Treatment Of Hepatoblastoma Research Articles

Hepatic resections for pediatric hepatoblastoma: analysis of 30-day outcomes using the National Surgical Quality Improvement Program-Pediatric database.

Surgical resection remains the cornerstone of treatment for hepatoblastoma in children and offers the best chance of disease-free survival. We aimed to analyze the 30day outcomes of hepatic resection for hepatoblastoma stratified by extent using the National Surgical Quality Improvement Program-Pediatric (NSQIP-P). We queried NSQIP-P for children undergoing resection of Hepatoblastoma from 2012 to 2021. Relevant clinical characteristics and outcomes were extracted for multivariate logistic regression to identify predictors of common adverse outcomes. We included 458 children with a median age of 1.90years. Overall complications were rare, and perioperative blood transfusion (64.2%) and postoperative ventilation > 48h (10.0%) were the only adverse events prevalent in more than 5% of patients. Median transfusion volume was 15.7ml/kg. On multivariate regression, only patients undergoing Trisectionectomy (aOR = 3.387, 95% C.I. = 1.348-8.510) had higher odds of receiving > 75th percentile blood transfusion. Furthermore, only perioperative transfusion and postoperative ventilation > 48h were statistically more common in patients undergoing extended versus standard resections. Outcomes following resection of hepatoblastoma are excellent, with low rates of postoperative adverse events. Although children undergoing trisectionectomy likely require greater transfusion volume, extended hepatic resections do not appear to have worse 30day outcomes despite greater operative complexity and duration.

Surgery for hepatoblastoma in children with trisomy 18: a monocentric study.

Recently, children with trisomy 18 have been receiving more active treatment for malignancies. We report herein seven cases complete resection was achieved, and discuss multidisciplinary treatment for hepatoblastoma in patients with trisomy 18. The medical records of children with trisomy 18 who were treated at the study center between 2010 and 2023 were reviewed. Six of 69 patients had hepatoblastoma development, and three of these underwent multidisciplinary treatment. In addition, 6 patients had been referred by another hospital for treatment, and four of these underwent multidisciplinary treatment. Among the seven patients who underwent multidisciplinary treatment, three, two, and two were categorized in Pre-treatment Extent of Disease (PRETEXT) classification group I, II, and III, respectively. Neoadjuvant chemotherapy resulting in tumor reduction was performed in three cases. In all the cases, complete resection was achieved with pathologically safe margins. Perioperative complications included circulatory failure in one case and bile leakage in two cases. Adjuvant chemotherapy was administered in four cases. The postoperative observation period ranged from 3months to 11years, and all the patients are recurrence-free. Children with trisomy 18 complicated with hepatoblastoma whose cardiopulmonary conditions are stable may be good candidates for chemotherapy and surgery.

Abstract 1100: Fascin-1 inhibitor decreases hepatoblastoma cells tumorigenicity via YAP 1

