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Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer. Accurate preoperative prediction of histological grade holds potential for improving clinical management and disease prognostication., Purpose: To evaluate the performance of a radiomics signature based on multiphase MRI in assessing histological grade in solitary HCC., Study Type: Retrospective., Subjects: A total of 405 patients with histopathologically confirmed solitary HCC and with liver gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI within 1 month of surgery., Field Strength/sequence: Contrast-enhanced T1-weighted spoiled gradient echo sequence (LAVA) at 1.5 or 3.0 T., Assessment: Tumors were graded (low/high) according to results of histopathology. Basic clinical characteristics (including age, gender, serum alpha-fetoprotein (AFP) level, history of hepatitis B, and cirrhosis) were collected and tumor size measured. Radiomics features were extracted from Gd-EOB-DTPA-enhanced MRI data. Three feature selection strategies were employed sequentially to identify the optimal features: SelectFromModel (SFM), SelectPercentile (SP), and recursive feature elimination with cross-validation (RFECV). Probabilities of five single-phase radiomics-based models were averaged to generate a radiomics signature. A combined model was built by combining the radiomics signature and clinical predictors., Statistical Tests: Pearson χ 2 test/Fisher exact test, Wilcoxon rank sum test, interclass correlation coefficient (ICC), univariable/multivariable logistic regression analysis, area under the receiver operating characteristic (ROC) curve (AUC), DeLong test, calibration curve, Brier score, decision curve, Kaplan-Meier curve, and log-rank test. A P-value <0.05 was considered statistically significant., Results: High-grade HCCs were present in 33.8% of cases. AFP levels (odds ratio [OR] 1.89) and tumor size (>5 cm; OR 2.33) were significantly associated with HCC grade. The combined model had excellent performance in assessing HCC grade in the test dataset (AUC: 0.801), and demonstrated satisfactory calibration and clinical utility., Data Conclusion: A model that combined a radiomics signature derived from preoperative multiphase Gd-EOB-DTPA-enhanced MRI and clinical predictors showed good performance in assessing HCC grade., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 5., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy with a high mortality rate worldwide. Suppressor of cytokine signaling (SOCS) family members play important roles in the proliferation, metabolism, and immunity of HCC cells by regulating cytokines and growth factors. However, it remains uncertain whether the level of SOCS family members can affect the prognosis of HCC patients., Aims: This study aimed to comprehensively assess the role and mechanisms of SOCS family members in the development of HCC and to guide clinical selection., Methods: We investigated the expression levels of SOCS family genes in HCC patients and their associations with various clinicopathological characteristics. We also utilized a public database to analyze the changes in the expression, potential functions, transcription factors, and immune invasion of SOCS family members. Additionally, we examined the prognostic value of the SOC family for HCC and its correlation with the SOC family and ferroptosis-related genes., Results: This study revealed that the expression of SOCS2-7, and CISH was downregulated in HCC. The SOCS4, SOCS5, and SOCS7 genes were associated with the clinicopathological features of HCC patients. SOCS family genes are mainly related to the PIK3R3, GHR, and TNS4 pathways. Additionally, this study revealed that STAT3, PPAR-gamma 2, and IRF-2 are important transcription factors that regulate SOCS family members. The expression levels of SOCS family members are closely related to immune infiltration in liver cancer. The study also indicated that SOCS2 and SOCS4 are risk-related genes for predicting the prognosis of patients with liver cancer. Finally, this study suggested that the SOCS2 gene may be involved in the development and progression of HCC., Conclusion: Our study enhances the current understanding of SOCS gene function in liver cancer and can help clinicians select appropriate drugs and predict the prognosis of HCC patients., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Background and Aims: Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs., Approach and Results: We found that HOIL-1, but not the other components of LUBAC, played a contributing role in LUBAC-mediated HCC sorafenib resistance, independent of its ubiquitin ligase activity. Both in vitro and in vivo assays revealed that the upregulated HOIL-1 expression enhanced the CSC properties of HCC. Mechanistically, HOIL-1 promoted sorafenib resistance and the CSC properties of HCC through Notch1 signaling. Mass spectrometry, co-immunoprecipitation, western blot, and immunofluorescence were used to determine that the A64/Q65 residues of HOIL-1 bound with the K78 residue of Numb, resulting in impaired Numb-mediated Notch1 lysosomal degradation. Notably, pixantrone was screened out by Autodock Vina, which was validated to disrupt HOIL-1/Numb interaction to inhibit Notch1 signaling and CSC properties by targeting the Q65 residue of HOIL-1. Moreover, pixantrone exerted synergistic effects with sorafenib for the treatment of HCC in different HCC mouse models., Conclusions: HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Cancer cells often exhibit fragmented mitochondria and dysregulated mitochondrial dynamics, but the underlying mechanism remains elusive. Here, we found that the mitochondrial protein death-associated protein 3 (DAP3) is localized to mitochondria and promotes the progression of hepatocellular carcinoma (HCC) by regulating mitochondrial function. DAP3 can promote the proliferation, migration, and invasion of HCC cells in vitro and in vivo by increasing mitochondrial respiration, inducing the epithelial-mesenchymal transition (EMT), and slowing cellular senescence. Mechanistically, DAP3 can increase mitochondrial complex I activity in HCC cells by regulating the translation and expression of MT-ND5. The phosphorylation of DAP3 at Ser185 mediated by AKT is the key event mediating the mitochondrial localization and function of DAP3 in HCC cells. In addition, the DAP3 expression in HCC samples is inversely correlated with patient survival. Our results revealed a mechanism by which DAP3 promotes mitochondrial function and HCC progression by regulating MT-ND5 translation and expression, indicating that DAP3 may be a therapeutic target for HCC., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na + /H + exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na + /H + exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na + /H + exchange., (© 2024 Wiley Periodicals LLC.)

