistically, transcription factor HNF4A binds to this enhancer region, with preference to the risk allele G, to promote PRMT7 expression. PRMT7 upregulation contributes to in vitro, in vivo, and clinical HCC-associated phenotypes, possibly by affecting the p53 signaling pathway. This concept of HCC pathogenesis may open a promising window for HCC prevention/treatment., (© 2022. The Author(s).)

Background: Liver cancer is one of the most common malignant tumors in the world. T cell-mediated antitumor immune response is the basis of liver cancer immunotherapy., Objective: To screen and analyze the RNAs associated with activated memory CD4 T cells and CD8 T cells in liver cancer., Methods: ESTIMATE was used to calculate the stromal and immune scores of tumor samples, which were downloaded from The Cancer Genome Atlas (TCGA). The differentially expressed genes (DEGs) in high and low stromal and immune scores were screened, followed by functional enrichment of overlapped DEGs. We then conducted a survival analysis to identify immune-related prognostic indicators and constructed protein-protein interaction (PPI) networks and ceRNA networks. Finally, chemical small-molecule-target interaction pairs associated with liver cancer were screened., Results: A total of 55,955 stromal-related DEGs and 1811 immune-related DEGs were obtained. The 1238 overlapped DEGs were enriched in 1457 biological process terms and 74 KEGG pathways. In addition, a total of 120 activated memory CD4 T cell-related genes and 309 CD8 T cell-related genes were identified. The survival analysis revealed that upregulated expression of T cell-related genes including EOMES, CST7, and CD5L indicated the favorable prognosis of liver cancer. EOMES was regulated by has-miR-23b-3p and has-miR-23b-3p was regulated by lncRNA AC104820.2 in the ceRNA network of activated memory CD4 T cell-related genes. In addition, EOMES was regulated by has-miR-23a-3p and has-miR-23a-3p was regulated by lncRNA AC000476.1 in the ceRNA network of CD8 T cells., Conclusion: T cell-related RNAs EOMES, CST7, CD5L, has-miR-23b-3p, and has-miR-23a-3p may be associated with the prognosis of liver cancer. And the molecular characteristics of these T cell-related genes were plotted., (© 2021. The Author(s).)

Beta-catenin (CTNNB1) is commonly mutated in hepatocellular carcinoma (HCC). CTNNB1-mutated HCC has important clinical correlates, such as being immune cold and less likely to respond to immune checkpoint inhibitor therapies. It remains unclear, however, if they are a morphologically homogenous group of tumors. To better understand the association between the morphology, CTNNB1 mutations, and other molecular features, a detailed study of 338 The Cancer Genome Atlas cases was performed. A characteristic histological morphology was strongly associated with CTNNB1 mutations but was present in only 58% of CTNNB1-mutated HCCs. Tumors with APC mutations tended to have the classic morphology; those with AXIN mutations did not. Pseudoglands are a key feature of the classic morphology, and they were associated with CTNNB1 mutations, male gender, specific CTNNB1 mutation site, and lack of TP53 mutations. Differential gene expression analysis stratified by the presence/absence of pseudoglands identified 60 differentially expressed genes (FDR <5%); clustering according to these differentially expressed genes revealed three groups of tumors, one with pseudoglands and a strong association with genes regulated by Wnt signaling; within this group, TP53 mutations were associated with a loss of the typical morphology of CTNNB1-mutated HCCs. When stratified by gender, further differential gene expression showed Wnt-regulated genes were associated with pseudoglands in men but not women. These findings indicate HCC with CTNNB1 mutations are morphologically heterogeneous, with gene penetrance for morphology dependent in part on gender, specific CTNNB1 mutations, and co-occurring TP53 mutations. This heterogeneity has important implications for the classification of HCC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the digestive system. Abnormal miR-373-3p and TFAP4 expressions are critical in many malignant tumors, but it is unclear whether they work in the context of HCC. qRT-PCR measured miR-373-3p expression in HCC tissues and adjacent normal tissues. Flow cytometry and Western blot analyzed cell apoptosis. EMT, Transwell, and wound healing assay examined HCC cell migration and EMT, respectively. Western blot determined the profile of TFAP4/PI3K/AKT. IHC detected Ki67, E-cadherin, and vimentin in the tumor tissues. Moreover, the downstream target of miR-373-3p was predicted using the database. Dual luciferase activity assay and RIP verified the binding correlation between TFAP4 and miR-373-3p. In HCC tissues and cell lines, miR-373-3p was downregulated, and its overexpression stepped up HCC cell apoptosis and suppressed migration and EMT. Furthermore, miR-373-3p overexpression elevated Bax and caspase 3 expressions and attenuated Bcl2's level. A xenograft tumor experiment in nude mice unveiled that miR-373-3p overexpression dampened tumor growth and proliferation. miR-373-3p cramped PI3K/AKT pathway activation. miR-373-3p negatively modulated TFAP4, and TFAP4 overexpression inverted miR-373-3p-mediated anti-tumor effects. Additionally, TFAP4 enhanced IGF1 expression, and promoted IGF1R-PI3K/AKT pathway activation. Collectively, miR-373-3p functions as an anti-tumor gene in HCC by inhibiting TFAP4/PI3K/AKT pathway.

