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1.
Pediatr Blood Cancer ; 71(2): e30774, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37990130

RESUMO

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time-specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2-independent mechanism via proto-oncogenic, direct protein interaction, including ß-catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2-independent manner. METHODS AND RESULTS: We demonstrate that EZH2 promotes proliferation in HB tumor-derived cell lines through interaction with ß-catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene-expression patterns and interaction with SUZ12, a PRC2 component, and ß-catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation. CONCLUSIONS: EZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with ß-catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.


Assuntos
Hepatoblastoma , Neoplasias Hepáticas , Humanos , Gravidez , Feminino , Proteína Potenciadora do Homólogo 2 de Zeste/genética , beta Catenina/genética , beta Catenina/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Hepatoblastoma/genética , Proliferação de Células , Linhagem Celular Tumoral , Neoplasias Hepáticas/patologia
2.
Cancer Rep (Hoboken) ; 6(1): e1685, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35859536

RESUMO

BACKGROUND: Pediatric hepatocellular carcinoma (HCC) is a group of liver cancers whose mechanisms behind their pathogenesis and progression are poorly understood. AIM: We aimed to identify alterations in the expression of miRNAs and their putative target mRNAs in not only tumor tissues of patients with pediatric HCC but also in corresponding non-tumorous background livers by using liver tissues without underlying liver disease as a control. METHODS AND RESULTS: We performed a small-scale miRNA and mRNA profiling of pediatric HCC (consisting of fibrolamellar carcinoma [FLC] and non-FLC HCC) and paired liver tissues to identify miRNAs whose expression levels differed significantly from control livers without underlying liver disease. ToppMiR was used to prioritize both miRNAs and their putative target mRNAs in a gene-annotation network, and the mRNA profile was used to refine the prioritization. Our analysis generated prioritized lists of miRNAs and mRNAs from the following three sets of analyses: (a) pediatric HCC versus control; (b) FLC versus control; and (c) corresponding non-tumorous background liver tissues from the same patients with pediatric HCC versus control. No liver disease liver tissues were used as the control group for all analyses. Many miRNAs whose expressions were deregulated in pediatric HCC were consistent with their roles in adult HCC and/or other non-hepatic cancers. Our gene ontology analysis of target mRNAs revealed enrichment of biological processes related to the sustenance and propagation of cancer and significant downregulation of metabolic processes. CONCLUSION: Our pilot study indicates that alterations in miRNA-mRNA networks were detected in not only tumor tissues but also corresponding non-tumorous liver tissues from patients with pediatric HCC, suggesting multi-faceted roles of miRNAs in disease progression. Our results may lead to novel hypotheses for future large-scale studies.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Adulto , Criança , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Carcinoma Hepatocelular/genética , Projetos Piloto , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perfilação da Expressão Gênica
3.
J Surg Res ; 282: 118-128, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36272230

RESUMO

INTRODUCTION: Glypican-3 (GPC3) is a surface-bound proteoglycan overexpressed in pediatric liver cancer and utilized clinically as an immunohistochemical tumor marker. Furin is a proprotein convertase that is ubiquitously expressed and shown to modify GPC3 post-translationally. In experimental models of epithelial-based cancers, furin inhibition decreased tumor cell migration and proliferation representing a potential therapeutic target. METHODS: Using a synthetic furin inhibitor, we evaluated proliferation, migration, protein, and RNA expression in two liver cancer cell lines, HepG2 (GPC3-positive) and SKHep1 cells (GPC3-negative). Total furin protein and GPC3 protein expression were assessed to evaluate functional levels of furin. RESULTS: There was a reduction in HepG2 proliferation with addition of furin inhibitor at the 48-h timepoint, however there was an increase in HepG2 migration. CONCLUSIONS: GPC3 cleavage in hepatoblastoma (HB) has a role in cell proliferation with therapeutic potential, however furin inhibition is not an appropriate target for GPC3-expressing HB due to increased migration which may enhance metastatic potential.


Assuntos
Carcinoma Hepatocelular , Glipicanas , Hepatoblastoma , Neoplasias Hepáticas , Processamento de Proteína Pós-Traducional , Criança , Humanos , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Furina , Glipicanas/metabolismo , Neoplasias Hepáticas/patologia
4.
Hepatol Commun ; 6(10): 2950-2963, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36000549