Introduction: Patients with liver cancer are susceptible to experiencing a decline in muscle mass and function, which can lead to physical frailty and have a negative impact on prognosis. However, there is currently a lack of physical activity interventions specifically tailored for these patients. Therefore, we have developed a modular multimodal hospital-home chain physical activity rehabilitation programme (3M2H-PARP) designed specifically for patients with liver cancer undergoing transarterial chemoembolisation (TACE). We aim to validate the effectiveness and feasibility of this programme through a randomised controlled trial (RCT)., Methods and Analysis: 3M2H-PARP RCT will compare a 12-week, modular, multimodal physical activity rehabilitation programme that includes supervised exercise in a hospital setting and self-management exercise at home. The programmes consist of aerobic, resistance, flexibility and balance exercise modules, and standard survivorship care in a cohort of liver cancer survivors who have undergone TACE. The control group will receive standard care. A total of 152 participants will be randomly assigned to either the 3M2H-PARP group or the control group. Assessments will be conducted at three time points: baseline, after completing the intervention and a 24-week follow-up visit. The following variables will be evaluated: liver frailty index, Functional Assessment of Cancer Therapy-Hepatobiliary subscale, Cancer Fatigue Scale, Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale and physical activity level. After the completion of the training programme, semi-structured interviews will be conducted with participants from the 3M2H-PARP group to investigate the programme's impact on their overall well-being. SPSS V.26.0 software will be used for statistical analyses., Ethics and Dissemination: Ethical approval has been granted by the Jiangnan University School of Medicine Research Ethics Committee. The findings will be disseminated through publication in a peer-reviewed journal., Trial Registration Number: ChiCTR2300076800., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hepatitis B virus (HBV) infection is a major etiology of hepatocellular carcinoma (HCC). An interesting question is how different are the molecular and phenotypic profiles between HBV-infected (HBV+) and non-HBV-infected (HBV-) HCCs? Based on the publicly available multi-omics data for HCC, including bulk and single-cell data, and the data we collected and sequenced, we performed a comprehensive comparison of molecular and phenotypic features between HBV+ and HBV- HCCs. Our analysis showed that compared to HBV- HCCs, HBV+ HCCs had significantly better clinical outcomes, higher degree of genomic instability, higher enrichment of DNA repair and immune-related pathways, lower enrichment of stromal and oncogenic signaling pathways, and better response to immunotherapy. Furthermore, in vitro experiments confirmed that HBV+ HCCs had higher immunity, PD-L1 expression and activation of DNA damage response pathways. This study may provide insights into the profiles of HBV+ and HBV- HCCs, and guide rational therapeutic interventions for HCC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) ranks as the third most common cause of cancer related death globally, representing a substantial challenge to global healthcare systems. In China, the primary risk factor for HCC is the hepatitis B virus (HBV). Aberrant serum glycoconjugate levels have long been linked to the progression of HBV-associated HCC (HBV-HCC). Nevertheless, few study systematically explored the dysregulation of glycoconjugates in the progression of HBV-associated HCC and their potency as the diagnostic and prognostic biomarker., Methods: An integrated strategy that combined transcriptomics, glycomics, and glycoproteomics was employed to comprehensively investigate the dynamic alterations in glyco-genes, N-glycans, and glycoproteins in the progression of HBV- HCC., Results: Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets uncovered dysregulation of fucosyltransferases (FUTs) in liver tissues from HCC patients compared to adjacent tissues. Glycomic analysis indicated an elevated level of fucosylated N-glycans, especially a progressive increase in fucosylation levels on IgA1 and IgG2 determined by glycoproteomic analysis., Conclusions: The findings indicate that the abnormal fucosylation plays a pivotal role in the progression of HBV-HCC. Systematic and integrative multi-omic analysis is anticipated to facilitate the discovery of aberrant glycoconjugates in tumor progression., (© 2024. The Author(s).)

Rationale and Objectives: To develop and validate a random forest model based on radiomic features in Gd-EOB-DTPA enhanced MRI for predicting the Ki-67 expression in solitary HCC., Materials and Methods: This retrospective study analyzed 258 patients with solitary HCC. Significant clinicoradiological factors were identified through univariate and multivariate analyses for distinguishing HCC with high (>20%) and low (≤20%) Ki-67 expression. Radiomic features were extracted at Gd-EOB-DTPA enhanced MRI. The recursive feature elimination (RFE) strategy was employed to screen robust radiomic features, and the Random Forest (RF) algorithm was utilized to rank radiomic features and construct prediction models. The AUC, accuracy, precision, recall, and f1-score were used to evaluate the performance of RF models., Results: Multivariate analysis identified serum AFP level, tumor size, growth type, and peritumoral enhancement as independent predictors for HCC with high Ki-67 expression. The clinicoradiological-radiomic model that incorporated the clinicoradiological predictors and the top ten radiomic features outperformed the clinicoradiological model in the training set (AUCs 0.876 vs. 0.780; p < 0.001), though the test set did not have a statistical significance (AUCs 0.809 vs. 0.723; p = 0.123). The addition of clinicoradiological predictors did not yield a significant improvement in the performance of radiomic features in both sets (training, p = 0.692; test, p = 0.229). Decision curve analysis further confirmed the clinical utility of the RF models., Conclusion: The RF models based on radiomic features of Gd-EOB-DTPA enhanced MRI achieved satisfactory performance in preoperatively predicting Ki-67 expression in HCC., Competing Interests: Declaration of Competing Interest 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 © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Circular RNA (circRNA) can influence the development of hepatocellular carcinoma (HCC) as a competitive endogenous RNA (ceRNA). However, there are still many circRNAs whose functions are unknown. Our research explores the role of a novel circRNA, hsa&#95;circ&#95;0079875, in HCC. The expression of hsa&#95;circ&#95;0079875 in HCC was verified by next-generation sequencing, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and fluorescence in situ hybridization (FISH). The distribution of hsa&#95;circ&#95;0079875 in HCC cells was investigated by RNA subcellular isolation and FISH assays. The functional effects on HCC proliferation, invasion, migration, cell cycle, and apoptosis were verified by overexpression and knockdown of hsa&#95;circ&#95;0079875. Moreover, xenograft mouse models and immunohistochemistry experiments were used to assess the function of hsa&#95;circ&#95;0079875 in vivo . Hsa&#95;circ&#95;0079875 was up-regulated in HCC tissues and mainly distributed in the cytoplasm. Higher hsa&#95;circ&#95;0079875 leads to larger tumor tissue, more microvascular invasion(MVI) and higher AFP levels, which in turn leads to a poor prognosis. Overexpression of hsa&#95;circ&#95;0079875 can promote the proliferation, migration, and invasion of HCC cells and inhibit apoptosis in vitro and in vivo . Knocking down hsa&#95;circ&#95;0079875 has the opposite effect. Sequencing and biological information predicted the target miRNA and mRNA of hsa&#95;circ&#95;0079875. Further bioinformatics and clinical correlation analysis revealed that hsa&#95;circ&#95;0079875 promote the malignant biological behaviors of HCC through hsa&#95;circ&#95;0079875/miR-519d-59/NRAS ceRNA net. Therefore, hsa&#95;circ&#95;0079875 can be a potential prognostic marker and therapeutic target for HCC.

Background and Aims: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes., Approach and Results: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases ( p <0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55-56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation)., Conclusions: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To explore the clinicopathological and molecular genetic features of adult hepatic mesenchymal hamartoma (MHL). Methods: A total of five confirmed adult MHL cases diagnosed at the Pathology Department of the First Medical Center of the People's Liberation Army General Hospital between 2009 and 2022 were collected. Histomorphological observation and immunohistochemical staining were conducted. Gene detection was performed by next-generation sequencing. Results: Among the five cases, four were male and one was female, aged 46-67 years, with an average age of 56.2 years. The maximum diameter was 5.3-13.5cm, and the average diameter was 9.2cm. Tumors were generally cystic, solid, or mixed cystic-solid. Histopathologically, in four out of five cases of MHL, malignant transformation occurred, of which three cases were malignantly transformed into undifferentiated embryonal sarcoma and one case was malignantly transformed into a malignant solitary fibrous tumor. NAB2-STAT6 gene rearrangements were identified. Conclusion: Adult MHL is a rare kind of tumor with malignant potential, and it is difficult to diagnose with preoperative imaging examinations. A fine-needle biopsy is rarely used for diagnosis, but surgical resection of symptomatic or enlarged lesions is recommended to rule out the possibility of malignancy and further diagnosis. Genetic testing results revealed the complex genetic alterations in MHL, and it was found that adult MHL can malignantly transform into malignant solitary fibrous tumors. We believe that genome-wide analysis is necessary to determine the unique molecular characteristics of MHL and identify potential targets for therapeutic intervention.

