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Background & Aims: Despite its growing incidence, hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) in non-cirrhotic livers remains poorly characterized. We compared the characteristics, management, survival, and trends of MASLD-related HCC in patients with or without underlying cirrhosis in a large multicenter cohort. Methods: A total of 354 cases of MASLD-related HCC presented at the liver tumor meetings of four French university hospitals between 2007 and 2018 were included in the study. Data were extracted from the meetings’ databases and from the French Birth and Death Registry. Results: Of HCC cases, 35% occurred in the absence of cirrhosis. HCC was diagnosed through screening in 60% of patients with cirrhosis, and incidentally in 72% of patients without it. Patients without cirrhosis were older, had a greater tumor burden, but also better liver function than patients with cirrhosis. Patients without cirrhosis showed better overall survival than those with cirrhosis (p = 0.043). However, cirrhosis was not independently associated with overall survival, the independent predictors were age, liver function, tumor burden and BCLC classification. Patients without cirrhosis underwent surgery more frequently than patients with cirrhosis (41% vs. 11%, p

Over-expression of glutathione S-transferase (GST) can promote Cisplatin resistance in hepatocellular carcinoma (HCC) treatment. Hence, inhibiting GST is an attractive strategy to improve Cisplatin sensitivity in HCC therapy. Although several synthesized GST inhibitors have been developed, the side effects and narrow spectrum for anticancer seriously limit their clinical application. Considering the abundance of natural compounds with anticancer activity, this study developed a rapid fluorescence technique to screen “green” natural GST inhibitors with high specificity. The fluorescence assay demonstrated that schisanlactone B (hereafter abbreviated as C1) isolated from Xue tong significantly down-regulated GST levels in Cisplatin-resistant HCC cells in vitro and in vivo. Importantly, C1 can selectively kill HCC cells from normal liver cells, effectively improving the therapeutic effect of Cisplatin on HCC mice by down-regulating GST expression. Considering the high GST levels in HCC patients, this compound demonstrated the high potential for sensitizing HCC therapy in clinical practice by down-regulating GST levels.

Background: Malignant cells may arise from dedifferentiation of mature cells and acquire features of the progenitor cells. Definitive endoderm from which liver is derived, expresses glycosphingolipids (GSLs) such as stage-specific embryonic antigen 3 (SSEA3), Globo H, and stage-specific embryonic antigen 4 (SSEA4). Herein, we evaluated the potential prognosis value of the three GSLs and biological functions of SSEA3 in hepatocellular carcinoma (HCC). Methods: The expression of SSEA3, Globo H, and SSEA4 in tumor tissues obtained from 328 patients with resectable HCC was examined by immunohistochemistry staining. Epithelial mesenchymal transition (EMT) and their related genes were analyzed by transwell assay and qRT-PCR, respectively. Results: Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with higher expression of SSEA3 (p

An 82-year-old man with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) complicated by hepatocarcinoma was presented. Remission induction therapy of hyper-CVAD with half dose reduction achieved hematological complete remission (CR), but accompanied with elevated alanine aminotransferase and hyperbilirubinemia. The patient was thought intolerable for hyper-CVAD with half dose reduction due to liver toxicity, and treatment was switched to blinatumomab. Hematological CR was sustained after nine cycles of blinatumomab without exacerbation of liver dysfunction. After five courses of blinatumomab, hepatocarcinoma was treated successfully by trans-arterial chemoembolization. Two years after the diagnosis of ALL, the patient was alive in CR status of ALL.

Herein, we investigated the effects of acetone precipitation on the bioactivity of blue-maize zein hydrolysates (BmapZDH) against hepatocarcinoma (HepG2) and non-tumor cells (fibroblasts). Zein proteins were extracted from blue-maize flour hydrolyzed with Alcalase for 6 h, and the peptide fractions were filtered (

Background: Mushroom-derived components have immense potential to become a safe alternative in identifying lead anti-cancer molecules. Termitomyces heimii Natarajan (T. heimii) is a traditionally used edible mushroom with no previous record of anti-hepatocarcinoma activity. Methods: The anti-proliferative efficacy of the mushroom ethyl acetate extract was screened against a panel of seven cancer cell lines, namely Hep G2, MCF-7, MDA-MB-231, MAD-MB-436, MOLT-4, Reh, and K-562, and against peripheral blood mononuclear cells isolated from normal healthy donors by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. The impact of the extract on nuclear morphology was examined by 4′,6-diamidino-2-phenylindole staining and the apoptotic potential of the extract was evaluated through flow cytometry and Annexin V-PI dual staining, followed by an in vitro scratch assay to elucidate the anti-migratory potential of the extract. The apoptotic and anti-migratory effects were further validated using in silico molecular docking with four compounds, ergosterol, ergosta-5,8-dien-3-ol, lanosterol, and eburicol, against two anti-apoptotic proteins, Bcl-2 and Bcl-XL, and two angiogenic receptors, VEGFR-1 and VEGFR-2. Results: The screening data revealed that ethyl acetate extract exhibited remarkable anti-proliferative efficacy against Hep G2 cells, with a half maximal inhibitory concentration (IC50) value of 263.53 (8.09) μg/mL, followed by MCF-7 cell lines and showed a negligible effect on peripheral blood mononuclear cells. A clear alteration of the cellular and nuclear morphology was concentration-dependently observed in Hep G2 cells. The extract induced robust apoptosis and a significant concentration-dependent increase in the scratch area. The results of in silico docking revealed that compared to standard drug sunitinib, both ergosterol and ergosta-5,8-dien-3-ol displayed lower binding energy, and satisfactory drugability and absorption, distribution, metabolism, excretion, and toxicity properties. Conclusions: T. heimii is a potential source for isolating lead anticancer molecules in the future. Ergosterol and ergosta-5,8-dien-3-ol hold great promise as new drugs against hepatocarcinoma.