Abstract Introduction: Hepatoblastoma (HB) is a liver tumor that arises in children. It's a sporadic malignancy that is often overly aggressive. The current treatment consists of chemotherapy. However, chemotherapy in young patients has disastrous and long-term side effects such as ototoxicity, cardiomyopathy, and infertility. Thus, alternative strategies are needed. One hint is to target the most common mutations in HB. It has been demonstrated that 90% of HB tumors are mutated for the Wnt pathway effector ß-catenin. This mutation leads to an aberrant constitutive activation of Wnt/ß-catenin signaling. Here, we investigate one of ß-catenin transcriptional targets, Fascin-1 that is found up-regulated in many tumors. Fascin1 affects actin organization into bundles, and this leads to cell migration and invasion. Whereas Fascin-1 is absent from normal hepatocytes, we found its expression associated to the poor prognosis C2 subtype of HB. In both human and murine HB samples, Fascin-1 is associated to undifferentiated tumor cells. We further demonstrated that Fascin-1 expression modulates tumor hepatocyte differentiation status through gene expression. In this study, we investigate how Fascin-1 can regulate tumor cell plasticity and whether Fascin-1 is a druggable target in HB tumors. Methods: We use two classical HB model cells Huh6 and HepG2 and 3 Patient-Derived-Xenograft cell lines. We explore the effect of Fascin-1 actin-bundling activity impairment by using inhibitors, on invasion and migration using Trans-well and wound-healing assays. We follow proliferation and cell death by Flow cytometry and investigate gene expression by PCR and reporter assay. We investigate Fascin modulation of the kinome with PamGene technology. Results: We show that the inhibition of Fascin actin-binding activity decreases cell invasion and migration as well as proliferation. We show an increase of cell death in Huh6/HepG2 cells but not in the PDX models. A cell cycle arrest is induced, and the cells become senescent. Differentiation genes are overexpressed and EMT genes are repressed. Yap expression is downregulated; Yap promoter activity is downregulated, and Yap is found translocated into the cytoplasm upon Fascin-1 inhibition. These data suggest that Fascin inhibition decreases tumors cell invasion, induces cell senescence, and favors a switch towards a differentiated and these effects on the cells are mediated via the Hippo pathway. The kinome is also modulated. Conclusion: Fascin-1 is an interesting target in hepatoblastoma, commercialized phase-2 drugs are available, and this study will confirm the potential use of those drugs in HB treatment and elucidate by which mechanism Fascin-1 inhibition impacts tumors. Citation Format: Lydia DIF, Amandine Martin, Sara Basbous, Gregoire Manaud, Violaine Moreau. Fascin-1 inhibitor decreases hepatoblastoma cells tumorigenicity via YAP 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1100.

Sporoderm-broken spores of Ganoderma lucidum modulate hepatoblastoma malignancy by regulating RACK1-mediated autophagy and tumour immunity.

Hepatoblastoma (HB), a primary liver tumour, is notorious for its high metastatic potential and poor prognosis. Ganoderma lucidum, an edible mushroom species utilized in traditional Chinese medicine for addressing various tumour types, presents an intriguing avenue for HB treatment. However, the effectiveness of G. lucidum in managing HB and its underlying molecular mechanism necessitates further exploration. Standard invitro assays were conducted to evaluate the impact of sporoderm-broken spores of G. lucidum (SBSGL) on the malignant characteristics of HB cells. The mechanism of SBSGL in treating HB and its tumour immunomodulatory effects were explored and validated by various experiments, including immunoprecipitation, Western blotting, mRFP-GFP-LC3 adenovirus transfection and co-localization analysis, as well as verified with invivo experiments in this regard. The results showed that SBSGL effectively inhibited the malignant traits of HB cells and suppressed the O-GlcNAcylation of RACK1, thereby reducing its expression. In addition, SBSGL inhibited immune checkpoints and regulated cytokines. In conclusion, SBSGL had immunomodulatory effects and regulated the malignancy and autophagy of HB by regulating the O-GlcNAcylation of RACK1. These findings suggest that SBSGL holds promise as a potential anticancer drug for HB treatment.

Focal adhesion kinase and its epigenetic interactors as diagnostic and therapeutic hints for pediatric hepatoblastoma.

Hepatoblastoma (HB) is the most common pediatric hepatic malignancy. Despite the progress in HB treatment, investigating HB pathomechanisms to optimize stratification and therapies remains a focal point to improve the outcome for high-risk patients. Here, we pointed to explore the impact of these mechanisms in HB. An observational study was performed on liver samples from a cohort of 17 patients with a diagnosis of HB and two normal liver samples. The in vitro experiments were executed on the Huh6 human HB cell line treated with the FAK inhibitor TAE226. Our results highlight a significant up-regulation of mRNA and protein expression of FAK in livers from HB with respect to normal livers. The increased protein expression of total and Tyr397 phosphorylated FAK (pTyr397FAK) was significantly correlated with the expression of some epigenetic regulators of histone H3 methylation and acetylation. Of note, the expression of pTyr397FAK, N-methyltransferase enzyme (EZH2) and tri-methylation of the H3K27 residue correlated with tumor size and alpha-fetoprotein (AFP) levels. Finally, TAE226 caused a significant reduction of pTyr397FAK, epigenetic regulators, AFP, EPCAM, OCT4, and SOX2, in association with anti-proliferative and pro-apoptotic effects on HB cells. Our results suggest a role of FAK in HB that requires further investigations mainly focused on the exploration of its effective diagnostic and therapeutic translatability.