Mitochondrial transcription termination factor 3 (MTERF3) negatively regulates mitochondrial DNA transcription. However, its role in hepatocellular carcinoma (HCC) progression remains elusive. Here, we investigate the expression and function of MTERF3 in HCC. MTERF3 is overexpressed in HCC tumor tissues and higher expression of MTERF3 positively correlates with poor overall survival of HCC patients. Knockdown of MTERF3 induces mitochondrial dysfunction, S-G2/M cell cycle arrest and apoptosis, resulting in cell proliferation inhibition. In contrast, overexpression of MTERF3 promotes cell cycle progression and cell proliferation. Mechanistically, mitochondrial dysfunction induced by MTERF3 knockdown promotes ROS accumulation, activating p38 MAPK signaling pathway to suppress HCC cell proliferation. In conclusion, ROS accumulation induced by MTERF3 knockdown inhibits HCC cell proliferation via p38 MAPK signaling pathway suggesting a promising target in HCC patients., (© 2024. The Author(s).)

Worldwide, primary liver cancer is the third leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Recent studies have shown that circular RNAs (circRNAs) that interact with microRNAs (miRNAs) are involved in the occurrence and development of various tumours. Transcriptional profile analysis was used to analyse expression of circRNAs in HCC in this study. The top ten upregulated circRNAs were selected and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in another 34 HCC patients. MiRNAs and mRNAs downstream of these circRNAs were explored through database analysis, and finally, the competitive endogenous RNA (ceRNA) networks were constructed for 5 selected circRNAs. We identified 9658 differentially expressed circRNAs by transcriptional profile analysis. QRT-PCR was performed to validate the top ten upregulated circRNAs, and five circRNAs were selected for further analysis. The miRNAs and mRNAs downstream of these five circRNAs were predicted to construct ceRNA network diagrams. Further analysis revealed five circRNA-miRNA-mRNA axes that correlate negatively with HCC prognosis. Numerous differentially expressed circRNAs exist in HCC, and they can regulate the biological behaviour of HCC through ceRNA networks. Bioinformatics analysis showed that ceRNA regulatory axes involved in HCC have high diagnostic and prognostic value and deserve further exploration., (© 2023. The Author(s).)

Purpose: Anoikis resistance is an important inducer of tumor metastasis. The role of anoikis-related genes (ARGs) in hepatocellular carcinoma (HCC) remains unclear., Methods: A list of ARGs was obtained and regression analysis was employed to assemble an anoikis-related prognostic signature and risk score formula from mRNA data and clinical prognostic data downloaded from The Cancer Genome Atlas database. Quantitative real-time PCR (qRT-PCR) was performed on clinical samples to validate the selected ARGs expressions. Kaplan‒Meier curves, ROC curves, and Cox regression analyses were used to demonstrated the prognostic value of this signature. Biological functional enrichment analysis and immune infiltration analysis were utilized to analyze the differences in potential biological functions, immune cell infiltration, immune functions, and immunotherapeutic responses., Results: A prognostic signature based on 6 ARGs and corresponding prognostic nomogram were established. Our qRT-PCR results showed a higher expression of 6 ARGs in HCC tissues (p value < 0.05). Kaplan‒Meier curves, ROC curves, and Cox regression analyses demonstrated good prognostic value of the signature in HCC (p value < 0.05). Significant differences between the enriched biological functions and immune landscapes of patients in different risk groups were discovered (p value < 0.05). In addition, patients with higher risk scores possibly had poor therapeutic response to transhepatic arterial chemotherapy and embolization or sorafenib, but their responses to immunotherapy might be more effective., Conclusion: A successful anoikis-related prognostic signature and corresponding clinical nomogram were established, which might facilitate better predictions of prognosis and therapeutic responses for HCC patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated., Methods: Fah -/-  mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8 + T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin., Results: RNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah -/- mice. Metformin prevented the formation of non-diabetic HCC in Fah -/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8 +  T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah -/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45β/JNK/c-Jun pathway., Conclusions: Metformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8 + T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Mass spectrometry technology can realize dynamic detection of many complex matrix samples in a simple, rapid, compassionate, precise, and high-throughput manner and has become an indispensable tool in accurate diagnosis. The mass spectrometry data analysis is mainly to analyze all metabolites in the organism quantitatively and to find the relative relationship between metabolites and physiological and pathological changes. A feature construction of mass spectrometry data (MSFS) method is proposed to construct the features of the original mass spectrometry data, so as to reduce the noise in the mass spectrometry data, reduce the redundancy of the original data and improve the information content of the data. Chi-square test is used to select the optimal non-redundant feature subset from high-dimensional features. And the optimal feature subset is visually analyzed and corresponds to the original mass spectrum interval. Training in 10 kinds of supervised learning models, and evaluating the classification effect of the models through various evaluation indexes. Taking two public mass spectrometry datasets as examples, the feasibility of the method proposed in this paper is verified. In the coronary heart disease dataset, during the identification process of mixed batch samples, the classification accuracy on the test set reached 1.000; During the recognition process, the classification accuracy on the test set advanced to 0.979. On the colorectal liver metastases data set, the classification accuracy on the test set reached 1.000. This paper attempts to use a new raw mass spectrometry data preprocessing method to realize the alignment operation of the raw mass spectrometry data, which significantly improves the classification accuracy and provides another new idea for mass spectrometry data analysis. Compared with MetaboAnalyst software and existing experimental results, the method proposed in this paper has obtained better classification results., (© 2023. Springer Nature Limited.)

Background and Aims: Natural killer (NK) cells are key players in tumor immunosurveillance, and metabolic adaptation manipulates their fate and functional state. The nicotinamide adenine dinucleotide (NAD + ) has emerged as a vital factor to link cellular metabolism and signaling transduction. Here, we identified NAD + metabolism as a central hub to determine the homeostasis and function of NK cells., Approach and Results: NAD + level was elevated in activated NK cells. NAD + supplementation not only enhanced cytokine production and cytotoxicity but also improved the proliferation and viability of NK cells. Intriguingly, the salvage pathway was involved in maintaining NAD + homeostasis in activated NK cells. Genetic ablation or pharmacological blockade of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD + salvage pathway, markedly destroyed the viability and function of NK cells. Mechanistically, NAD + salvage dictated the mitochondrial homeostasis and oxidative phosphorylation activity to support the optimal function of NK cells. However, in human HCC tissues, NAMPT expression and NAD + level were significantly down-regulated in tumor-infiltrating NK cells, which negatively correlated with patient survival. And lactate accumulation in the tumor microenvironment was at least partially responsible for the transcriptional repression of NAMPT in NK cells. Further, deficiency of Nampt in NK cells accelerated the growth of HCC and melanoma. Supplementation of the NAD + precursor nicotinamide mononucleotide (NMN) significantly improved NK antitumor response in both mouse and human cell-derived xenografts., Conclusions: These findings reveal NAD + salvage as an essential factor for NK-cell homeostasis and function, suggesting a potential strategy for invigorating NK cell-based immunotherapy., (Copyright © 2023 American Association for the Study of Liver Diseases.)