Cryoablation is a valuable treatment for liver cancer. To investigate the effect of KCl solution on the immunological response post cryoablation, we created a tumor-bearing mice model by subcutaneously implanting Hepal-6 cells in adult Balb/c mice. Subsequently, the mice were randomly assigned to three groups: group A (sham cryoablation), group B (cryoablation), and group C (cryoablation plus KCl solution). Mice were sacrificed on days 0, 7, and 14 post-treatment. Immune cell populations were assessed using flow cytometry. Blood samples were analyzed for serum IL-4, HSP70, and TGF-β1 levels with ELISA assays. Ablated tissues stained with immunohistochemistry were utilized to evaluate Ki67 expression at the margins of the ablation site. Our findings revealed higher HSP70 expression levels in groups B and C compared to group A. Cryoablation triggered an immune response, which was enhanced by KCl. On days 0, 7, and 14, the percentages of CD4 + T cells, CD8 + T cells, and NK cells in the spleen of group C were significantly increased compared with groups A and B. Additionally, the Th1/Th2 ratio was significantly increased in group C. Serum TGF-β1 expression was elevated after cryoablation, but KCl solution reduced the high TGF-β1 expression after cryoablation and decreased the invasiveness of cancer cells. Finally, the proliferative activity of untreated tumor tissue was significantly reduced in group C compared to groups A and B. In summary, Cryoablation triggered a systemic immune response in tumor-bearing mice, which was further boosted by combining cryoablation with a KCl solution., 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 Society for Cryobiology. Published by Elsevier Inc. All rights reserved.)

Introduction: As a member of annexin family proteins, annexin A3 (ANXA3) has 36-kDa and 33-kDa isoforms. ANXA3 plays crucial roles in the tumorigenesis, aggressiveness and drug-resistance of cancers. However, previous studies mainly focused on the role of total ANXA3 in cancers without distinguishing the distinction between the two isoforms, the role of 33-kDa ANXA3 in cancer remains unclear. Objectives: Current work aimed to investigate the function and regulation mechanism of 33-kDa ANXA3 in hepatocarcinoma. Methods: The expressions of ANXA3, CRKL, Rac1, c-Myc and pAkt were analyzed in hepatocarcinoma specimens by Western blotting. The biological function of 33-kDa ANXA3 in the growth, metastasis, apoptosis, angiogenesis, chemoresistance of hepatocarcinoma cells with the underlying molecular mechanism were investigated using gain-of-function strategy in vitro or in vivo. Results: 33-kDa ANXA3 was remarkably upregulated in tumor tissues compared with corresponding normal liver tissues of hepatocarcinoma patients. Its stable knockdown decreased the in vivo tumor growing velocity and malignancy of hepatocarcinoma HepG2 cells transplanted in nude mice. The in vitro experimental results indicated 33-kDa ANXA3 knockdown suppressed the proliferation, colony forming, migration and invasion abilities of HepG2 cells through downregulating CRKL, Rap1b, Rac1, pMEK, pERK2 and c-Myc in ERK pathway; inhibited angiogenesisability of HepG2 cells through inactivating PI3K/Akt-HIF pathway; induced apoptosis and enhanced chemoresistance of HepG2 cells through increasing Bax/decreasing Bcl-2 expressions and inactivating caspase 9/caspase 3 in intrinsic apoptosis pathway. Accordingly, CRKL, Rac1, c-Myc and pAkt were also upregulated in hepatocarcinoma patients ’ tumor tissues compared with corresponding normal liver tissues. Conclusions: The overexpression of 33-kDa ANXA3 is involved in the clinical progression of hepatocarcinoma and in the malignancy, angiogenesis and apoptosis of hepatocarcinoma cells. It is of potential use in hepatocarcinoma diagnosis and treatment.

Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.

The extracts of Pinus koraiensis pinecones have been proved to be highly cytotoxic to tumor cells, with ambiguous material basis of antitumor efficacy. In the present study, screening of compounds with antitumor activity was performed through successive applications of various purification technologies, accompanied with anticancer activity tracking. Futhermore, structures of target molecules were confirmed. In order to obtain highly active compounds, the lead compound dehydroabietic acid was chemically modified into its hexamer (DD2) by a simple method and its mechanisms for antitumor were explored in vivo and in vitro by some cell phenotype experiments, western blot, immunohistochemistry, TUNEL assay. Results showed that cytotoxins composed of 5-hydroxydehydroabietic acid, dehydroabietic acid, 15-hydroxy-7-oxodehydroabietic acid, 7α-hydroxydehydroabietic acid and inonotusic acid, exerted the synergistic antitumor effects against HepG2 cells. Especially, polymerization of multiple tricyclic skeletons effectively increased the cytotoxicity of dehydroabietic acid to tumor cells. Notably, DD2 exhibited stronger antitumor efficacy in vitro and in vivo mainly through the induction of G2/M cell cycle arrest and mitochondria apoptosis involving p53-Puma-Bcl-2/Bax axis. The analysis of liver / kidney function and HE staining demonstrated the no/low in vivo toxicity of DD2 to BALB/c nude mice. The findings will provide the theoretical reference to the discovery of new antitumor drugs and chemical modification of abietane diterpenoids.