Current trends and prospects of surgical techniques for hepatoblastoma.

Hepatoblastoma, a common extracranial malignant solid tumor in childhood, is often detected at an advanced stage and is difficult to treat surgically. Despite the availability of multiple comprehensive treatments that can be combined with surgery, hepatoblastoma treatment outcomes remain poor. Surgery is the main treatment strategy for hepatoblastoma, but it faces many challenges, including tumor attachment to surrounding tissues, tumor wrapping or invading of vital organs and tissues, the presence of giant or multiple tumors, distant metastasis, the formation of a tumor thrombus, and significant surgical trauma. In this review, we discuss recent research advances and propose potential strategies for overcoming these challenges. Such strategies may improve the rate of hepatoblastoma resection and local control in children, as well as reduce complications and trauma.

An update on diagnosis and treatment of hepatoblastoma.

Hepatoblastoma (HB) remains the most common paediatric liver tumour and survival in children with hepatoblastoma has improved considerably since the advent of sequential surgical regimens of chemotherapy based on platinum-based chemotherapeutic agents in the 1980s. With the advent of modern diagnostic imaging and pathology techniques, new preoperative chemotherapy regimens and the maturation of surgical techniques, new diagnostic and treatment options for patients with hepatoblastoma have emerged and international collaborations are investigating the latest diagnostic approaches, chemotherapy drug combinations and surgical strategies. Diagnosis of hepatoblastoma relies on imaging studies (such as ultrasound, computed tomography, and magnetic resonance imaging), alpha-fetoprotein (AFP) levels, and histological confirmation through biopsy. The standard treatment approach involves a multimodal strategy with neoadjuvant chemotherapy followed by surgical resection. In cases where complete resection is not feasible or tumors exhibit invasive characteristics, liver transplantation is considered. The management of metastatic and recurrent hepatoblastoma poses significant challenges, and ongoing research focuses on developing targeted therapies and exploring the potential of immunotherapy. Further studies are necessary to gain a better understanding of the etiology of hepatoblastoma, develop prevention strategies, and personalize treatment approaches. We aim to review the current status of diagnosis and treatment of hepatoblastoma.

SOCS2 inhibits hepatoblastoma metastasis via downregulation of the JAK2/STAT5 signal pathway

Metastasis of hepatoblastoma (HB) is a key factor that impairs the prognosis and treatment of children. The suppressor of cytokine signaling 2 (SOCS2) is a classical negative feedback protein that regulates cytokine signal transduction and has been known to be downregulated in several tumor, but the molecular mechanisms of its involvement in HB metastasis are unknown. We found that SOCS2 was a gene down-regulated in hepatoblastoma and associated with HB metastasis through bioinformatics. The qRT-PCR, Western blot and IHC showed that SOCS2 was significantly lower in HB tissues. Clinicopathological correlation analysis revealed that low expression of SOCS2 was significantly correlated with tumor metastasis (P = 0.046) and vascular invasion (P = 0.028), associated with poor prognosis. Overexpression of SOCS2 inhibited the migration and invasion of hepatoblastoma cells, while knockdown of SOCS2 expression promoted these malignant phenotypes. In vivo studies revealed overexpression of SOCS2 inhibited the formation of lung metastasis. Up-regulation of SOCS2 in HB cell inhibited EMT and JAK2/STAT5. Conversely, down-regulation of SOCS2 promoted EMT and JAK2/STAT5. The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB.