The accumulation of lipid droplets (LDs) in hepatocytes is the main pathogenesis in nonalcoholic fatty liver disease (NAFLD), which is also the key risk factor for the progression of hepatocellular carcinoma (HCC). LDs behaviors are demonstrated to be associated with HCC advancement, and are tightly regulated by a subset protein localized on the surface of LDs. However, the role of LDs-localized protein in HCC has been rarely investigated. This study is focused on the transcriptional dynamic and prognostic value of LDs-localized protein in HCC. Firstly, we summarized the known LDs-localized proteins, which are demonstrated by immunofluorescence according to previous studies. Next, by the use of GEPIA/UALCAN/The Human Protein Atlas databases, we screened the transcriptional change in tumor and normal liver tissues, and found that 13 LDs-localized proteins may involve in the progression of HCC. Then we verified the transcriptional changes of 13 LDs-localized proteins by the use of HCC samples. Moreover, based on the assays of fatty liver of mice and human NAFLD liver samples, we found that the hepatic steatosis mainly contributed to the transcriptional change of selected LDs-localized proteins, indicating the involvement of these LDs-localized proteins in the negative role of NAFLD in HCC progression. Finally, we focused on the role of PLIN3 in HCC, and revealed that NAFLD status significantly promoted PLIN3 transcription in HCC tissue. Functional studies revealed that PLIN3 knockdown significantly limited the migration and chemosensitivity of hepatoma cells, suggesting the positive role of PLIN3 in HCC progression. Our study not only revealed the transcriptional change and prognostic value of lipid droplet-localized proteins in HCC, but also built the correlation between HCC and hepatic steatosis., (© 2023. The Author(s).)

This review aimed to perform a scoping review of promising MRI methods in assessing tumor hypoxia in hepatocellular carcinoma (HCC). The hypoxic microenvironment and upregulated hypoxic metabolism in HCC are determining factors of poor prognosis, increased metastatic potential, and resistance to chemotherapy and radiotherapy. Assessing hypoxia in HCC is essential for personalized therapy and predicting prognoses. Oxygen electrodes, protein markers, optical imaging, and positron emission tomography can evaluate tumor hypoxia. These methods lack clinical applicability because of invasiveness, tissue depth, and radiation exposure. MRI methods, including blood oxygenation level-dependent, dynamic contrast-enhanced MRI, diffusion-weighted imaging, MRI spectroscopy, chemical exchange saturation transfer MRI, and multinuclear MRI, are promising noninvasive methods that evaluate the hypoxic microenvironment by observing biochemical processes in vivo, which may inform on therapeutic options. This review summarizes the recent challenges and advances in MRI techniques for assessing hypoxia in HCC and highlights the potential of MRI methods for examining the hypoxic microenvironment via specific metabolic substrates and pathways. Although the utilization of MRI methods for evaluating hypoxia in patients with HCC is increasing, rigorous validation is needed in order to translate these MRI methods into clinical use. Due to the limited sensitivity and specificity of current quantitative MRI methods, their acquisition and analysis protocols require further improvement. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 4., (© 2023 International Society for Magnetic Resonance in Medicine.)

Background: Long noncoding RNA ubiquitin-conjugating enzyme E2 R2 antisense RNA 1 (UBE2R2-AS1) has been recently reported to participate in the progression of tumors, including glioma and liver cancer. However, the roles of UBE2R2-AS1 in prostate cancer (PC) remained poorly understood., Methods: The expression of UBE2R2-AS1 was determined in tumor tissues and paired adjacent tissues from PC patients using quantitative reverse transcription PCR analysis. Correlation between UBE2R2-AS1 expression and clinicopathological parameters and overall survival were investigated by Chi-square test and Kaplan-Meier method analysis. The in vitro experiments, including CCK-8 assay, colony formation, flow cytometry and transwell assay were performed to investigate the functional role of UBE2R2-AS1 knockdown or overexpression on PC cell lines (PC-3 and DU145). Related protein expression levels were measured by western blot analysis., Results: Our data showed that UBE2R2-AS1 expression was significantly upregulated in PC tissues compared with that in adjacent tissues. The high levels of UBE2R2-AS1 were associated with high Gleason score, advanced clinical T stage, lymph node metastasis and poor prognosis. Knockdown of UBE2R2-AS1 suppressed cell proliferation, migration and invasion, induced cell cycle G0/G1 arrest and apoptosis in PC cells, along with decreased expression of PCNA, CDK4, Cyclin D1, Bcl-2, N-cadherin and Vimentin, and increased E-cadherin expression. Overexpression of UBE12R2-AS1 obtained the opposite results in PC cells., Conclusions: Our findings suggest that UBE2R2-AS1 might be a potential diagnostic and/or therapeutic target in PC., (©The Author(s) 2023. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium-glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib-dapagliflozin and donafenib-canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (C max ) to increase 37.01%. Canagliflozin increased donafenib C max 1.77-fold and the area under the plasma concentration-time curves (AUC 0-t and AUC inf ) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CL z ) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC 0-t 1.61-fold, AUC inf 1.77-fold, whereas its CL z reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM., Competing Interests: Conflicts of interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: Liver metastasis, a lethal malignancy of gastric cancer (GC) patients, execrably impairs their prognosis. As yet, however, few studies have been designed to identify the driving molecules during its formation, except screening evidence pausing before their functions or mechanisms. Here, we aimed to survey a key driving event within the invasive margin of liver metastases., Methods: A metastatic GC tissue microarray was used for exploring malignant events during liver-metastasis formation, followed by assessing the expression patterns of glial cell-derived neurotrophic factor (GDNF) and GDNF family receptor alpha 1 (GFRA1). Their oncogenic functions were determined by both loss- and gain-of-function studies in vitro and in vivo, and validated by rescue experiments. Multiple cell biological studies were performed to identify the underlying mechanisms., Results: In the invasive margin, GFRA1 was identified as a pivotal molecule involved in cellular survival during liver metastasis formation, and we found that its oncogenic role depends on tumor associated macrophage (TAM)-derived GDNF. In addition, we found that the GDNF-GFRA1 axis protects tumor cells from apoptosis under metabolic stress via regulating lysosomal functions and autophagy flux, and participates in the regulation of cytosolic calcium ion signalling in a RET-independent and non-canonical way., Conclusion: From our data we conclude that TAMs, homing around metastatic nests, induce the autophagy flux of GC cells and promote the development of liver metastasis via GDNF-GFRA1 signalling. This is expected to improve the comprehension of metastatic pathogenesis and to provide a novel direction of research and translational strategies for the treatment of metastatic GC patients., (© 2023. The Author(s).)