Background: Malignant cells may arise from dedifferentiation of mature cells and acquire features of the progenitor cells. Definitive endoderm from which liver is derived, expresses glycosphingolipids (GSLs) such as stage-specific embryonic antigen 3 (SSEA3), Globo H, and stage-specific embryonic antigen 4 (SSEA4). Herein, we evaluated the potential prognosis value of the three GSLs and biological functions of SSEA3 in hepatocellular carcinoma (HCC)., Methods: The expression of SSEA3, Globo H, and SSEA4 in tumor tissues obtained from 328 patients with resectable HCC was examined by immunohistochemistry staining. Epithelial mesenchymal transition (EMT) and their related genes were analyzed by transwell assay and qRT-PCR, respectively., Results: Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with higher expression of SSEA3 (p < 0.001), Globo H (p < 0.001), and SSEA4 (p = 0.005) and worse overall survival (OS) for those with high expression of either SSEA3 (p < 0.001) or SSEA4 (p = 0.01). Furthermore, multivariable Cox regression analysis identified the SSEA3 as an independent predictor for RFS (HR: 2.68, 95% CI: 1.93-3.72, p < 0.001) and OS (HR: 2.99, 95% CI: 1.81-4.96, p < 0.001) in HCC. Additionally, SSEA3-ceramide enhanced the EMT of HCC cells, as reflected by its ability to increase migration, invasion and upregulate the expression of CDH2, vimentin, fibronectin, and MMP2, along with ZEB1. Moreover, ZEB1 silencing abrogated the EMT-enhancing effects of SSEA3-ceramide., Conclusions: Higher expression of SSEA3 was an independent predictor for RFS and OS in HCC and promoted EMT of HCC via upregulation of ZEB1., Competing Interests: Conflicts of interest The authors declare that there is no competing interests., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.

Fontan-associated liver disease is a hepatic disorder arising from hemodynamic changes and systemic venous congestion following Fontan surgery. The histological changes produced in the liver are similar but not equivalent to those seen in other forms of cardiac liver disease. While the natural history of this form of liver disease is not well established, over time many Fontan patients develop portal hypertension-related complications such as ascites, variceal hemorrhage or encephalopathy. Fontan survivors also show an increased risk of hepatocellular carcinoma. Early diagnosis of advanced liver disease is mandatory for the prevention and treatment of complications such as hepatocellular carcinoma, esophageal varices and malnutrition. This review updates current knowledge of the pathophysiology and management of Fontan-associated liver disease including new diagnostic methods and treatments.

Introducción: Los niveles séricos de alfafetoproteína (AFP) preoperatoria pueden tener valor predictivo para la sobrevida del hepatocarcinoma (HCC). Objetivo: Analizar la correlación entre los niveles séricos de AFP preoperatoria y la sobrevida posterior al tratamiento quirúrgico del HCC. Métodos: Diecinueve pacientes fueron seguidos prospectivamente (julio del 2005-enero del 2016). Se realizó una curva ROC para determinar la sensibilidad y la especificidad de la AFP con relación con la sobrevida (Kaplan-Meier). Resultados: Se evaluó a 19 pacientes, 57.9% hombres, edad media 68.1 ± 8.5 años con sobrevida a 1, 3 y 5 años del 89.4, el 55.9 y el 55.9%. El punto de corte de AFP fue 15.1 ng/ml (sensibilidad 100%, especificidad 99.23%). Los niveles preoperatorios de AFP menores de 15.1, 200, 400 y 463 ng/ml correlacionaron con mejor sobrevida a 1 y 5 años que niveles mayores de AFP (p < 0.05). Conclusiones: Los niveles séricos preoperatorios elevados de AFP tienen valor predictivo en relación con la sobrevida de HCC.

La esteatosis hepática no alcohólica es la acumulación excesiva de grasa en el hígado, en ausencia de causas secundarias y constituye la etiología frecuente de enfermedad hepática crónica sin terapia efectiva demostrada. La enfermedad incluye esteatosis, inflamación, fibrosis/cirrosis y hepatocarcinoma. El fenómeno inicial ocurre en la grasa corporal, con hipertrofia adipocitaria, liberación de adipoquinas y citoquinas pro-inflamatorias, que inducirán resistencia a la insulina. Este fenómeno provocará liberación de ácidos grasos a la circulación, captados por hepatocitos. En su evaluación clínica existen diferentes algoritmos con múltiples variables, limitando la biopsia hepática solo a casos excepcionales. Es esencial modificar el estilo de vida y bajar de peso. En diabéticos, metformina y pioglitazona son de primera elección. Los bloqueadores de la angiotensina son útiles en hipertensos con EHNA. Para prevenir la progresión de la enfermedad y en pacientes no diabéticos, asociar vitamina E. Las estatinas pueden utilizarse dada la asociación con patología cardiovascular.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths throughout the world. This study was aimed to analyze oxidative stress and cell damage in a multistage model of liver carcinogenesis induced by diethylnitrosamine (DEN) in rats. Male Wistar rats weighing 145–150 g were divided into three groups: control, precancerous lesions (PL) (which received 100 mg DEN once a week every 6 weeks up to 28 weeks), and advanced HCC (50 mg DEN once/twice per week up to 19 weeks). Lipid peroxidation (TBARS), superoxide dismutase (SOD) activity, and expression of transforming growth factor-1 beta (TGF)-1β, endothelial and inducible nitric oxide syntahese (eNOS, iNOS), NADPH quinone oxireductase (NQO)-1, nuclear factor erythroid 2-related factor (NrF)2, kelch-like ECH-associated protein (Keap)1 and heat shock protein (HSP)70 were measured. TBARS concentration was augmented in the PL and advanced HCC groups. SOD activity, TGF-1β and Nrf2 expression were higher in animals with precancerous lesions. In advanced HCC, expression of NQO1 and iNOS increased while there was a decrease in HPS70 expression. Data obtained provide evidence for the differential activation of proteins involved in oxidative stress and cell damage during progression of carcinogenesis in an animal model of HCC.

