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1.
Biol Open ; 11(9)2022 09 15.
Article in English | MEDLINE | ID: mdl-35451474

ABSTRACT

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence-activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB. This article has an associated First Person interview with the first author of the paper.


Subject(s)
Hepatoblastoma , Liver Neoplasms , Neoplastic Cells, Circulating , Animals , Cell Line, Tumor , Disease Models, Animal , Hepatoblastoma/genetics , Hepatoblastoma/metabolism , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mice
3.
Sci Rep ; 11(1): 2967, 2021 02 03.
Article in English | MEDLINE | ID: mdl-33536467

ABSTRACT

Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Hepatoblastoma/drug therapy , Liver Neoplasms/drug therapy , Oxadiazoles/pharmacology , Piperazines/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis/drug effects , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Child, Preschool , Cohort Studies , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Hepatoblastoma/genetics , Hepatoblastoma/pathology , Humans , Liver/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Oxadiazoles/therapeutic use , Piperazines/therapeutic use , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Suppressor Protein p53/genetics , Up-Regulation/drug effects , Xenograft Model Antitumor Assays
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