Computed tomography imaging phenotypes of hepatoblastoma identified from radiomics signatures are associated with the efficacy of neoadjuvant chemotherapy

BackgroundThough neoadjuvant chemotherapy has been widely used in the treatment of hepatoblastoma, there still lacks an effective way to predict its effect.ObjectiveTo characterize hepatoblastoma based on radiomics image features and identify radiomics-based lesion phenotypes by unsupervised machine learning, intended to build a classifier to predict the response to neoadjuvant chemotherapy.Materials and methodsIn this retrospective study, we segmented the arterial phase images of 137 cases of pediatric hepatoblastoma and extracted the radiomics features using PyRadiomics. Then unsupervised k-means clustering was applied to cluster the tumors, whose result was verified by t-distributed stochastic neighbor embedding (t-SNE). The least absolute shrinkage and selection operator (LASSO) regression was used for feature selection, and the clusters were visually analyzed by radiologists. The correlations between the clusters, clinical and pathological parameters, and qualitative radiological features were analyzed.ResultsHepatoblastoma was clustered into three phenotypes (homogenous type, heterogenous type, and nodulated type) based on radiomics features. The clustering results had a high correlation with response to neoadjuvant chemotherapy (P=0.02). The epithelial ratio and cystic components in radiological features were also associated with the clusters (P=0.029 and 0.008, respectively).ConclusionsThis radiomics-based cluster system may have the potential to facilitate the precise treatment of hepatoblastoma. In addition, this study further demonstrated the feasibility of using unsupervised machine learning in a disease without a proper imaging classification system.Graphical abstract

Key Modulation of ROS and HSP for Effective Therapy Against Hypoxic Tumor with Multifunctional Nanosystem.

Though nanomedicine-based photothermal therapy (PTT) has demonstrated promising prospect in tumor treatment due to its high therapeutic efficiency and controllable range, the overexpression of heat shock proteins (HSPs) during PTT can lead to intracellular thermal resistance and reduce its effectiveness. Reactive oxygen species (ROS), followed by the application of chemodynamic therapy (CDT) and photodynamic therapy (PDT), can eliminate HSPs and overcome thermal resistance. However, the tumor microenvironment, including hypoxia and glutathione (GSH) overexpression, impedes the production of ROS and therapeutic efficacy of CDT and PDT. Therefore, we proposed a multifunctional nanoplatform (HMPB@TCPP-Cu) driving PTT/ PDT/ CDT synergistic therapy for tumor treatment via modulating ROS and HSPs. In this work, a novel nanoplatform (HMPB@TCPP-Cu) composed of O2/PTT supplier HMPB (hollow mesoporous Prussian blue) and the loaded PDT/CDT agent (TCPP-Cu2+) was prepared. HMPB acts as an photothermal converter, effectively raising the tumor temperature and inducing apoptosis. HMPB is also a potent catalase-like nanozyme, which can catalyze hydrogen peroxide into oxygen and reduce tumor hypoxia, thus elevating the efficiency of ROS production and the effectiveness of PDT with the wing of sonosensitizer-TCPP. The intracellular glutathione(GSH) was depleted by Cu2+ and •OH was generated along with the Cu2+/Cu+ converting and Cu+-mediated Fenton-like reaction. Subsequently, the increased levels of ROS effectively eliminate intratumoral thermal resistance. The HMPB@TCPP-Cu has achieved synergistic PTT/PDT/CDT for hepatoblastoma treatment and significant inhibition of tumor growth was detected both in vitro and in vivo. This study presents a multifunctional nanoplatform that combines photothermal/ chemodynamic/ photodynamic therapy for efficient hepatoblastoma treatment via modulating ROS and HSPs. Collectively, this study provides an appealing strategy in the cleavage of thermal resistance and a novel assistance and enhancement on thermal-related therapies.