Gastrointestinal cancers are one of the most frequent cancers and a leading cause of cancer deaths worldwide. We provide an overview of the most important practice-changing trials that were either published or presented at the international scientific meetings in 2021-2023. Highlights included reports on three phase III trials (CONCORDE/PRODIGE 26, ARTDECO, and a study by Xu et al.) that evaluated dose escalation in the definitive setting for locally advanced oesophageal cancers, as well as two phase III trials that evaluated the role of chemotherapy (neo-AEGIS) and targeted therapy (NRG/RTOG 1010) in the neoadjuvant setting for adenocarcinoma oesophageal cancers or gastroesophageal junction cancer. CheckMate 577 evaluated nivolumab in patients who had residual pathological disease after neoadjuvant chemoradiation followed by complete resection. The use of radiation therapy for borderline and locally advanced pancreatic cancer is also discussed (SMART and CONKO-007 trials). Stereotactic body radiation therapy followed by sorafenib was compared to sorafenib alone in patients with hepatocellular carcinoma in the NRG/RTOG 1112 study. New options in the management of rectal cancer are emerging such as total neoadjuvant treatment (PRODIGE 23, RAPIDO, PROSPECT), organ preservation (OPRA, OPERA), and the role of immunotherapy in patients with DNA mismatch-repair deficient/microsatellite instability. Finally, preliminary results of the ACT 4 trial that evaluated de-escalation in anal cancer are presented., (Copyright © 2023 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Arsenic trioxide (ATO) has been identified as an effective treatment for acute promyelocytic leukemia (APL) but is much less effective against solid tumors such as hepatocellular carcinoma (HCC). In the search for ways to enhance its therapeutic efficacy against solid tumors, we have examined its use in combination with a novel derivative of β-elemene, N-(β-elemene-13-yl)tryptophan methyl ester (ETME). Here we report the effects of the combination on cell viability, apoptosis, the cell cycle and mitochondria membrane potential (MMP) in HCC SMMC-7721 cells. We found that the two compounds acted synergistically to enhance antiproliferative activity and apoptosis. The combination also decreased the MMP, down-regulated Bcl-2 and pro-proteins of the caspase family, and up-regulated Bax and BID, all of which were reversed by the p53 inhibitor, pifithrin-α. In addition, the combination induced cell cycle arrest at the G2/M phase and reduced tumor volume and weight in an xenograft model of nude mice. Overall, the results suggest that ETME in combination with ATO may be useful in the treatment of HCC patients particularly those unresponsive to ATO alone.

Background. Cyclooxygenase-2 (COX-2) enzyme over expression is reported in many human HCC cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with HCC. COX-2 is often increased and involved in drug resistance and poor prognosis.Method. Between January 2001 and December 2007, 15 patients with MDR-positive-HCC from 34 HCC patients based on tissue and serum liver of glypican-3 and fitting the preset eligibility criteria, were treated with a combination regimen with intravenous infusion of (5-FU) 750 mg once per week, 100mg/day cyclophosphamide (Endoxan) and 400 mg/day celecoxib taken orally in divided doses, while the rest of the patients received only 5-FU and Endoxan. Twenty-one patients (62%) had liver disease associated with hepatitis C virus (HCV) and 5 patients with hepatitis B virus (62%). Results. We found that celecoxib reduced P-glycoprotein with activation of caspase-3 and marked regression of tumor sizes. Sera angiogenic factors (VEGF & bFGF) levels measurement in HCC patients indicated that, the sera levels of both angiogenic factors were reduced significantly (p < 0.05) after treatment. Based on the tumor markers AFP & Glypican-3, 11 of the patients had a PR (11/15), including 3 patients who had normalization of AFP, and four patients had CR (4/15).Conclusions. These data suggest that the combination of 5-FU, Endoxan and Celecoxib is highly effective palliative regimen for patients with HCC with good performance status (score ≤ 3). The study suggests a framework for Celecoxib-based combination treatment of HCC.

