Search Results (149)

A quinoline unit is present in many natural products and is an attractive pharmacophore for the development of clinical drugs, including antineoplastics. The title compound (QN) was synthesized via the condensation reaction between quinoline-2-carboxaldehyde and 2-nitrobenzhydrazide. QN’s structure was examined by X-ray diffraction and features extensive stacking interactions in the crystal. The compound is weakly toxic to HepG2 cells, with an IC₅₀ exceeding 400 μM for 48 h exposure. QN at 50 μM, with the dose reduction index in the range of 1.9–4.4, potentiated the cytotoxicity of several clinical chemotherapeutic drugs, including doxorubicin and other topoisomerase inhibitors, vincristine, and carboplatin, but not cisplatin or 5-fluorouracil. The calculated ADME parameters predict satisfactory drug-like properties for QN. Full article

Background/Objectives: The membrane protein a disintegrin and metalloproteases (ADAMs) are highly expressed in various human carcinomas and play an important role in cancer characteristics. And among these, ADAM32 is highly expressed in hepatoblastoma (HBL) and plays an important role in oncogenic properties. However, the regulatory mechanism has not been determined. Recently, it has been reported that some ADAMs are regulated by HIF, which is an important transcription factor in response to hypoxia. Therefore, we decided to study the regulatory mechanisms of ADAM32 under hypoxic conditions by using HBL, breast, and lung cancer cell lines. Methods/Results: When these cells were exposed to 1% O₂ (hypoxia), it was found that the levels of ADAM32 increased at 48 h in HepG2, MCF7, and MDA-MB-231 but not in HUH-6 or lung cancer lines. However, the promoter activity of the ADAM32 gene in HepG2 remained unchanged under hypoxic conditions, suggesting that the level of ADAM32 in HBL is regulated by factors other than the promoter activity. From the microarray data, we found that the level of IGF2BP2, which is an m⁶A-related molecule, correlated with that of ADAM32, and these levels were decreased by HIF1A knockdown. And IGF2BP2 knockdown decreased the expression of ADAM32 and attenuated the increased expression of ADAM32 under hypoxic conditions. Conclusions: This study demonstrated that the oncogenic gene ADAM32 is regulated by IGF2BP2 and that IGF2BP2 could be a molecular target for HBL anticancer therapy. Full article

Hepatoblastoma (HB) is the most common pediatric primary liver tumor. About 20% of affected children have pulmonary metastasis at presentation. Survival rates for these children are dismal, not exceeding 25%. To study this subset of patients, we sequenced a metastatic HB cell line, HLM_2, and identified downregulation of the Liver X Receptor (LXR)/Retinoid X Receptor (RXR) pathway. LXR/RXRs function as transcriptional regulators that influence genes implicated in HB development, including the Wnt/β-catenin signaling pathway. We assessed the effects of a novel LXR/RXR agonist, UAB116, on metastatic HB, hypothesizing that this compound would affect genes governing the Wnt/β-catenin pathway, decreasing the metastatic phenotype of HLM_2 metastatic HB cells. We evaluated its effects on viability, proliferation, stemness, clonogenicity, and motility, and performed RNA sequencing to study differential gene regulation. Treatment with UAB116 for 72 h decreased HLM_2 proliferation, stemness, clonogenicity, and invasion. RNA sequencing identified an eight-fold increase in TRIM29, a gene known to inhibit β-catenin, in cells treated with UAB116. Administration of the LXR/RXR agonist, UAB116, reduces proliferation, stemness, and invasiveness of metastatic HB cells, potentially by upregulation of TRIM29, a known modulator of the Wnt/β-catenin pathway, providing support for further exploration of LXR/RXR agonism as a therapeutic strategy for metastatic HB. Full article

Background/Objectives: Hepatoblastoma, the most common malignant liver tumor in pediatric patients, is characterized by a remarkably low mutation rate, thereby impeding targeted therapies. Current treatment regimens rely on conventional cytotoxic agents that often cause severe adverse effects, necessitating the search for novel, less toxic therapeutic approaches. Methods: In this study, we explored the anti-tumor potential of heat shock protein 90 (HSP90) inhibitors using a unique collection of hepatoblastoma in vitro models. Results: Among the five tested inhibitors, we identified ganetespib as the most effective, significantly suppressing tumor cell growth while sparing healthy, non-tumor cells. Ganetespib treatment at low nanomolar concentrations markedly reduced cell proliferation, impaired long-term survival, and inhibited three-dimensional spheroid growth, ultimately leading to the induction of apoptosis. Mechanistically, ganetespib downregulated the expression of the HSP90 client protein cyclin-dependent kinase 1, a key cell cycle regulator controlling G2/M phase transition, which is heavily upregulated in hepatoblastoma. This disruption consequently resulted in cell cycle arrest, further contributing to its anti-tumor effects. Conclusions: HSP90 inhibition by ganetespib demonstrates significant potential as a novel therapeutic strategy for hepatoblastoma, offering a potential alternative to current cytotoxic treatments with fewer adverse effects. Full article