Hepatocellular carcinoma (HCC), which has become one of the most significant malignancies causing cancer-related mortality, presents genetic and phenotypic heterogeneity that makes predicting prognosis challenging. Aging-related genes have been increasingly reported as significant risk factors for many kinds of malignancies, including HCC. In this study, we comprehensively dissected the features of transcriptional aging-relevant genes in HCC from multiple perspectives. We applied public databases and self-consistent clustering analysis to classify patients into C1, C2, and C3 clusters. The C1 cluster had the shortest overall survival time and advanced pathological features. Least absolute shrinkage and selection operator (LASSO) regression analysis was adopted to build the prognostic prediction model based on six aging-related genes ( HMMR , S100A9 , SPP1 , CYP2C9 , CFHR3 , and RAMP3 ). These genes were differently expressed in HepG2 cell lines compared with LO2 cell lines measured by the mRNA expression level. The high-risk score group had significantly more immune checkpoint genes, higher tumor immune dysfunction and exclusion score, and stronger chemotherapy response. The results indicated that the age-related genes have a close correlation with HCC prognosis and immune characteristics. Overall, the model based on six aging-associated genes demonstrated great prognostic prediction ability., Competing Interests: The author(s) declare(s) that they have no conflicts of interest., (Copyright © 2023 Junjie Zhao et al.)

At present, malignant tumors are an urgent global threat to human health. Conversion of cancer cells to normal-like or normal cells will open new therapeutic avenues for eradicating cancer. It has been reported that compounds extracted from grains display biological activities, such as antioxidant, antiviral and antitumor activities. In this study, we identified clear changes in a liver tumor cell line (HepG2) after stimulation with zymolytic grain extract (ZGE) supernatants. The expression levels of hepatocyte nuclear factor 1A (HNF1A), hepatocyte nuclear factor 4A (HNF4A) and forkhead box protein A3 (FOXA3) were significantly increased. Eukaryotic transcriptome analyses revealed that trends in the transcriptional changes for genes were similar in HepG2 cells stimulated with ZGE (zHeps) and the normal hepatocyte cell line L02. Changes in the expression levels of genes involved in drug transport, metabolism and the malignant characteristics of cancer cells in nude mice further indicated that ZGE regulated the expression of HNF1A, HNF4A and FOXA3, which altered the expression of a series of hepatocyte-specific genes. It was also confirmed that zHeps acquired some of the characteristics of hepatocyte-like cells. Our results not only provide new ideas for the treatment of liver tumors but also lay a solid foundation for the application of combination therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The presence or absence of damage to the liver organ is crucial to a person's health. Nutritional disorders, alcohol consumption, and drug abuse are the main causes of liver disease. Liver transplantation is the last irrevocable option for liver disease and has become a serious economic burden worldwide. Andrographolide (AP) is one of the main active ingredients of Herba Andrographitis. It has several biological activities and has been reported to have protective and therapeutic effects against liver diseases. Earlier literature has been written on AP's role in treating inflammation and other diseases, and there has not been a systematic review on liver diseases. This review is dedicated to sorting out the research results of AP against liver diseases. Pharmacokinetics, toxicity, and nanotechnology to improve bioavailability are discussed. Finally, an outlook and assessment of its future are provided., Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed and web of Science databases were used to search all relevant literature on AP for liver disease up to 2022., Results: Studies have shown that AP plays an important role in different liver disease phenotypes, mainly through anti-inflammatory and antioxidant activities. AP regulates HO-1 and inhibits hepatitis virus replication. It affects the NF-κB pathway, downregulates inflammatory factors such as IL-1β, IL-6, and TNF-α, and reduces liver damage. In preventing liver fibrosis, AP inhibits angiogenesis and activation of hepatic stellate cells and reduces oxidative stress involved in the Nrf2 and TGF-β1/Smad pathways. In addition, AP impedes the development of liver cancer by promoting apoptosis and autonomous phagocytosis in a cell-dependent way. Interestingly, miRNAs are involved in the therapeutic process of liver cancer and hepatic fibrosis. The poor solubility of AP limits the development of dosage forms. Therefore, the advent of nanoformulations has improved bioavailability. Although the effect of AP is dose- and time-dependent, the magnitude of its toxicity is not negligible. Some clinical trials have shown that AP has mild side effects., Conclusions: AP, as an effective natural product, has a good effect on the liver disease through multiple pathways and targets. However, the dose reaches a certain level, leading to its toxicity and side effects. For better clinical application of AP, high-quality clinical and toxic intervention mechanisms are needed to validate current studies. In addition, modulation of miRNA-mediated hepatocellular carcinoma and liver fibrosis and synergistic action with drugs may be the future focus of AP. In conclusion, AP can be regarded as an important candidate for treating different liver diseases in the future., Competing Interests: Declaration of Competing Interest All authors declare that there is no conflict of interest in publishing the content of this work., (Copyright © 2022. Published by Elsevier GmbH.)

Background: Although transjugular intrahepatic portosystemic shunt (TIPS) is recommended for secondary prophylaxis of variceal bleeding if standard therapy fails and for patients with high risk of recurrent bleeding, no guidelines for the treatment of symptomatic portal hypertension in HCC patients are available. This study aimed to compare the efficacy and safety of TIPS with endoscopic + β-blocker for prevention of the rebleeding in such patients., Methods: 106 consecutive advanced HCC patients receiving tyrosine kinase inhibitor (TKI) who had been treated with vasoactive drugs plus endoscopic therapy for variceal bleeding were randomly assigned to receive either TIPS (n = 52) or endoscopic + β-blocker therapy (n = 54) for the prevention of rebleeding. The primary endpoint was variceal rebleeding after randomization., Results: During a median follow-up of 16 months, rebleeding occurred in 14 patients in the endoscopic + β-blocker group and 3 patients in the TIPS group (p < 0.001). Forty-nine patients died (38 in endoscopic + β-blocker group and 11 in TIPS group, p < 0.001). The 6-, 12-, and 18-month overall survival rates were 95, 81, and 73% for TIPS group and 35, 21, and 15% for endoscopic + β-blocker group, respectively (p < 0.001). Eight patients in endoscopic + β-blocker group received TIPS as rescue therapy, but two died. TKIs was discontinued in 32 patients, including 24 in the endoscopic + β-blocker group and 8 in the TIPS group (p < 0.001). No significant differences were observed between the two groups with respect to serious adverse events., Conclusions: In advanced HCC patients receiving TKIs and presented with variceal bleeding, the use of TIPS was associated with significant reduction in rebleeding, improved a higher adherence to TKIs therapy, and prolonged survival., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background & Aims: Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial., Methods: After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis., Results: A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results., Conclusions: ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention., Lay Summary: Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To conduct a cost-effectiveness analysis of drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) and conventional transcatheter arterial chemoembolization (cTACE) for first-line treatment of hepatocellular carcinoma (HCC) from the perspective of the Chinese healthcare system., Methods: Based on the real-world clinical data of HCC patients receiving interventional therapy, a partitioned survival model was constructed for cost-effectiveness analysis. The model period is 1 month, and the research time limit is 10 years. The incremental cost-effectiveness ratio (ICER) is used as the evaluation index. One-way sensitivity analysis and probabilistic sensitivity analysis were used to analyze the uncertainty of parameters to test the stability of the model results., Results: The ICER of the DEB-TACE group was 11,875.62 $/QALYs, which was lower than the willingness to pay threshold (WTP) of 31,499.23 $/QALYs. One-way sensitivity analysis suggested that the utility value of progression-free survival (PFS) in the DEB-TACE group had the greatest impact. Probabilistic sensitivity analysis showed that at the level of WTP of 31,499.23 $/QALYs, DEB-TACE had a cost-effective probability of 92%., Conclusion: Under the current economic level in my country, DEB-TACE is more cost-effective than cTACE in the treatment of HCC patients., 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 Shao, Wang, Zhou, Sun and Dong.)