The pro- or antitumoral properties of nitric oxide (NO) are dependent on local concentration, redox state, cellular status, duration of exposure and compartmentalization of NO generation. The intricate network of the tumor microenvironment (TME) is constituted by tumor cells, stromal and immune cells surrounded by active components of extracellular matrix that influence the biological behavior and, consequently, the treatment and prognosis of cancer. The review describes critical events in the crosstalk of cellular and stromal components in the TME, with special emphasis in the impact of NO generation in the regulation of hepatocellular carcinoma (HCC). The increased expression of nitric oxide synthase (NOS) in tumors and NO-end products in plasma have been associated with poor prognosis of cancer. We have assessed the level of the different isoforms of NOS in tumors and its relation to cell proliferation and death markers, and cell death receptor expression in tumors, and apoptotic markers and ligands of TNF-α receptor family in blood from a cohort of patients with HCC from different etiologies submitted to orthotopic liver transplantation (OLT). The high levels of NOS2 in tumors were associated with low plasma concentration of apoptotic markers (M30 and M65), FasL and TNF-α in HCV patients. By contrast, the low levels of NOS2 in tumors from alcohol-derived patients was associated with increased Trail-R1 expression in tumors, and circulating Trail levels compared to observed in plasma from HCV- and alcohol + HCV-derived patients. This study reinforces the association between increased NOS2 expression and potential risk of low patients' survival in HCC. However, a differential functional relevance of NOS expression in HCC seems to be influenced by etiologies., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic hepatitis C virus infection is a well-recognized risk factor for occurrence of hepatocellular carcinoma (HCC). In Europe, Oceania and America, chronic hepatitis C and alcoholic cirrhosis are the main risk factors for HCC. In Latin America, a few retrospective and one prospective study have also shown the pre-dominant role played by hepatitis C in this setting. Furthermore, the incidence of HCC has been increasing in industrialized countries in the last decades; partially as a consequence of the increase in HCV-related cirrhosis (as the long-term sequel of the peak of infections occurring 2-4 decades ago). The main risk factor for HCC development in patients with hepatitis C is the presence of cirrhosis. Among patients with hepatitis C and cirrhosis, the annual incidence rate of HCC ranges between 1-8%, being higher in Japan (4-8%) intermediate in Italy (2-4%) and lower in USA (1.4%). Some studies have also found that HCC may be the first complication to develop and the more frequent cause of death in the compensated HCV-associated cirrhosis. Other risk factors for HCC occurrence are older age at infection, male gender, decreased platelet count, esophageal varices, presence of porphyria cutanea tarda, liver steatosis or diabetes, infection with genotype 1b, coinfection with hepatitis B virus or with HIV and chronic alcoholism. Many studies and also meta-analysis have reported that antiviral therapy based on interferon may reduce the incidence of HCC in chronic hepatitis C, especially in patients with sustained virologic response. Patients with HCV-related cirrhosis should undergo surveillance for HCC.

This study examines the hepatoprotective activity of naringin loaded solid nanoparticles (NRG-SLNs) and compared with free naringin (FNRG) against aflatoxin B1 (AFB1) induced hepatocellular carcinoma. The liver's self-healing ability was studied using a self-recovery group that received no therapy. Following AFB1 therapy, rats were given NRG-SLNs produced using the ion-gelation technique. Histology, serum injury indicators, oxidative stress biomarkers, a pro-inflammatory response biomarker, and tumor indicators were used to evaluate the liver tumor and its responsiveness to therapy. At a dosage of 6.18 mg/kg BW, NRG-SLNs (128 ± 4 nm) provided substantially greater hepatoprotection than free NRG. The actions of NRG-SLNs were equivalent to those of silymarin (SILY), which was given at a dosage of 20 mg/kg BW. The lack of regeneration potential of liver tissue after the damage was verified by the self-recovery group. NRG's efficiency in treating hepatic cancer was increased by using SLN's approach. The increased impact is most likely due to: a) enhanced oral bioavailability, b) the regulated and sustained action of enclosed NRG, and c) a decrease in discomfort and toxicity if any after orally administered. NRG-SLNs may be considered as a therapeutic option for hepatic ailments as effectiveness post-induction of liver carcinoma, is demonstrated presently., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mesoionic compounds, 4-phenyl-5-(4-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride derivatives (MI-J: X = OH; MI-D: X = NO 2 ), possess significant antitumor and cytotoxic effects on several cancer cells. In this work, we evaluated the cytotoxicity of MI-J and MI-D on human hepatocellular carcinoma (HepG2 cells) grown in either high glucose (HG) or galactose medium (GAL) to clarify whether the effects of mesoionics on mitochondrial bioenergetics are associated with their cytotoxicity in these cells. MI-J and MI-D (5-50 μM) decreased the viability of HepG2 cells in a dose- and time-dependent manner, as assessed by MTT, LDH release and dye with crystal violet assays. Both compounds at lower (5 μM) and intermediate (25 μM) concentrations were more toxic to cells grown in GAL medium. MI-J inhibited the basal state of respiration in HepG2 cells cultured in HG and GAL media; however, in GAL medium, this effect occurred at the lowest concentration (5 μM). A leak-state stimulus was observed only after incubation with MI-J (5 μM) for GAL medium. MI-D stimulated and inhibited the leak state in cells grown in HG medium at concentrations of 5 μM and 25 μM, respectively. In cells cultured in GAL medium, respiration was strongly inhibited by MI-D at the highest concentration (25 μM). In contrast, at 5 μM, the mesoionic inhibited the basal and uncoupled states at 30% and 50%, respectively. The inhibition of the basal state by MI-J and MI-D was consistent with the increase in lactate levels in both media, which was higher for the GAL medium. Both mesoionics slightly decreased pyruvate levels only in cells cultured in GAL medium. Additionally, MI-J (25 μM) reduced the ATP amount in cells cultured in both media, while MI-D (25 μM) promoted a reduction only in cells grown in GAL medium. Our results show that MI-J and MI-D depress mitochondrial respiration and consequently change metabolism and reduce ATP levels, effects associated with their toxicity in hepatocarcinoma cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Methylglyoxal is a dicarbonyl compound recruited as a potential cytotoxic marker, initially presents in cells and considered as a metabolite of the glycolytic pathway. Our aim is to demonstrate the inhibitory effect of 3, 3'-[3-(5-chloro-2-hydroxyphenyl)-3-oxopropane-1, 1-diyl] Bis (4-hydroxycoumarin) on the glyoxalase system, and indirectly its anticancer activity. The docking of OT-55 was conducted by using Flexible docking protocol, ChiFlex and libdock tools inside the active site of Glo-I indicated that both hydrogen bonding and hydrophobic interactions contributed significantly in establishing potent binding with the active site which is selected as a strong inhibitor with high scoring values and maximum Gibbs free energy. Coumarin-liposome formulation was characterized and evaluated in vivo against chemically induced hepatocarcinoma in Wistar rats. After Diethylnitrosamine (DEN) induction, microscopic assessment was realized; precancerous lesions were developed showing an increase of both tumor-associated lymphocyte and multiple tumor acini supported by the blood investigation. Our finding also suggested a preferential uptake of liposomes respectively in liver, kidney, lung, brain and spleen in the DEN-treated animals. OT-55 has also been shown to inhibit the activity of Glo-I in vitro as well as in DEN-treated rats. An abnormal high level of MGO of up to 50% was recorded followed by a reduction in glucose consumption and lactate dehydrogenase production validated in the positive control. MGO generates apoptosis as depicted by focal hepatic lesions. Also, no deleterious effects in the control group were observed after testing our coumarin but rather a vascular reorganization leading to nodular regenerative hyperplasia. Involved in the detoxification process, liver GSH is restored in intoxicated rats, while no changes are seen between controls. At the endothelial cell, OT-55 appears to modulate the release of NO only in the DEN-treated group. OT-55 would behave both as an anticancer agent but also as an angiogenic factor regarding results obtained., (Copyright © 2021. Published by Elsevier B.V.)