Background/Objectives: Early-onset cancer is an emerging global health concern, including in the United States. However, data on early-onset liver and intrahepatic bile duct cancer remain limited. This study aims to fill this gap by analyzing trends in early-onset liver and intrahepatic bile duct cancer in the United States over the past two decades. Methods: This study used National Childhood Cancer Registry data to examine temporal trends in early-onset liver and intrahepatic bile duct cancer in the United States. The analysis involved estimating age-adjusted incidence rates of early-onset liver and intrahepatic bile duct cancer, stratified by histological type, ethnicity, and sex. Results: In 2021, the age-adjusted incidence rate of early-onset liver and intrahepatic bile duct cancer was estimated at 0.53 per 100,000 population (95% Confidence Interval [CI]: 0.48–0.59). From 2001 to 2021, the age-adjusted incidence rate showed a significant annual percent change (APC) of 1.35% (95% CI: 0.87–1.83%). When stratified by sex, the age-adjusted incidence rate in females increased significantly (APC: 3.07%, 95% CI: 2.26–3.87%) while remaining stable in males. Among racial and ethnic groups, non-Hispanic American Indian and Alaska Native (AIAN) individuals had the highest age-adjusted incidence rate, recorded at 2.67 per 100,000 population (95% CI: 0.95–5.85). By histological type, hepatic carcinoma had the highest age-adjusted incidence rate, significantly increasing over time (APC: 1.47%, 95% CI: 0.96–1.99%). In contrast, the incidence rates for hepatoblastoma and unspecified hepatic tumors remained stable between 2001 and 2021. Conclusions: Our study identified an increasing incidence of early-onset liver and intrahepatic bile duct cancer in the United States, primarily driven by cases in females and hepatic carcinoma. Full article

Hepatoblastoma (HB) is the most common malignant liver tumor in children under five years of age. Although globally rare, it accounts for a large proportion of liver cancer in children and has poor survival rates in high-risk and metastatic cases. This review discusses the molecular mechanisms, diagnostic methods, and therapeutic strategies of HB. Mutations in the CTNNB1 gene and the activation of the Wnt/β-catenin pathway are essential genetic factors. Furthermore, genetic syndromes like Beckwith–Wiedemann syndrome (BWS) and Familial Adenomatous Polyposis (FAP) considerably heighten the risk of associated conditions. Additionally, epigenetic mechanisms, such as DNA methylation and the influence of non-coding RNAs (ncRNAs), are pivotal drivers of tumor development. Diagnostics include serum biomarkers, immunohistochemistry (IHC), and imaging techniques. Standard treatments are chemotherapy, surgical resection, and liver transplantation (LT). Emerging therapies like immunotherapy and targeted treatments offer hope against chemotherapy resistance. Future research will prioritize personalized medicine, novel biomarkers, and molecular-targeted therapies to improve survival outcomes. Full article

Pediatric hepatocellular carcinoma (HCC) is a rare malignant liver tumor affecting children and adolescents and occurring either sporadically or in the context of underlying liver disease. In this review, we detail the epidemiology of pediatric HCC with a focus on predisposing factors including hepatic or systemic disease, genetic disorders, and familial cancer syndromes. We summarize existing research on the pathophysiology of pediatric HCC, including molecular mechanisms of oncogenesis, highlighting unique disease features differentiating pediatric HCC from adult HCC. We then survey the landscape of therapeutic options for pediatric HCC, including novel therapeutics. Lastly, we discuss the pathologic spectrum upon which pediatric HCC is postulated to exist, ranging from hepatoblastoma to HCC and including the hybrid entity hepatocellular neoplasm not otherwise specifed (HCN-NOS). In summary, we highlight the key clinical and molecular features of pediatric HCC that may inform future research and novel approaches to the clinical care of these patients. Full article