Sorafenib (SOR), an inhibitor of multiple kinases, is a classic targeted drug for advanced hepatocellular carcinoma (HCC) which often coexists with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Notably, co-administration of SOR with DAPA is common in clinical settings. Uridine diphosphate-glucuronosyltransferase family 1 member A9 (UGT1A9) is involved in the metabolism of SOR and dapagliflozin (DAPA), and SOR is the inhibitor of UGT1A1 and UGT1A9 (in vitro). Therefore, changes in UGT1A9 activity caused by SOR may lead to pharmacokinetic interactions between the two drugs. The objective of the current study was to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of SOR and DAPA in plasma and to evaluate the effect of the co-administration of SOR and DAPA on their individual pharmacokinetic properties and the mechanism involved. The rats were divided into four groups: SOR (100 mg/kg) alone and co-administered with DAPA (1 mg/kg) for seven days, and DAPA (1 mg/kg) alone and co-administered with SOR (100 mg/kg) for seven days. Liquid-liquid extraction (LLE) was performed for plasma sample preparation, and the chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5 mM ammonium acetate (Phase A) and acetonitrile (Phase B). The levels of Ugt1a7 messenger RNA (mRNA) were determined in rat liver and intestine using quantitative real-time polymerase chain reaction (qRT-PCR). The method was successfully applied to the study of pharmacokinetic interactions. DAPA caused a significant decrease in the maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC 0-t ) of SOR by 41.6% and 50.5%, respectively, while the apparent volume of distribution (V z/F ) and apparent clearance (CL z/F ) significantly increased 2.85- and 1.98-fold, respectively. When co-administering DAPA with SOR, the AUC 0-t and the elimination half-life (t 1/2Z ) of DAPA significantly increased 1.66- and 1.80-fold, respectively, whereas the CL z/F significantly decreased by 40%. Results from qRT-PCR showed that, compared with control, seven days of SOR pretreatment decreased Ugt1a7 expression in both liver and intestine tissue. In contrast, seven days of DAPA pretreatment decreased Ugt1a7 expression only in liver tissue. Therefore, pharmacokinetic interactions exist between long-term use of SOR with DAPA, and UGT1A9 may be the targets mediating the interaction. Active surveillance for the treatment outcomes and adverse reactions are required., Competing Interests: The authors declare no conflict of interest.

Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune-modulatory strategy to provoke a robust immune response is to simultaneously regulate T-cell exhaustion and infiltration. Here, a new kind of carrier-free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti-TOX small interfering RNA (thymocyte selection-associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as "offense" signaling to increase CD8 + T-cell infiltration, while the decreased TOX expression interfered with siTOX can serve as "defense" signaling to mitigate CD8 + T-cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting "cold" tumors into "hot" ones., (© 2022 Wiley-VCH GmbH.)

Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca 2+ fixed by alginate as Ca 2+ -surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca 2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca 2+ homeostasis. Resultantly, Ca 2+ -surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn 2+ , an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ-formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.

Objective: To evaluate the safety of performing surgery on cavernous haemangiomas in the liver larger than 10 cm and establish preoperative predictors of intraoperative blood transfusion and morbidity., Methods: A total of 373 patients with haemangiomas larger than 10 cm who underwent surgery in our hospital were retrospectively analysed. According to tumour diameter, the patients were divided into a giant haemangioma (GH) group (241 cases) (10 cm ≤ diameter < 15 cm) and an enormous haemangioma (EH) group (132 cases) (diameter ≥ 15 cm). Clinical parameters were then compared between the two groups., Results: Compared with the GH group, the EH group had higher rates of leukopenia (10.6% vs. 4.5%), anaemia (26.5% vs. 15.7%), and thrombocytopenia (13.6% vs. 6.2%). The occlusion time in the EH group was longer than that in the GH group (26.33 ± 14.10 min vs. 31.85 ± 20.09 min, P < 0.01). The blood loss and blood transfusion in the EH group were greater than those in the GH group (P < 0.05). Moreover, the morbidity in the EH group was higher than that in the GH group (17.4% vs. 9.13%, P < 0.05). According to the results of the multivariable analysis, the operation time and size of the haemangioma may be independent risk factors for blood transfusion (P < 0.05). Additionally, the size of the haemangioma may be an independent risk factor associated with complications (P < 0.05)., Conclusion: Enormous haemangioma is more likely to cause haematologic abnormalities than giant hepatic haemangioma. The risks of the operation and postoperative complications of enormous haemangioma are higher than those of giant hepatic haemangioma., (© 2022. The Author(s).)

Objective: To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma., Methods: We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups., Results: There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI : 0.299-1.213, P =0.156; multivariate analysis: OR=0.693, 95% CI : 0.330-1.458, P =0.334), PFS (univariate analysis: HR=1.230, 95% CI : 0.789-1.916, P =0.361; multivariate analysis: HR=1.151, 95% CI : 0.732-1.810, P =9.544), or OS (univariate analysis: HR=0.552, 95% CI : 0.208-1.463, P =0.232; multivariate analysis: HR=1.085, 95% CI : 0.685-1.717, P =0.729)., Conclusion: Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.

Background: Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown., Methods: RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms., Results: Hsa&#95;circ&#95;0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m 6 A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (β-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models., Conclusions: CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC., (© 2022. The Author(s).)

Background & Aims: Management of elderly patients with hepatocellular carcinoma (HCC) has become a major concern. Some data suggest that cryoablation improves the outcomes of elderly patients with HCC, but its efficacy and safety remain unknown. This study aimed to evaluate and compare the efficacy and safety of percutaneous cryoablation with those of radiofrequency ablation (RFA) for elderly HCC patients., Methods: In all, 223 patients with small HCC aged ≥70 years, treatment-naïve, without metastasis were enrolled and randomized into a cryoablation group (n = 112) or a RFA (n = 111) group from July 2015 to October 2018. The primary endpoint was local tumour progression (LTP) at 3 years after treatment. The secondary endpoints including overall survival (OS), tumour-free survival (TFS), LTP and safety were analysed for these two groups after both treatments., Results: LTP rates at 1-, 3- and 5-year were 12%, 17% and 20% for cryoablation and 17%, 18% and 21% for RFA respectively (P = .735). For lesions >3 cm in diameter, LTP rates at 1- and 3-year were 13% and 22% in cryoablation group and 22% and 42% respectively, in the RFA group (P = .039). The 1-, 3- and 5-year OS rates were 90, 75% and 62% for cryoablation and 90%, 68% and 63% for RFA respectively (P = .331). The 1-, 3- and 5-year TFS rates were 59%, 32% and 25% in the cryoablation and 59%, 28% and 20% in the RFA respectively (P = .309). Major complications occurred in 6 patients (5%) following cryoablation and 6 patients (6%) following RFA (P = .886)., Conclusion: Cryoablation and RFA had similar LTP in elderly patients with small HCC and this study failed to meet the primary endpoint, although for a relatively large early-stage HCC the LTP rate after cryoablation was significantly lower than that after RFA., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. HBV infection is an important risk factor for the tumorigenesis of HCC, given that the inflammatory environment is closely related to morbidity and prognosis. Consequently, it is of urgent importance to explore the immunogenomic landscape to supplement the prognosis of HCC. The expression profiles of immune-related genes (IRGs) were integrated with 377 HCC patients to generate differentially expressed IRGs based on the Cancer Genome Atlas (TCGA) dataset. These IRGs were evaluated and assessed in terms of their diagnostic and prognostic values. A total of 32 differentially expressed immune-related genes resulted as significantly correlated with the overall survival of HCC patients. The Gene Ontology functional enrichment analysis revealed that these genes were actively involved in cytokine-cytokine receptor interaction. A prognostic signature based on IRGs (HSPA4, PSME3, PSMD14, FABP6, ISG20L2, TRAF3, NDRG1, NRAS, CSPG5, and IL17D) stratified patients into high-risk versus low-risk groups in terms of overall survival and remained as an independent prognostic factor in multivariate analyses after adjusting for clinical and pathologic factors. Several IRGs (HSPA4, PSME3, PSMD14, FABP6, ISG20L2, TRAF3, NDRG1, NRAS, CSPG5, and IL17D) of clinical significance were screened in the present study, revealing that the proposed clinical-immune signature is a promising risk score for predicting the prognosis of HCC., Competing Interests: The authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence the work., (Copyright © 2021 Peng Qin et al.)