Treatment Outcomes for Hepatoblastoma: 15-Years-Experience of a Single Institution – Sheikh Khalifa Medical City, Abu Dhabi, UAE

Background: Hepatoblastoma is the most common malignant liver tumor in children. Treatment protocols varies. In our center, we have adopted the Children’s Oncology Group (COG) AHEP0731 protocol, in addition to some experimental regimens for relapsed solid tumors. Methods: We aimed to investigate the outcome of the current hepatoblastoma treatment protocol at our center. 15 patients were included between January 2008 and June 2023. A retrospective review was carried to review the clinical presentation, serum α-fetoprotein (AFP) level at diagnosis, histological subtype, treatment, and outcomes. Results: 12 patients (80%) were symptomatic at time of diagnosis, with abdominal mass being the most common presenting complaint. Nine patients (60%) presented in stage 3 PRETEXT staging system. Epithelial histopathological subtype was predominant subtype. Thirteen patients have received preoperative chemotherapy, followed by surgical resection; only one patient underwent upfront surgical resection followed by chemotherapy. Preoperative chemotherapy consists of 2 to 4 cycles of Cisplatin, Fluorouracil, Vincristine and Doxorubicin (C5VD), followed by surgical resection. Four of them underwent neoadjuvent experimental chemotherapy utilizing agents such as Pazopanib, Pembrolizumab and Sorafenib. During followup, six patients died of progressive disease. The median survival time was 42 months (95% confidence interval: 18–42%). Five-year overall survival was 44.09% (95% confidence interval: 18–42%). Conclusions: The combination of surgery and chemotherapy for hepatoblastoma is an effective approach. Utilization of new-targeted therapies and relapsed solid tumors regimens may prolong life in patients who did not respond to standard therapy. Further studies are required to validate its usage on patients with advanced hepatoblastoma.

Anti-ferroptotic PRKAA2 serves as a potential diagnostic and prognostic marker for hepatoblastoma.

The incidence rate of hepatoblastoma (HB), which is the most prevalent malignant tumour among children, rises each year. According to recent studies, a number of neoplastic disorders and ferroptosis are intimately connected. This study aims to identify key ferroptosis-related genes in HB and explore new directions for the diagnosis and treatment of HB. Differentially expressed ferroptosis-related genes were identified using the Gene Expression Omnibus datasets. The functional annotation of candidate genes was evaluated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Machine learning and receiver operating characteristic (ROC) curves revealed protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), tribbles homolog 2 (TRIB2), and liver-type glutaminase (GLS2) as potential diagnostic genes of HB. By using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, relative expression of PRKAA2 was examined. The effect of PRKAA2 on proliferation, apoptosis, and ferroptosis of HB cells was verified in vitro and in vivo. Fisher's exact test was used to evaluate the clinical significance of PRKAA2 in HB. The prognostic indicators had a substantial correlation with PRKAA2 expression, which rose dramatically in HB tissues. PRKAA2 promotes proliferation and inhibits ferroptosis in HB cells. PRKAA2 plays a role in ferroptosis by regulating hypoxia-inducible factor 1α (HIF-1α) and transferrin receptor 1 (TFR1). PRKAA2 functions as a tumor-promoting factor in HB by promoting cell proliferation and prohibiting ferroptosis. Ferroptosis-related genes PRKAA2 is a potential diagnostic and prognostic marker for HB as well as a novel therapeutic target in the future.

Liver Transplantation in Children with Advanced Hepatoblastoma: a Systematic Review and Meta-Analysis