Background and Aim: Previous studies suggest that serum ferritin may be associated with higher risk of liver cancer. However, additional studies of the association are needed. It is also not clear whether serum ferritin is associated with mortality from chronic liver disease (CLD)., Methods: We performed a nested case-control study in the Linxian Nutrition Intervention Trials. Baseline serum ferritin was measured for 226 incident primary liver cancer cases, 281 CLD mortalities diagnosed, and 1061 age-matched, gender-matched, and trial-matched controls. We used multivariable logistic regression models to calculate odds ratios and 95% confidence intervals. Subgroup analysis and interaction tests were performed by age, gender, alcohol drinking, hepatitis B virus seropositivity (HBV+)/hepatitis C virus seropositivity (HCV+), and trial., Results: Participants with serum ferritin in the highest quartile, as compared with those in the lowest quartile, had an increased risk of CLD mortality (odds ratio = 1.72, 95% confidence interval = 1.12, 2.64, P-trend < 0.01). Moreover, the association with higher serum ferritin was stronger among alcohol drinkers and those who were HCV+ (P-interaction < 0.05). For incident liver cancer, risk estimates were above one but were not statistically significant., Conclusion: In this study, higher levels of serum ferritin at baseline were associated with subsequent mortality from CLD, particularly if combined with alcohol drinking or viral hepatitis. Further work is warranted to confirm our findings., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide due to its high degree of malignancy, high incidence, and low survival rate. However, the underlying mechanisms of hepatocarcinogenesis remain unclear. Long non coding RNA (lncRNA) has been shown as a novel type of RNA. lncRNA by acting as ceRNA can participate in various biological processes of HCC cells, such as tumor cell proliferation, migration, invasion, apoptosis and drug resistance by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can predict the efficacy of treatment strategies for HCC and serve as a potential target for the diagnosis and treatment of HCC. Therefore, lncRNA serving as ceRNA may become a vital candidate biomarker for clinical diagnosis and treatment. In this review, the epidemiology of HCC, including morbidity, mortality, regional distribution, risk factors, and current treatment advances, was briefly discussed, and some biological functions of lncRNA in HCC were summarized with emphasis on the molecular mechanism and clinical application of lncRNA-mediated ceRNA regulatory network in HCC. This paper can contribute to the better understanding of the mechanism of the influence of lncRNA-mediated ceRNA networks (ceRNETs) on HCC and provide directions and strategies for future studies., (© 2021. The Author(s).)