(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: The cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. The analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT medulloblastoma, 13 of which are involved in Wnt pathway regulation: RNF43, LEF1, NKD1, AXIN2, DKK4, DKK1, LGR6, FGFR2, NXN, TCF7L1, STK3, YAP1, and NFATC4. The ROC curve analysis of the combined expression of these 13 WNT-related LEF1 targets yielded an area under the curve (AUC) of 1.00, indicating 100% specificity and sensitivity for predicting the WNT subtype in the PBTA medulloblastoma cohort. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma. Full article

Background and Aims: Hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC) are the most common liver malignancies in children and young adults. FLC oncogenesis is associated with the generation of the fusion kinase, DNAJB1-PKAc (J-PKAc). J-PKAc has been found in 90% of FLC patients’ tumors but not in other liver cancers. Since previous studies of J-PKAc were performed with adolescent patients, we asked if young children may express J-PKAc and if there are consequences of such expression. Methods: The biobank of the pediatric HBL/HCN-NOS specimens was examined by QRT-PCR, Western blots, RNA-Seq, and immunostaining with fusion-specific antibodies. Results: J-PKAc is expressed in 70% of the HBL/HCN-NOS patients. RNA-Seq analysis revealed that HBL tumors that do not have cells expressing J-PKAc show elevated expression of the membrane attack complex (MAC), which eliminates cells expressing J-PKAc. The fusion-positive HBL/HCN-NOS samples have several signaling pathways that are different from fusion-negative HBLs. Upregulated pathways included genes involved in the G1 to S transition and in liver cancer. Downregulated pathways included over 60 tumor suppressors, the CYP family, and the SLC family. The repression of these genes involves J-PKAc-β-catenin-TCF4-mediated elevation of the HDAC1-Sp5 pathway. The identified upregulated and downregulated pathways are direct targets of the fusion kinase. The J-PKAc kinase is also detected in livers of 1-year-old children with biliary atresia (BA). Conclusions: J-PKAc is expressed in both HBL tumor and BA liver samples, contributing to the development of HBL and creating a transcriptome profiling consistent with the potential development of liver cancer in young patients. Full article

Hepatoblastoma is the most common primary liver malignancy in children, with metabolic reprogramming playing a critical role in its progression due to the liver’s intrinsic metabolic functions. Enhanced glycolysis, glutaminolysis, and fatty acid synthesis have been implicated in hepatoblastoma cell proliferation and survival. In this study, we screened for altered overexpression of metabolic enzymes in hepatoblastoma tumors at tissue and single-cell levels, establishing and validating a hepatoblastoma tumor expression metabolic score using machine learning. Starting from the Mammalian Metabolic Enzyme Database, bulk RNA sequencing data from GSE104766 and GSE131329 datasets were analyzed using supervised methods to compare tumors versus adjacent liver tissue. Differential expression analysis identified 287 significantly regulated enzymes, 59 of which were overexpressed in tumors. Functional enrichment in the KEGG metabolic database highlighted a network enriched in amino acid metabolism, as well as carbohydrate, steroid, one-carbon, purine, and glycosaminoglycan metabolism pathways. A metabolic score based on these enzymes was validated in an independent cohort (GSE131329) and applied to single-cell transcriptomic data (GSE180665), predicting tumor cell status with an AUC of 0.98 (sensitivity 0.93, specificity 0.94). Elasticnet model tuning on individual marker expression revealed top tumor predictive markers, including FKBP10, ATP1A2, NT5DC2, UGT3A2, PYCR1, CKB, GPX7, DNMT3B, GSTP1, and OXCT1. These findings indicate that an activated metabolic transcriptional program, potentially influencing epigenetic functions, is observed in hepatoblastoma tumors and confirmed at the single-cell level. Full article

Background/objectives: Nucleolin is a major component of the nucleolus and is involved in various aspects of ribosome biogenesis. However, it is also implicated in non-nucleolar functions such as cell cycle regulation and proliferation, linking it to various pathologic processes. The aim of this study was to use differential gene expression analysis and Weighted Gene Co-expression Network analysis (WGCNA) to identify nucleolin-related regulatory pathways and possible key genes as novel therapeutic targets for cancer, viral infections and other diseases. Methods: We used two different siRNAs to downregulate the expression of nucleolin in a human hepatoblastoma (HepG2) cell line. We carried out RNA-sequencing (RNA-Seq), performed enrichment analysis of the pathways of the differentially expressed genes (DEGs) and identified protein–protein interaction (PPI) networks. Results: Both siRNAs showed high knockdown efficiency in HepG2 cells, resulting in the disruption of the nucleolar architecture and the downregulation of rRNA gene expression, both downstream hallmarks of a loss of nucleolin function. RNA-Seq identified 44 robust DEGs in both siRNA cell models. The enrichment analysis of the pathways of the downregulated genes confirmed the essential role of nucleolin in DNA replication and cell cycle processes. In addition, we identified seven hub genes linked to NCL: MCM6, MCM3, FEN1, MYBL2, MSH6, CDC6 and RBM14; all are known to be implicated in DNA replication, cell cycle progression and oncogenesis. Conclusions: Our findings demonstrate the functional consequences of nucleolin depletion in HepG2 and confirm the importance of nucleolin in DNA replication and cell cycle processes. These data will further enhance our understanding of the molecular and pathologic mechanisms of nucleolin and provide new therapeutic perspectives in disease. Full article