AbstractSurgery is a key factor for the curative treatment of hepatoblastoma. Recent evidence suggests that liver transplantation has a strong effect in treating advanced hepatoblastoma. However, there is no consensus on the effects of liver transplantation. This meta-analysis aims to identify the efficacy and safety of liver transplantation for advanced hepatoblastoma, compared with those of conventional liver resection. Electronic databases were searched for relevant studies published prior to June 2022 to evaluate the survival benefit and safety in patients with advanced hepatoblastoma. The primary outcomes were the overall survival and disease-free survival rates, and the secondary outcomes were the complication and tumor recurrence rates. Five relevant clinical studies with a total of 134 participants were included in this meta-analysis. Compared with aggressive liver resection, liver transplantation had similar overall survival rates and disease-free survival rates after 1 year, 3 years, and 5 years (odds ratio (OR) 1 year = 0.89, 95% CI 0.21–3.79, P = 0.88; OR 3 years = 0.54, 95% CI 0.16–1.81, P = 0.32; OR 5 years = 1.24, 95% CI 0.22–6.82, P = 0.81; OR disease-free 1 year = 2.17, 95% CI 0.56–8.42, P = 0.26; OR disease-free 3 years = 1.42, 95% CI 0.48–4.17, P = 0.53; OR disease-free 5 years = 2.91, 95% CI 0.56–8.52, P = 0.26), tumor recurrence rates (OR = 0.62, 95% CI 0.24–1.60, P = 0.32), and complication rates (OR = 1.46, 95% CI 0.48–4.49, P = 0.51). Sensitivity analysis also demonstrated the same outcomes in terms of the tumor recurrence rate, complication rate, and overall and disease-free survival rates after 1 year, 3 years, and 5 years. The funnel plot indicated a low publication bias. Liver transplantation is an excellent option for advanced hepatoblastoma in children with acceptable perioperative complications, which is not inferior to liver resection. And liver transplantation should be considered the primary curative option when liver resection is not possible.

Racial disparities in treatment and outcomes of pediatric hepatoblastoma.

10062 Background: Hepatoblastoma is the most common malignant liver tumor which affects pediatric patients. However, the incidence is rare with 100 cases reported per year.1 Current management consists of surgery and adjuvant cisplatin chemotherapy and radiation depending on tumor histology, resectability, and metastasis.2 However, due to its rarity, optimal treatment protocol remains unclear. The 5-year overall survival rate in the US is approximately 57-69%1. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with hepatoblastoma from 2004 to 2020 using the histology codes 8970 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, Chi-Square, and ANOVA tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: This study identified 1215 patients with hepatoblastoma. Black patients had a significantly lower median survival rate compared to White and other race patients (126.2 months vs 165.4 months vs 166.1 months; all p<0.05). Black patients were more likely to be from low-income households than White patients (29.6% vs 17.3%; p<0.05). The mean age of diagnosis was higher for Black patients compared to White patients (2.42 vs 1.99; p<0.05). Black patients were less likely to receive surgery (63.5% vs. 75.4%; p<0.05). Black patients on average had shorter distances to travel from their residence to the hospital (30.61 vs. 59.52 miles; p<0.05). Black patients had longer mean stay times compared to white patients (16.7 days vs 11.2 days; p<0.05). There was no significant difference in survival across incomes. When comparing Black and White patients there was no significant difference in insurance type, surgical margins, grade, stage, size of tumor, regional lymph nodes and time of diagnosis to treatment. No significant difference was shown between adjuvant therapies including chemotherapy and radiation. Conclusions: This study showed Black patients experienced inferior overall survival when diagnosed and treated for hepatoblastoma compared to White patients. This population was less likely to receive surgery, older when diagnosed, and had longer hospital stays. Poorer outcomes suggest a disparity in hepatoblastoma treatment.

LncRNA SNHG1 Accelerates Cell Proliferation, Migration, and Invasion of Hepatoblastoma Through Mediating miR-6838-5p/PIM3/RhoA Axis.