Background: The long-term trend in cancer death in a rapidly developing country provides information for cancer prophylaxis. Here, we aimed to identify the trends in cancer mortality in China during the 2004-2018 period., Methods: Using raw data from the national mortality surveillance system of China, we assessed the mortalities of all cancer and site-specific cancers during the 2004-2018 period. The participants were divided into three age groups: ≥65 years, 40-64 years, and ≤39 years. Changing trends in cancer death by gender, residency, and tumor location were estimated using fitting joinpoint models to log-transformed crude mortality rates (CMRs) and age-standardized mortality rates (ASMRs)., Results: Cancer death accounted for 24% of all-cause of death in China during 2014-2018. The CMR of all cancer was 150.0 per 100,000 persons. Cancer was the leading cause of death in the population <65 years. The six major cancer types (lung/bronchus cancer, liver cancer, stomach cancer, esophagus cancer, colorectal cancer, and pancreas cancer) accounted for 75.85% of all cancer deaths. The CMR of all cancer increased while the ASMR decreased during 2014-2018 (P < 0.001). Lung/bronchus cancer and liver cancer were the leading causes of cancer death in the population <65 years, accounting for 45.31% (CMR) and 44.35% (ASMR) of all cancer death, respectively. The ASMR of liver cancer was higher in the 40-64 years population than in the ≥65 years population, in contrast to the other five major cancers. The ASMRs of liver cancer, stomach cancer, and esophagus cancer decreased although they were higher in rural residents than in urban residents; the ASMRs of lung/bronchus cancer, colorectal cancer, and pancreas cancer increased in rural residents although they were higher in urban residents than in rural residents during 2014-2018., Conclusion: Although the ASMR of all cancer decreased in China during 2004-2018, lung/bronchus cancer and liver cancer remained the leading causes of cancer-related premature death. Lung/bronchus cancer, colorectal cancer, and pancreas cancer increased in rural residents., (© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: Hepatitis B virus (HBV) variants in the preS region have been associated with hepatocellular carcinoma (HCC). However, the effect of the preS variants on HCC prognosis remains largely unknown. We aimed to identify the preS variants that reliably predict postoperative prognosis in HCC., Methods: RNA-seq data of 203 HCC patients retrieved from public database were screened for the preS variants related to HCC prognosis. The variants in the sera and tumors were then validated in our prospective cohort enrolling 103 HBV-associated HCC patients., Results: By analyzing prognosis-related gene sets in the RNA-seq data, 12 HBV preS variants were associated with HCC recurrence. Of those, G40C and C147T in the sera predicted an unfavorable recurrence-free survival in our cohort (hazard ratio [HR]=2.18, 95% confidence interval [CI]=1.37-3.47, p =0.001 for G40C; HR=1.84, 95% CI=1.15-2.92, p =0.012 for C147T). G40C and C147T were significantly associated with microscopic vascular invasion, larger tumor size, and abnormal liver function. Multivariate Cox regression analysis showed that G40C significantly increased the risk of HCC recurrence in patients with postoperative antiviral treatment. The HCC prognosis-prediction model consisting of α-fetoprotein and G40C in the sera achieved the best performance (sensitivity=0.80, specificity=0.70, and area under the curve=0.79). Functional analysis indicated that these two variants were associated with cell proliferation, chromosome instability, carcinogenesis, metastasis, and anticancer drug resistance., Conclusions: G40C and C147T are serological biomarkers for HCC prognosis and the prognostic model consisting of serological α-fetoprotein and G40C achieved the best performance in predicting postoperative prognosis.

The lack of cancer cell specificity and the occurrence of multidrug resistance (MDR) are two major obstacles in the treatment of hepatocellular carcinoma (HCC). To tackle these challenges, a novel nanoparticle (NP)-based drug delivery system (DDS) with a core/shell structure consisted of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-galactose (Gal)/polydopamine (PDA) is fabricated. The NP is loaded with doxorubicin (DOX) and a nitric oxide (NO) donor N , N '-di- sec -butyl- N , N '-dinitroso-1,4-phenylenediamine (BNN) sensitive to heat to afford NO-DOX@PDA-TPGS-Gal. The unique binding of Gal to asialoglycoprotein receptor (ASGPR) and the pH-sensitive degradation of NP ensure the targeted transportation of NP into liver cells and the release of DOX in HCC cells. The near-infrared (NIR) light further facilitates DOX release and initiates NO generation from BNN due to the photothermal property of PDA. In addition to the cytotoxicity contributed by DOX, NO, and heat, TPGS and NO act as MDR reversal agents to inhibit P-glycoprotein (P-gp)-related efflux of DOX by HepG2/ADR cells. The combined chemo-photothermal therapy (chemo-PTT) by NO-DOX@PDA-TPGS-Gal thus shows potent anti-cancer activity against drug-resistant HCC cells in vitro and in vivo and significantly prolongs the life span of drug-resistant tumor-bearing mice. The present work provides a useful strategy for highly targeted and MDR reversal treatment of HCC.

REC8 is a member of the cohesin family, and its abnormal activation has been detected in cancer cells. This study explored the role and possible mechanism of REC8 in hepatocellular carcinoma (HCC). A total of 40 pairs of HCC and adjacent tissues were collected, and the clinical significance of REC8 expression in HCC was evaluated. REC8 expression in human HCC tissues and HCC cell lines was investigated by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The biological functions of REC8 in HCC cell lines were detected by wound-healing assay, Matrigel invasion assay and tube formation assay. The proteins interacting with REC8 were identified by mass spectrometry after immunoprecipitation screening. There was a correlation between the high expression of REC8 and positive alpha-fetoprotein levels. The expression level of REC8 protein in HCC tissues was higher than that in adjacent tissues. REC8 has mainly located in the nucleus of HCC tissue cells and HCC cell lines, but it was expressed in the cytoplasm of adjacent normal tissue cells and hepatocytes. The results of wound healing, transwell invasion and tubular formation assays indicated that the overexpression of REC8 accelerated the metastasis of HCC in vitro; however, metastasis was suppressed after REC8 was silenced by small interference RNA. A total of 57 differentially expressed proteins were identified by mass spectrometry, and it was found that REC8 and PKA RII-α staining was colocalized in the nucleus. The expression levels of MMP-9 and VEGF-C were decreased after treatment with the PKA inhibitor H89. Overall, REC8 promotes the migration, invasion and angiogenesis of HCC cells through the PKA pathway.