Water-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 µm at 25 mg/mL to 69 µm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. STATEMENT OF SIGNIFICANCE: We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most lethal cancer worldwide. Although gene mutations associated with HCC development have been intensively studied, how epigenetic factors specifically modulate the functional properties of HCC by regulating target gene expression is unclear. Here we demonstrated the overexpression of KDM3B in liver tissue of HCC patients using public RNA-seq data. Ablation of KDM3B by CRISPR/Cas9 retarded the cell cycle and proliferation of hepatocarcinoma HepG2 cells. Approximately 30% of KDM3B knockout cells exhibited mitotic spindle multipolarity as a chromosome instability (CIN) phenotype. RNA-seq analysis of KDM3B knockout revealed significantly down-regulated expression of cell cycle related genes, especially cell proliferation factor CDC123. Furthermore, the expression level of Cyclin D1 was reduced in KDM3B knockout by proteosomal degradation without any change in the expression of CCND1, which encodes Cyclin D1. The results implicate KDM3B as a crucial epigenetic factor in cell cycle regulation that manipulates chromatin dynamics and transcription in HCC, and identifies a potential gene therapy target for effective treatment of HCC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

PAK4 is overexpressed in a variety of human cancers and considered a promising candidate for therapeutic target. However, its functions remain poorly understood, especially in liver carcinogenesis which could be triggered by inflammation. In the present study, endogenous PAK4 was knockdown using siRNA in HepG2 and SK-Hep1 cells. The two cell lines performed reduced cell viability, altered cell cycle composed of decreased S and arrest in G2, and apoptosis. Meanwhile, expression of NF-κB p65 in the nuclei and caspase-8 activity did not show significant differences from control. However, after treating cells with TNF-α, an inflammatory cytokine, we investigated repressed nuclear expression and localization of NF-κB p65, and induced apoptosis with increased caspase-8 activity in PAK4-knockdown cells. The findings revealed that ablation of PAK4 inhibited cell viability via blocking cell cycle and progressing apoptosis. The apoptosis was partially dependent upon caspase-8 concomitant with attenuated NF-κB survival signal due to stimulus of TNF-α. It suggests that PAK4 as target is a switch between caspase-8 apoptosis and NF-κB survival signals induced by TNF-α in hepatocarcinoma cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

MicroRNA-125a exhibits an antiproliferative activity and is downregulated in several types of tumors, including hepatocellular carcinoma where it targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Another target of miR-125a is Lin28, a pluripotency factor that is generally undetectable in differentiated cells but is often upregulated/reactivated in tumors where it acts as an oncogenic factor promoting cell proliferation and tumor progression. In this study we show that downregulation of Lin28b by miR-125a partially accounts for its antiproliferative activity toward hepatocellular carcinoma cells. We also found that Lin28b is able to bind a conserved GGAG motif of pre-miR-125a and to inhibit its maturation in hepatocellular carcinoma cells. Reciprocal inhibition between miR-125a and Lin28b reasonably generates a positive feedback loop where reactivation of Lin-28b inhibits the expression of both miR-125a and let-7, reinforcing its own expression and leading to a marked overexpression of the mitogenic targets of the two miRNAs. On the other hand, perturbation of these circuits by overexpression of miR-125a suppresses Lin28b leading to a decreased cell proliferation. Overall, these data support a tumor suppressive role for miR-125a and contribute to the elucidation of its molecular targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To describe immunological consequences induced by cryoablation against H22 cells in vivo., Methods: Adult BALB/c mice underwent subcutaneous implantation of H22 cells. All of them were assigned into three groups randomly: group A (false surgery), group B (cryoablation) and group C (cryoablation plus Freund's adjuvant). Animals were sacrificed 1, 2 and 3 weeks after treatment. Serum IFN-γ and IL-4, Th1/Th2 in spleens and cytotoxicity were detected., Results: Compared with that of group A, (1) INF-γ of group B was higher, but IL-4 was lower; cryoablation plus Freund's adjuvant enhanced these effects. (2) Th1/Th2 rose significantly in both group B and group C. (3) Strong cytolytic activity against H22 cells of group B and group C was found on day 7, 14 and 21., Conclusions: Our study showed a marked shift toward Th1 and IFN-γ expression after cryoablation, with an immuno-stimulatory effect against murine H22 hepatoma Cell., (Copyright © 2017. Published by Elsevier Inc.)