RESUMO

Fibrolamellar hepatocellular carcinoma (FLC) is a disease that occurs in children and young adults. The development of FLC is associated with creation of a fusion oncoprotein DNAJB1-PKAc kinase, which activates multiple cancer-associated pathways. The aim of this study was to examine the role of human genomic regions, called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs), in the development of FLC. Previous studies revealed that CEGRs/ALCDs are located in multiple oncogenes and cancer-associated genes, regularly silenced in normal tissues. Using the regulatory element locus intersection (RELI) algorithm, we searched a large compendium of chromatin immunoprecipitation-sequencing (ChIP) data sets and found that CEGRs/ALCDs contain regulatory elements in several human cancers outside of pediatric hepatic neoplasms. The RELI algorithm further identified components of the ß-catenin-TCF7L2/TCF4 pathway, which interacts with CEGRs/ALCDs in several human cancers. Particularly, the RELI algorithm found interactions of transcription factors and chromatin remodelers with many genes that are activated in patients with FLC. We found that these FLC-specific genes contain CEGRs/ALCDs, and that the driver of FLC, fusion oncoprotein DNAJB1-PKAc, phosphorylates ß-catenin at Ser675, resulting in an increase of ß-catenin-TCF7L2/TCF4 complexes. These complexes increase a large family of CEGR/ALCD-dependent collagens and oncogenes. The DNAJB1-PKAc-ß-catenin-CEGR/ALCD pathway is preserved in lung metastasis. The inhibition of ß-catenin in FLC organoids inhibited the expression of CEGRs/ALCDs-dependent collagens and oncogenes, preventing the formation of the organoid's structure. Conclusion: This study provides a rationale for the development of ß-catenin-based therapy for patients with FLC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , beta Catenina/metabolismo , Carcinoma Hepatocelular/genética , Cromatina , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano , Genômica , Proteínas de Choque Térmico HSP40/genética , Humanos , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , beta Catenina/genética
5.
Commun Biol ; 4(1): 1049, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497364

RESUMO

Hepatoblastoma (HB) is the most common primary liver malignancy of childhood, and molecular investigations are limited and effective treatment options for chemoresistant disease are lacking. There is a knowledge gap in the investigation of key driver cells of HB in tumor. Here we show single cell ribonucleic acid sequencing (scRNAseq) analysis of human tumor, background liver, and patient derived xenograft (PDX) to demonstrate gene expression patterns within tumor and to identify intratumor cell subtype heterogeneity to define differing roles in pathogenesis based on intracellular signaling in pediatric HB. We have identified a driver tumor cell cluster in HB by genetic expression which can be examined to define disease mechanism and treatments. Identification of both critical mechanistic pathways combined with unique cell populations provide the basis for discovery and investigation of novel treatment strategies in vitro and in vivo.


Assuntos
Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Animais , Humanos , Camundongos , Análise de Célula Única
6.
Cancer Med ; 10(13): 4322-4343, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34117727

RESUMO

BACKGROUND: Hepatoblastoma is the most common primary pediatric liver malignancy. Indocyanine green (ICG) has been described as an adjunct to resection in small series. Its utility remains undefined in larger cohorts. METHODS: Records for 29 patients diagnosed with hepatoblastoma who received ICG prior to surgical resection from 2017 to 2020 at a single institution were retrospectively reviewed. The primary outcome was correlation between intraoperative ICG-avidity and histologic presence of hepatoblastoma. A secondary outcome included the histologic margin designation for resected liver specimens. RESULTS: ICG sensitivity was 91% for 120 resected thoracic specimens from 21 patients. Specificity was 57%. In 10% of operations, HB-positive specimens were resected solely on ICG-avidity. In an additional 40% of cases, ICG assisted in localizing a preoperatively diagnosed lesion. ICG sensitivity during thoracotomy and thoracoscopic surgery was 95 and 74%, respectively; primary and relapsed disease demonstrated sensitivity of 94 and 73%, respectively. Sensitivity was 92% for 25 resected liver specimens from nine patients with all parenchymal margins grossly negative for disease. Four multifocal lesions were identified with two resected solely by ICG-avidity. CONCLUSIONS: ICG is a sensitive adjunct for identifying local and metastatic hepatoblastoma, including lesions not visualized on preoperative imaging, and delineating margins during liver resection. False positives limit specificity; however, there were no adverse outcomes from additional resections. We noted that thoracoscopic surgery can be completed safely in patients with less significant disease burden, and conversion to thoracotomy, if necessary, is straightforward.


Assuntos
Corantes , Hepatoblastoma/cirurgia , Verde de Indocianina , Neoplasias Hepáticas/cirurgia , Margens de Excisão , Metastasectomia , Neoplasias Torácicas/cirurgia , Criança , Pré-Escolar , Feminino , Hepatoblastoma/diagnóstico por imagem , Hepatoblastoma/patologia , Hepatoblastoma/secundário , Humanos , Lactente , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Torácicas/diagnóstico por imagem , Neoplasias Torácicas/secundário
7.
Semin Pediatr Surg ; 28(6): 150856, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31931965

RESUMO

Advanced stage hepatoblastoma, including both locally advanced primary tumors as well as metastatic disease, poses unique clinical challenges. Despite substantial advances in chemotherapeutics, surgical extirpation remains the mainstay of cure for this tumor. Locally advanced tumors that involve multiple hepatic lobes and/or invade significant vascular structures can be managed either by complex hepatic resections or liver transplantation. We review the indications, roles, and outcomes of these surgical approaches as well as those for the resection of pulmonary metastases.


Assuntos
Hepatoblastoma/patologia , Hepatoblastoma/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Criança , Humanos
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