Background and Aim: Immune checkpoint inhibitors (ICIs) have been widely used in hepatocellular carcinoma (HCC), while only a subset of patients experience clinical benefit. We aimed to investigate the effects of viral etiology on response to ICIs in HCC and depict the tumor immune microenvironment (TIME) of virally infected and uninfected HCC., Methods: A systematic search was conducted in PubMed, Web of Science, Embase, and the Cochrane central register of controlled trials up to August 2021. Clinical trials reporting the efficacy of ICIs in HCC were eligible. Baseline characteristics including first author, year of publication, National Clinical Trials (NCT) registry number, study region, sample sizes, interventions, line of treatment, and viral status were extracted. Meta-analysis was conducted to generate combined odds ratios (ORs) with 95% confidence intervals (CI) based on random or fixed effect model, depending on heterogeneity. Tumor immune microenvironment was depicted using ESTIMATE and CIBERSORT algorithm., Results: Eight studies involving 1,520 patients were included. Combined data suggested that there was no significant difference of objective response rate (ORR) between virally infected HCC and non-viral HCC patients [OR = 1.03 (95% CI, 0.77-1.37; I 2 = 30.9%, p H  = 0.152)]. Similarly, difference was not observed on ORR between HBV-HCC and HCV-HCC patients [OR = 0.74 (95% CI, 0.52-1.06; I 2 = 7.4%, p H = 0.374)]. The infiltration of immune cells in the tumor microenvironment did not differ by etiology except for M0 macrophages, M2 macrophages, regulatory T cells, naive B cells, follicular helper T cells, activated dendritic cells, activated mast cells, and plasma cells. Despite differences in infiltration observed in specific cell types, the immune score and stromal score were generally comparable among etiology groups., Conclusion: Viral etiology may not be considered as the selection criteria for patients receiving ICIs in HCC, and viral status has little impact on TIME remodeling during HCC tumorigenesis., 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 © 2021 Ding, Dong, Chen, Hong, Yan, Li, Yao, Yan, Yang, Yang and Li.)

BACKGROUND Cryoablation of hepatocellular carcinoma (HCC) close to major organs or viscus is challenging because it can cause complications. This retrospective study aimed to investigate the safety and efficacy of percutaneous argon-helium cryoablation of small HCC located adjacent to major organs or viscus. MATERIAL AND METHODS Ninety-two patients who underwent percutaneous argon-helium cryoablation between February 2012 and December 2018 at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital were included. Treatment efficacy was evaluated by magnetic resonance imaging or triphasic computed tomography scan within 1 week after each cryoablation procedure. Local tumor progression, distant recurrence, and overall survival were analyzed using the Kaplan-Meier method and log-rank test. RESULTS A total of 92 patients with small HCC located adjacent to major organs or viscus who underwent cryoablation were retrospectively reviewed. The number of patients with tumors adjacent to the gallbladder, portal or hepatic vein, diaphragm, stomach, heart, and intestine was 22, 1, 39, 6, 8, and 16, respectively. Cumulative local tumor progression rates at 1 and 2 years were 2.8% and 7.3%, respectively. Cumulative distant recurrence rates at 1, 2, and 3 years were 11.1%, 17.6%, and 20.7%, respectively. The overall survival rates at 1, 2, and 4 years were 100%, 93.6%, and 74.9%, respectively. Major complications were observed in 5 (5.4%) patients. Minor complications were observed in 85 (92.4%) patients. CONCLUSIONS This experience from a single center showed that percutaneous argon-helium cryoablation was safe and effective in the management of small HCC that is located adjacent to major organs or viscus.

Ultrasound localization microscopy can image microvasculature in vivo without sacrificing imaging penetration depth. However, the reliance on super-resolution inference limits the applicability of the technique because subpixel tissue motion can corrupt microvascular reconstruction. Consequently, the majority of previous pre-clinical research on this super-resolution procedure has been restricted to low-motion experimental models with ample motion correction or data rejection, which precludes the imaging of organ sites that exhibit a high degree of respiratory and other motion. In this article, we present a novel anesthesia protocol in rabbits that induces safe, controllable periods of apnea to enable the long image-acquisition times required for ultrasound localization microscopy. We apply this protocol to a VX2 liver tumor model undergoing sorafenib therapy and compare the results to super-resolution images from conventional high-dose isoflurane anesthesia. We find that the apneic protocol was necessary to correctly identify the poorly vascularized tumor cores, as verified by immunohistochemistry, and to reveal the tumoral microvascular architecture., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2021 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: Lenvatinib is a long-awaited alternative to Sorafenib for first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to Lenvatinib results in tumor progression and has become a major obstacle to improving the prognosis of HCC patients. Exploring the mechanisms underlying Lenvatinib resistance is considered essential for the treatment of advanced HCC., Methods: Lenvatinib resistant HCC (LR-HCC) cells were generated and potential long non-coding RNAs (Lnc-RNAs) upregulated in LR-HCC cells were identified by RNA sequencing. The effects of upregulated Lnc-RNAs were evaluated in vitro in cell models and in vivo in experimental animals using quantitative cell viability and apoptosis assays., Results: We found that Lnc-RNA MT1JP (MT1JP) was upregulated in LR-HCC cells and inhibited the apoptosis signaling pathway. In addition, we found that sponging of microRNA-24-3p by MT1JP released Bcl-2 like 2 (BCL2L2), an anti-apoptotic protein, thereby forming a positive-feedback loop. The role of this feedback loop was validated using rescue assays. Additionally, we found that upregulation of MT1JP and BCL2L2 impaired the sensitivity of HCC cells to Lenvatinib both vitro and vivo., Conclusions: Our results suggest a novel molecular feedback loop between MT1JP and apoptosis signaling in Lenvatinib sensitive HCC cells., (© 2021. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Recent studies have shown that the polytopic enzyme membrane associated ring-CH-type finger 6 (MARCH6) participates in tumorigenesis, but its function in HCC development needs to be investigated. This study aimed to explore the role of MARCH6 in HCC., Methods: Expression of MARCH6 in human HCC samples was checked by immunohistochemical staining assay. Clinical relevance of MARCH6 and activating transcription factor 2 (ATF2) was analyzed from TCGA database. CCK-8, EdU staining, colony formation and transwell were performed to assess cell proliferation, growth and migration. Xenografted tumorigenesis was used to examine in vivo role MARCH6. Immunoblotting was applied to detect protein abundance., Results: We found that MARCH6 expression was elevated in human HCC samples. Over-expression of MARCH6 was associated with poor prognosis of HCC patients. Up-expression of MARCH6 promoted cell growth and migration of HCC cells. In contrast, the HCC cell growth and migration were suppressed by MARCH6 knockdown. Furthermore, the DNA synthesis was enhanced by MARCH6. The expression of ATF2 was potentiated by MARCH6 over-expression, while it was suppressed by MARCH6 silencing. TCGA database showed positive correlation between the expression of MARCH6 and ATF2. Importantly, ATF2 expression contributed to the oncogenic function of HCC cells., Conclusion: Our findings suggest that MARCH6-mediated ATF2 up-regulation contributes to HCC development. MARCH6 may be a promising target for the diagnosis and treatment of HCC., (© 2021. The Author(s).)