The liver is an essential organ that ensures many vital functions such as metabolism of bilirubin, glucose, lipids, synthesis of coagulation factors, destruction of many toxins, etc. The hepatic parenchyma can be irradiated during the management of digestive tumors, right basithoracic, esophagus, abdomen in toto or TBI. In addition, radiotherapy of the hepatic area, which is mainly stereotactic, now occupies a central place in the management of primary or secondary hepatic tumors. Irradiation of the whole liver, or part of it, may be complicated by radiation-induced hepatitis. It is therefore necessary to respect strict dosimetric constraints both in stereotactic and in conformational irradiation in order to limit the undesired irradiation of the hepatic parenchyma which may vary according to the treatment techniques, the basic hepatic function or the lesion size. The liver is an organ with a parallel architecture, so the average tolerable dose in the whole liver should be considered rather than the maximum tolerable dose at one point. The purpose of this article is to propose a development of dose recommendations during conformation or stereotactic radiotherapy of the liver., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The SASH1 gene is discovered as a tumor suppressor recently. However, the molecular mechanisms of SASH1 in hepatocarcinoma (HCC) remain unclear. In present studies, we investigated the molecular mechanisms of SASH1 on cell invasion and metastasis of hepatocarcinoma in vivo and in vitro. In this study, SASH1 overexpression HCC cell lines were treated with purmorphamine (0, 0.5, 1, 2μmol/l). Western blot and qRT-PCR were used to examine the related gene expression of EMT markers and the Shh-Gli1 and PI3K/Akt-dependent pathway. Cell migration and invasion were assessed by Transwell assay. In addition, a mice SASH1 overexpression HCC orthotopic xenograft model was established and treated with purmorphamine or 740Y-P or PDGF. Tumor volume was assessed, and H&E staining was applied to histopathologic analysis. The results showed that purmorphamine exposure significantly increased the mRNA and protein expression levels of Shh and Gli1 in a dose-dependent manner in the SASH1 overexpression HepG2 and HCCLM3 cells. Besides, purmorphamine promoted the migration and invasion of SASH1 overexpression HCC cells, as well as the EMT progress. Moreover, purmorphamine significantly increased the synthesis of PI3K and pAkt in a dose-dependent manner. Furthermore, the invasion and migration abilities were also improved by treatment with 740Y-P or PDGF in the SASH1 overexpression HCC cells. Additionally, the agonists promoted tumor growth and intrahepatic and pulmonary metastasis of the orthotopic transplantation tumors grown from SASH1 overexpression HCC cells in vivo. In conclusion, SASH1 may inhibit hepatocarcinoma cell invasion and metastasis through down-regulating the Shh-Gli1 and PI3K-AKT pathways in vivo and in vitro., (Copyright © 2017. Published by Elsevier Ltd.)

Portal vein embolization consists of occluding a part of the portal venous system in order to achieve the hypertrophy of the non-embolized liver segments. This technique is used during the preoperative period of major liver resection when the future remnant liver (FRL) volume is insufficient, exposing to postoperative liver failure, main cause of death after major hepatectomy. Portal vein embolization indication depends on the FRL, commonly assessed by its volume. Nowadays, FRL function evaluation seems more relevant and can be measured by 99mTc labelled mebrofenin scintigraphy. Portal vein embolization procedure is mostly performed with percutaneous trans-hepatic access by using ultrasonography guidance and consists of embolic agent injection, such as cyanoacrylate, in the targeted portal vein branches with fluoroscopic guidance. It is a safe and well-tolerated technique, with extremely low morbi-mortality. Portal vein embolization leads to sufficient FRL hypertrophy in about 80% of patients, allowing them to undergo surgery from which they were initially rejected. The two main reasons of non-resection are tumor progression (≈15% of cases) and FRL insufficient hypertrophy (≈5% of cases). When portal vein embolization is not enough to obtain adequate FRL regeneration, hepatic vein embolization may potentiate its effect (liver venous deprivation technique)., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Toxicity of the SYD-1 mesoionic compound (3-[4-chloro-3-nitrophenyl]-1,2,3-oxadiazolium-5-olate) was evaluated on human liver cancer cells (HepG2) grown in either high glucose (HG) or galactose (GAL) medium, and also on suspended cells kept in HG medium. SYD-1 was able to decrease the viability of cultured HepG2 cells in a dose-dependent manner, as assessed by MTT, LDH release and dye with crystal violet assays, but no effect was observed on suspended cells after 1-40 min of treatment. Respiration analysis was performed after 2 min (suspended cells) or 24 h (cultured cells) of treatment: no change was observed in suspended cells, whereas SYD-1 inhibited as well basal, leak and uncoupled states of the respiration in cultured cells with HG medium. These inhibitions were consistent with the decrease in pyruvate level and increase in lactate level. Even more extended results were obtained with HepG2 cells grown in GAL medium where, additionally, the ATP amount was reduced. Furthermore, SYD-1 appears not to be transported by the main ABC multidrug transporters. These results show that SYD-1 is able to change the metabolism of HepG2 cells, and suggest that its cytotoxicity is related to impairment of mitochondrial metabolism. Therefore, we may propose that SYD-1 is a potential candidate for hepatocarcinoma treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Arsenic trioxide (ATO) has been identified as an effective treatment for acute promyelocytic leukemia (APL) but is much less effective against solid tumors such as hepatocellular carcinoma (HCC). In the search for ways to enhance its therapeutic efficacy against solid tumors, we have examined its use in combination with a novel derivative of β-elemene, N-(β-elemene-13-yl)tryptophan methyl ester (ETME). Here we report the effects of the combination on cell viability, apoptosis, the cell cycle and mitochondria membrane potential (MMP) in HCC SMMC-7721 cells. We found that the two compounds acted synergistically to enhance antiproliferative activity and apoptosis. The combination also decreased the MMP, down-regulated Bcl-2 and pro-proteins of the caspase family, and up-regulated Bax and BID, all of which were reversed by the p53 inhibitor, pifithrin-α. In addition, the combination induced cell cycle arrest at the G2/M phase and reduced tumor volume and weight in an xenograft model of nude mice. Overall, the results suggest that ETME in combination with ATO may be useful in the treatment of HCC patients particularly those unresponsive to ATO alone.