Aim: Hepatocellular carcinoma (HCC) is considered to be the third leading cause of cancer death. The homologous gene of TP53 is significant in the occurrence and development of cancer. This study explored the relationship between TP53 rs28934571 polymorphism and HCC risk in Guangxi, China. Materials & methods: We first screened the association through bioinformatics. Additionally, a case-control study was performed to further verify the relationship between gene polymorphism and HCC risk after collecting clinical characteristics. Results: Results showed that allele A on TP53 rs28934571 was a risk factor for HCC and mutation from C to A on TP53 rs28934571 would increase the risk of poor prognosis of HCC. Conclusion: Therefore, the study concluded that TP53 rs28934571 may become a diagnostic indicator in judging the prognosis of HCC.

Background and Aims: Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers., Approach and Results: To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with VI using the multiplatform cancer genome atlas (The Cancer Genome Atlas; TCGA) data (n = 373). In the TCGA Liver Hepatocellular Carcinoma cohort, macrovascular invasion was present in 5% (n = 17) of tumors and microvascular invasion in 25% (n = 94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA, and proteomic changes in VI. We performed comparative proteomic analyses of invasive human HCC and MYC-driven murine HCC and identified fibronectin to be a proteomic biomarker of invasive HCC (mouse fibronectin 1 [Fn1], P = 1.7 × 10 -11 ; human FN1, P = 1.5 × 10 -4 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n = 153; P < 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n = 35; mean = 307.7 μg/mL; SEM = 35.9) when compared to cirrhosis (n = 10; mean = 41.8 μg/mL; SEM = 13.3; P < 0.0001)., Conclusions: Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up-regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC., (© 2020 by the American Association for the Study of Liver Diseases.)

Recent studies have illustrated the role of aberrant regulatory interactions in the mediation of malignant phenotypes of cancer cells, which could potentially provide novel therapeutic targets to limit the destructive recurrence and metastasis of hepatocellular carcinoma (HCC). Herein, we clarify the oncogenic role of the long noncoding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) in HCC in vivo and in vitro. To this end, we knocked down lncRNA DLX6-AS1 and manipulated the expression of miR-513c to characterize their effects in HCC cell viability, migration, invasion, and apoptosis. Furthermore, we probed the interactions with miR-513c's target gene Cullin4A (Cul4A) and the degradation of Annexin A10 (ANXA10) protein. Our data show that lncRNA DLX6-AS1 and Cul4A were highly expressed, while miR-513c and ANXA10 were poorly expressed in HCC tissues and cells. Moreover, the silencing of lncRNA DLX6-AS1 impeded the viability, invasion, and migration of HCC cells, while stimulating cell apoptosis. Further data indicated that lncRNA DLX6-AS1 targeted and repressed miR-513c expression, where the tumor-inhibiting effects of lncRNA DLX6-AS1 silencing was achieved by elevating miR-513c expression. Importantly, the lncRNA DLX6-AS1 upregulated the expression of Cul4A through sponging of miR-513c. The silencing of Cul4A restricted the malignant phenotypes of HCC cells by repressing the ubiquitination-mediated degradation of ANXA10. In vivo experiments verified that lncRNA DLX6-AS1 promoted the progression of HCC through the miR-513c/Cul4A/ANXA10 axis. Thus, the silencing of lncRNA DLX6-AS1 impaired miR-513c-dependent Cul4A inhibition and subsequently elevated ubiquitination-mediated degradation of ANXA10, thereby preventing the occurrence and development of HCC.