Hepatocellular carcinoma (HCC) is the most common form of liver cancer in humans, with an increasing incidence worldwide. The current study aimed to explore the molecular mechanisms that inhibit the proliferation of HepG2 cells, a hepatoblastoma-derived cell line. MSC-derived exosomes (UC-MSCs) were prepared with a median particle size (N50) of 135.8 nm. Concentrations of UC-MSCs ranging from 10 μg/mL to 1000 μg/mL were applied to HepG2 cell cultures and compared to untreated and anticancer drug-treated HepG2 cells. A combined approach was employed, integrating a proteomic analysis of UC-MSCs, metabolomic analysis of HepG2 cells, and transcriptomic profiling of HepG2 cells to decipher the inhibitory mechanisms of UC-MSC exosomes on HepG2 cell growth. Treatment with a high concentration of UC-MSCs led to a notable reduction in HepG2 cell viability, with survival decreasing by 65%. A proteomic analysis of UC-MSCs revealed enriched degranulation processes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in addition to the known exosomal pathways. Transcriptomic profiling showed distinct changes in the expression of genes related to hepatocellular diseases in UC-MSC-treated HepG2 cells, contrasting with changes observed in HepG2 cells treated with the chemotherapeutic agent doxorubicin (DOX). Combined with a metabolomic analysis, the detailed GO and KEGG pathway analyses indicated that pathways associated with neutrophil extracellular trap formation played a critical role in mediating protein degradation and suppressing central carbon metabolism in cancer cells. Our results revealed that the UC-MSC treatment mimicked molecular mechanisms similar to those involved in neutrophil extracellular trap formation, exhibiting effects on HepG2 cell growth suppression that differed from those of chemical cancer drugs. Notably, the UC-MSC treatment demonstrated that protein degradation in HepG2 cells was regulated through canonical signaling pathways activated by bacterial peptides in neutrophils. This research has provided valuable insights into the potential of MSC-derived exosomes as a therapeutic approach for cancer treatment in the future. Full article

Hepatoblastoma is the most common primary liver cancer in children. Poor outcomes are primarily associated with patients who have distant metastases. Using the Mammalian Metabolic Enzyme Database, we investigated the overexpression of metabolic enzymes in hepatoblastoma tumors compared to noncancerous liver tissue in the GSE131329 transcriptome dataset. For the overexpressed enzymes, we applied ElasticNet machine learning to assess their predictive value for metastasis. A metabolic expression score was then computed from the significant enzymes and integrated into a clinical-biological logistic regression model. Forty-one overexpressed enzymes distinguished hepatoblastoma tumors from noncancerous liver tissues. Eighteen of these enzymes predicted metastasis status with an AUC of 0.90, demonstrating 85.7% sensitivity and 92.3% specificity. ElasticNet machine learning identified DNMT3B and PFKFB4 as key predictors of metastasis. Univariate analyses confirmed the significance of these enzymes, with respective p-values of 0.0058 and 0.0091. A metabolic score based on DNMT3B and PFKFB4 expression discriminated metastasis status and high-risk CHIC scores (p-value = 0.005). The metabolic score was more sensitive than the C1/C2 classifier in predicting metastasis (accuracy: 0.72 vs. 0.55). In a regression model integrating the metabolic score with epidemiological parameters (gender, age at diagnosis, histological type, and clinical PRETEXT stage), the metabolic score was confirmed as an independent adverse predictor of metastasis (p-value = 0.003, odds ratio: 2.12). This study identified the dual overexpression of PFKFB4 and DNMT3B in hepatoblastoma patients at risk of metastasis (high-risk CHIC classification). The combined tumor expression of DNMT3B and PFKFB4 was used to compute a metabolic score, which was validated as an independent predictor of metastatic status in hepatoblastoma. Full article

Background: Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. Methods: Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. Results: Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. Conclusions: The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments. Full article