Hepatoblastoma (HB) is a common primary liver malignant tumor in children. Long non-coding RNAs (lncRNAs) are closely engaged in HB progression. The role and regulatory molecule mechanism of lncRNA small nucleolar RNA host gene 1 (SNHG1) in HB remain unclear. Through qRT-PCR or western blot, we found that SNHG1 and proviral integration site for moloney murine leukemia virus 3 (PIM3) were elevated but miR-6838-5p was decreased in HB cells. Cell biology experiments revealed that SNHG1 depletion or miR-6838-5p upregulation suppressed cell proliferation, migration, and invasion of HB cells. Mechanistically, luciferase activity assay validated that miR-6838-5p could interact with SNHG1 or PIM3. SNHG1 up-regulated PIM3 expression via sponging miR-6838-5p. Moreover, miR-6838-5p inhibitor abolished SNHG1 depletion-mediated suppression of malignant behaviors in HB cells. PIM3 overexpression neutralized miR-6838-5p mimics-mediated repression of malignant phenotypes in HB cells. Furthermore, miR-6838-5p overexpression suppressed RhoA activation, which was restored by PIM3 upregulation. What's more, the results at the cellular level were further verified by nude mice tumor formation experiment. In conclusion, SNHG1 regulated miR-6838-5p/PIM3/RhoA axis to promote malignant phenotypes of HB, which might provide novel therapeutic target for HB treatment.

ACLY-β-catenin axis modulates hepatoblastoma cell proliferation

HB (hepatoblastoma) is most common in children with liver cancer and few options for treating HB. Thus, it is of great significance to investigate the regulatory mechanism of HB and/or identify new therapeutic targets for clinical treatment of HB. Here, we showed that ACLY (ATP citrate lyase), an important lipometabolic enzyme for de novo biosynthesis of fatty acids and steroids, has a higher expression in HB tissues than noncancerous tissues, and is required for HB cell proliferation. Moreover, knocking down ACLY in HB cells caused severe S-phase arrest and apoptosis. Mechanistically, ACLY knockdown significantly silenced the Wnt signaling pathway and reduced β-catenin expression in HB cells. Conversely, the apoptotic alleviation of HB cells by overexpressing ACLY was blocked by silencing β-catenin, suggesting the modulation of HB cells by ACLY-β-catenin axis. Our results uncovered the role of ACLY in HB cells and presented a theoretical approach for HB targeted therapy in the future.

Phase separation of YAP mediated by CC domain promotes hepatoblastoma proliferation via activation of transcription.

Yes-associated protein (YAP), a key transcriptional co-activator associated with cell fate and tumor progression, has been reported to be a powerful driver of hepatoblastoma (HB). In this study, we investigated the mechanism underlying oncogenic role of YAP in HB. The expression of YAP in HB tissues was measured through WB and qRT-PCR. The IHC and IF were performed to determine the distribution of YAP. The phase separation of YAP was proved by living cell imaging and FRAP experiment. The effect of YAP phase separation in HB cells in vitro an in vivo were tested using CCK8, flow cytometry and xenograft tumors. YAP was overexpressed and activated in HB. Nuclear YAP formed an active transcriptional site via LLPS to recruit the crucial transcription factor TEAD4. Thus, YAP phase separation facilitated transcription of oncogenic genes and subsequently mediated chemoresistance of HB. Mechanistically, the phase separation ability of YAP depends on the coiled-coil domain, which is a typical phase-separation domain. The electrostatic interactions and hydrophobic interactions within YAP are also vital to YAP phase separation. More importantly, YAP inhibitor Verteporfin is potential treatment for HB and combination with cisplatin enhanced therapeutic efficacy. Highly expressed and active YAP exerts an oncogenic effect in HB via phase separation and provides new insights for the treatment of HB.

MiR-139-3p/Wnt5A Axis Inhibits Metastasis in Hepatoblastoma.