HIV infection is related to an increased risk of cancer compared with general population, both AIDS-defining cancers (Kaposi's sarcoma, non Hodgkin's lymphoma, invasive cervical cancer) and non-AIDS-defining cancers. Although the advent of the highly active antiretroviral therapy era has decreased the Kaposi's sarcoma and non-Hodgkin's lymphoma incidences, non-AIDS-defining malignancies, such as lung cancer, hepatocarcinoma, anal cancer and skin cancers, remain a major cause of morbidity and death in the HIV-infected population. The clinical presentation is often different between the infected and non-infected populations, often with a more advanced stage at diagnosis, a more aggressive pathology, and associated morbidities like immunosuppression, leading to poorer outcomes. Numerous studies have focused on HIV-related malignancies' treatment, however specific guidelines are still missing. Practitioners have to be careful with interactions between antiretroviral and antineoplastic drugs, particularly through the cytochrome P 450. Because of this, a national multidisciplinary approach, "Cancer and HIV, " was started in 2013 thanks to the National Institute of Cancer (INCa). The aim of this review is to present a scientific update about AIDS-and non-AIDS-defining malignancies, both in their clinical aspects and regarding their specific therapeutic management.

Rhizoma Paridis Saponins (RPS), which is the effective part of Rhizoma Paridis, showed strong anti-lung cancer and anti-hepatocarcinoma activities. In this research, a gas chromatography/mass spectrometry (GC/MS) method was developed and validated for the metabolic profiling of RPS intervention in H22 hepatocarcinoma mice. Data were analyzed with partial least-squares discrimination analysis (PLS-DA). As a result, RPS displayed different pathway to decrease energy production of the mice. For the normal mice, RPS significantly decreased the concentration of lipid, glycerate, succinate and lactate, but increased glucose and valine levels. All these indicated that RPS inhibited glucose and valine to transform ketones which participated in the ATP production. For the H22 cancer mice, RPS increased the concentration of lipid and glycerate, but significantly decreased glucose, glycine and alanine levels in the serum. This phenomenon indicated that RPS inhibited the oxidation of fatty acids pathway and the gluconeogenesis pathway which participated in the energy supply for the body. RPS also inhibited glycine and alanine production to block the tumor growth. This selective effect of RPS to different condition of mice would improve understanding of the antitumor pathway of RPS involved in H22 hepatocarcinoma mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The proteasome inhibitor-based combinational therapy has been reported to be an efficient cancer treatment. Our recent studies demonstrated that the natural compound gambogic acid (GA) is a tissue-specific proteasome inhibitor, comparable to bortezomib (Bor), and sensitizes malignant cells to the proteasome inhibitor MG132/MG262 both in vitro and in vivo. The aim of this study was to further extend our investigation by combining GA with the clinically used proteasome inhibitor Bor to test their combined efficacy against human hepatoma HepG2 and mouse hepatoma H22 cells. GA and Bor synergistically induced cytotoxicity and cell death in human HepG2 and mouse H22 cells, and accelerated proteasome inhibition, endoplasmic reticulum (ER) stress and caspase activation in HepG2 cancer cells. However, unexpectedly, GA did not enhance or even antagonized Bor-induced tumor growth inhibition in H22 allograft and HepG2 xenograft tumor models. These findings demonstrated that GA increased Bor activity in vitro but limited the efficacy of Bor in vivo. We suggest that the combination of GA and Bor be avoided when administering these drugs to patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

In the present study, we investigated the antitumor and immunomodulatory activity of Astragalus membranaceus polysaccharide (AMP) on liver cancer using murine H22 hepatocarcinoma model. The results showed that AMP (100 and 400 mg/kg) could effectively inhibit the solid tumor growth of H22 hepatocarcinoma transplanted in BALB/c mice. Besides, the body weight, spleen/thymus indexes and phagocytotic function of macrophage of H22 tumor bearing mice were also improved in two AMP treated groups. Furthermore, AMP treatment could promote the secretion of IL-2, IL-12 and TNF-α and decreased IL-10 level in serum. Taken together, these findings indicate that AMP has antitumor activity in vivo at least partly via improving immune responses of host organism, and seems to be safe and effective for the use of anti-tumor therapy., (Copyright © 2013 Elsevier B.V. All rights reserved.)