Background: Liver cancer is one of the most common cancers and causes of cancer death worldwide. The objective was to elucidate novel hub genes which were benefit for diagnosis, prognosis, and targeted therapy in liver cancer via integrated analysis., Methods: GSE84402, GSE101685, and GSE112791 were filtered from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified by using the GEO2R. The GO and KEGG pathway of DEGs were analyzed in the DAVID. PPI and TF network of the DEGs were constructed by using the STRING, TRANSFAC, and Harmonizome. The relationship between hub genes and prognoses in liver cancer was analyzed in UALCAN based on The Cancer Genome Atlas (TCGA). The diagnostic value of hub genes was evaluated by ROC. The relationship between hub genes and tumor-infiltrate lymphocytes was analyzed in TIMER. The protein levels of hub genes were verified in HPA. The interaction between the hub genes and the drug were identified in DGIdb., Results: In total, 108 upregulated and 60 downregulated DEGs were enriched in 148 GO terms and 20 KEGG pathways. The mRNA levels and protein levels of CDK1, HMMR, PTTG1, and TTK were higher in liver cancer tissues compared to normal tissues, which showed excellent diagnostic and prognostic value. CDK1, HMMR, PTTG1, and TTK were positively correlated with tumor-infiltrate lymphocytes, which might involve tumor immune response. The CDK1, HMMR, and TTK had close interaction with anticancer agents., Conclusions: The CDK1, HMMR, PTTG1, and TTK were hub genes in liver cancer; hence, they might be potential biomarkers for diagnosis, prognosis, and targeted therapy of liver cancer.

Objective: Tumour pathology contains rich information, including tissue structure and cell morphology, that reflects disease progression and patient survival. However, phenotypic information is subtle and complex, making the discovery of prognostic indicators from pathological images challenging., Design: An interpretable, weakly supervised deep learning framework incorporating prior knowledge was proposed to analyse hepatocellular carcinoma (HCC) and explore new prognostic phenotypes on pathological whole-slide images (WSIs) from the Zhongshan cohort of 1125 HCC patients (2451 WSIs) and TCGA cohort of 320 HCC patients (320 WSIs). A 'tumour risk score (TRS)' was established to evaluate patient outcomes, and then risk activation mapping (RAM) was applied to visualise the pathological phenotypes of TRS. The multi-omics data of The Cancer Genome Atlas(TCGA) HCC were used to assess the potential pathogenesis underlying TRS., Results: Survival analysis revealed that TRS was an independent prognosticator in both the Zhongshan cohort (p<0.0001) and TCGA cohort (p=0.0003). The predictive ability of TRS was superior to and independent of clinical staging systems, and TRS could evenly stratify patients into up to five groups with significantly different prognoses. Notably, sinusoidal capillarisation, prominent nucleoli and karyotheca, the nucleus/cytoplasm ratio and infiltrating inflammatory cells were identified as the main underlying features of TRS. The multi-omics data of TCGA HCC hint at the relevance of TRS to tumour immune infiltration and genetic alterations such as the FAT3 and RYR2 mutations., Conclusion: Our deep learning framework is an effective and labour-saving method for decoding pathological images, providing a valuable means for HCC risk stratification and precise patient treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC., Results: In this study, the use of poly(L-Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects-enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models., Conclusions: We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment.

Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner., 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 © 2021 Elsevier Masson SAS. All rights reserved.)

Liver cancer has a high incidence and a poor prognosis, which seriously affects human health. Doxorubicin is one of the chemotherapeutics used in the treatment of tumours, but its severe adverse reactions, especially cardiac toxicity, have limited its clinical application. The nanometre drug delivery system enables drug-loaded nanoparticles to be specifically concentrated in tumour tissues, increasing cell uptake and improving curative effect. Therefore, in this paper, folic acid-modified mesoporous silica nanoparticles (MSN-NH2-PEG-FA) were synthesized by modifying the folic acid on the surface of a drug carrier by using the characteristics of the expression of folic acid receptors, and using it as a drug. The carrier was loaded with antitumor drug doxorubicin hydrochloride (DOX), and a nanometre drug delivery system (MSN-NH2-PEG-FA/DOX) was constructed. At the same time, the near-infrared dye Cy5 was used to mark the mother nucleus to construct fluorescent nanoparticles (MSN-NH2-PEG-FA/DOX-Cy5) for cell and tumour imaging, so as to obtain the abdominal image of liver cancer patients, thereby realizing diagnosis and treatment. The research results show that the carrier can specifically gather in the liver area, reduce the distribution in the heart, reduce the toxic and side effects of drugs, and prolong the survival time of patients. The results of this study provide new ideas for the treatment of liver cancer, and provide a new theoretical basis and experimental basis for the study of inorganic nanomaterials as targeted drug delivery systems.

Background: Involvements of microRNA-22 (miR-22) in cancer have attracted much attention, but its role in diagnosis of hepatocellular carcinoma (HCC) is still largely unknown. Therefore, the aim of this study was to investigate the expression level and the prognostic value of miR-22 in HCC patients. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate serum level of miR-22 in 108 HCC patients and 67 healthy controls. The relationship between miR-22 expression level and clinicopathologic characteristics was analysed via chi-square test. Receiver operating characteristic (ROC) curve was built to estimate the diagnostic value of serum miR-22 in HCC. Results: miR-22 expression was significantly down-regulated in HCC compared to that in healthy controls ( p  < .05). And the low miR-22 expression was significantly associated with vein invasion ( p  = .002), TNM stage ( p  = .013) and high serum levels of AFP (α-fetoprotein), ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALP (alkaline phosphatase. miR-22 had a high diagnostic value with area under the curve of 0.866 corresponding with a sensitivity of 89.3% and a specificity of 68.9%, respectively. Conclusion: miR-22 expression was down-regulated in HCC patients. Serum miR-22 might be a novel diagnostic marker in HCC.

Sorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.