In order to examine new potential treatment options for the treatment of hepatoblastoma (HB), we identified the differential expression of five-candidate tumor suppressor miRNAs in HB and explored possible regulatory mechanisms of target miRNA molecule. By using real-time quantitative polymerase chain reaction (qPCR), we examined the expression of miRNAs in HB tissues and cells. The effect of has-miR-139-3p mimics on the invasion and migration ability was assessed by transwell assay and scratch-wound assay in HepG2 cells. Subsequently, we analyzed the target genes of miR-139-3p and their enrichment signaling pathways through bioinformatics. qPCR, Western-blot and dual-luciferase assays were further used to assess whether has-miR-139-3p targets Wnt5A. The results showed that hsa-miR-139-3p was significantly decreased in HB cells. Upregulation of hsa-miR-139-3p inhibited the invasive and migratory ability of HepG2. Bioinformatics analysis showed that hsa-miR-139-3p may target Wnt5A to regulate the WNT pathway, which was further confirmed by Western-blot and dual-luciferase assays. Overexpression of Wnt5A can reverse the miR-139-3p mimic-induced declines in the expression of WNT pathway-related proteins and restore the invasion and migration of HepG2. These data indicated that the hsa-miR-139-3p/Wnt5A axis inhibited HB metastasis, suggesting that miR-139-3p and Wnt5A may be potential targets for the treatment of HB.

Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma

Hepatoblastoma (HB) is a common pediatric malignant liver tumor that is characterized by a low level of genetic mutations. Alternative splicing (AS) has been shown to be closely associated with cancer progression, especially in tumors with a low mutational burden. However, the role of AS in HB remains unknown. Transcriptome sequencing was performed on 5 pairs of HB tissues and matched non-tumor tissues to delineate the AS landscape in HB. AS events were validated in 92 samples from 46 patients. RNA pull-down and RNA immunoprecipitation assays were carried out to identify splicing factors that regulate the AS of small nucleolar RNA host genes (SNHG). Patient-derived organoids (PDOs) were established to investigate the role of the splicing factor polyadenylate-binding nuclear protein 1 (PABPN1). This study uncovered aberrant alternative splicing in HB, including lncRNAs from SNHG family that undergo intron retention in HB. Further investigations revealed that PABPN1, a significantly upregulated RNA binding protein, interacts with splicing machinery in HB, inducing the intron retention of these SNHG RNAs and the downregulation of intronic small nucleolar RNAs (snoRNAs). Functionally, PABPN1 acts as an oncofetal splicing regulator in HB by promoting cell proliferation and DNA damage repair via inducing the intron retention of SNHG19. Knock-down of PABPN1 increases the cisplatin sensitivity of HB PDOs. Our findings revealed the role of intron retention in regulating snoRNA expression in hepatoblastoma, explained detailed regulatory mechanism between PABPN1 and the intron retention of SNHG RNAs, and provided insight into the development of new HB treatment options.

Efficacy and safety of HIFU in combination with TACE in unresectable pediatric HB: A randomized, controlled, single-center clinical trial

Hepatoblastoma (HB) is the most common liver tumor in children, and the main treatment for HB is currently surgery. Studies have shown that transcatheter arterial chemoembolization (TACE) combined with high intensity focused ultrasound (HIFU) has significant efficacy, but there are relatively few studies on TACE combined with HIFU in China. To investigate the effect of using HIFU combined with TACE on patients' liver function impairment and immune function in pediatric HB patients and to analyze the effectiveness and safety. The clinical data of 110 unresectable pediatric HB patients treated in our hospital from December 2019 to December 2021 were selected as the subjects and divided into 2 groups. The comparison group was treated with TACE, and the combination group was treated with HIFU on the basis of the comparison group. The differences in immune function, survival, treatment side effects and clinical efficacy between the 2 groups were observed. In the combined group, the 1-year survival rate was 100%, the 3-year survival rate was 84.0%, the 5-year survival rate was 16.0%; while in comparison group, it was 82%, 16%, 0%, respectively. The ratio of CD4+/CD8+ in the combined group were significantly higher than in the comparison group after treatment (P < .05). Granulocytopenia, mucositis, thrombocytopenia, and cardiac and renal toxicity were significantly lower in the combined group than in the comparison group, and the effective rate of the combined group was 98.00% which was significantly higher than that of the control group (76.00%) (P < .05). Comparative study of HB in children treated with HIFU combined with TACE is more effective, effectively improving the immune level of patients, significantly increasing the remission rate, which can improve the tumor necrosis and improve the survival quality of patients, and is a better choice for HB in children.