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011-15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide. One major obstacle to treatment is a lack of effective molecular-targeted therapies. In this study, we find that EphA2 expression and signaling are enriched in human HCC and associated with poor prognosis. Loss of EphA2 suppresses the initiation and growth of HCC both in vitro and in vivo. Furthermore, CRISPR/CAS9-mediated EphA2 inhibition significantly delays tumor development in a genetically engineered murine model of HCC. Mechanistically, we discover that targeting EphA2 suppresses both AKT and JAK1/STAT3 signaling, two separate oncogenic pathways in HCC. We also identify a small molecule kinase inhibitor of EphA2 that suppresses tumor progression in a murine HCC model. Together, our results suggest EphA2 as a promising therapeutic target for HCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Long extracellular RNAs (exRNAs) in plasma can be profiled by new sequencing technologies, even with low abundance. However, cancer-related exRNAs and their variations remain understudied. Methods: We investigated different variations (i.e. differential expression, alternative splicing, alternative polyadenylation, and differential editing) in diverse long exRNA species (e.g. long noncoding RNAs and circular RNAs) using 79 plasma exosomal RNA-seq (exoRNA-seq) datasets of multiple cancer types. We then integrated 53 exoRNA-seq datasets and 65 self-profiled cell-free RNA-seq (cfRNA-seq) datasets to identify recurrent variations in liver cancer patients. We further combined TCGA tissue RNA-seq datasets and validated biomarker candidates by RT-qPCR in an individual cohort of more than 100 plasma samples. Finally, we used machine learning models to identify a signature of 3 noncoding RNAs for the detection of liver cancer. Results: We found that different types of RNA variations identified from exoRNA-seq data were enriched in pathways related to tumorigenesis and metastasis, immune, and metabolism, suggesting that cancer signals can be detected from long exRNAs. Subsequently, we identified more than 100 recurrent variations in plasma from liver cancer patients by integrating exoRNA-seq and cfRNA-seq datasets. From these datasets, 5 significantly up-regulated long exRNAs were confirmed by TCGA data and validated by RT-qPCR in an independent cohort. When using machine learning models to combine two of these validated circular and structured RNAs ( SNORD3B-1, circ-0080695 ) with a miRNA ( miR-122 ) as a panel to classify liver cancer patients from healthy donors, the average AUROC of the cross-validation was 89.4%. The selected 3-RNA panel successfully detected 79.2% AFP-negative samples and 77.1% early-stage liver cancer samples in the testing and validation sets. Conclusions: Our study revealed that different types of RNA variations related to cancer can be detected in plasma and identified a 3-RNA detection panel for liver cancer, especially for AFP-negative and early-stage patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Hepatocellular carcinoma (HCC) is a type of common cancer, often accompanied by tumor recurrence and metastasis after surgery with poor prognosis. Therefore, searching into potential biomarkers that can effectively predict the prognosis and progression of HCC is crucial. In this study, we identified 1,981 differentially expressed genes (DEGs) using mRNA expression profiles from the TCGA-LIHC dataset. Subsequently, weighted gene co-expression network analysis found that the turquoise module closely associated with the pathological grade and clinical stage of HCC was identified. Then, from the key genes in the turquoise module and protein-protein interaction network analysis, 13 hub genes significantly related to the prognosis of HCC were screened. Through co-expression and functional enrichment analyses, these 13 hub genes were found to play an important role in mitosis. Finally, we evaluated the relationship between these hub genes and overall survival and disease-free survival through survival analysis. The result indicated that HCC patients with high hub gene expression had a poorer prognosis than HCC patients with low expression. Receiver operating characteristic curves showed that each hub gene could predict the prognosis of HCC patients. In summary, a total of 13 hub genes were identified that play an important role in the progression of HCC, which can be used as potential biomarkers for HCC patients.

Objective: This study aims to explore the mechanism of the miR-424-5p/E2F7 axis in hepatocellular carcinoma (HCC) and provide new ideas for targeted therapy of HCC., Methods: Bioinformatics analysis was used to identify the target differentially expressed miRNA in HCC and predict its target gene. qRT-PCR was employed to verify the expression of miR-424-5p and E2F7 mRNA in HCC cells. Western blot was performed to detect the effect of miR-424-5p ectopic expression on the protein expression of E2F7. CCK-8 was used to detect proliferative activity of HCC cells and flow cytometry was carried out for analyzing cell cycle distribution. Dual luciferase reporter assay was conducted to verify the direct targeting relationship between miR-424-5p and E2F7., Results: We observed that miR-424-5p was down-regulated in HCC cells. CCK-8 showed that overexpression of miR-424-5p inhibited cell proliferation, and flow cytometry showed that miR-424-5p could block cells in G0/G1 phase. E2F7 was up-regulated in HCC cells, and E2F7 overexpression could facilitate the proliferative ability of HCC cells and promote the cell cycle progressing from G0/G1 to S phase. Furthermore, dual-luciferase reporter assay indicated that miR-424-5p could directly down-regulate E2F7 expression. Analysis on cell function demonstrated that miR-424-5p inhibited the proliferation of HCC cells and blocked cell cycle at G0/G1 phase by targeting E2F7., Conclusion: Our results proved that E2F7 was a direct target of miR-424-5p, and miR-424-5p could regulate cell cycle and further inhibit the proliferation of HCC cells by targeting E2F7., Competing Interests: The authors have declared that no competing interests exist.