Hepatoblastoma (HB) Dotaz Zobrazit nápovědu
BACKGROUND & AIMS: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.
- Klíčová slova
- 14q32, BLCAP, CHKA, DLK1-DIO3 locus, Hepatoblastoma (HB), Molecular risk stratification, Prognostic biomarker, RNA editing,
- MeSH
- beta-katenin genetika MeSH
- cholinkinasa * antagonisté a inhibitory metabolismus MeSH
- epigeneze genetická MeSH
- hepatoblastom * genetika metabolismus mortalita patologie MeSH
- hodnocení rizik metody MeSH
- kojenec MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- metylace DNA MeSH
- nádorové biomarkery analýza MeSH
- nádorové proteiny genetika MeSH
- nádory jater * genetika metabolismus mortalita patologie MeSH
- objevování léků metody MeSH
- prognóza MeSH
- proteiny vázající vápník genetika MeSH
- rychlé screeningové testy MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- beta-katenin MeSH
- BLCAP protein, human MeSH Prohlížeč
- CHKA protein, human MeSH Prohlížeč
- cholinkinasa * MeSH
- CTNNB1 protein, human MeSH Prohlížeč
- DLK1 protein, human MeSH Prohlížeč
- membránové proteiny MeSH
- nádorové biomarkery MeSH
- nádorové proteiny MeSH
- proteiny vázající vápník MeSH
Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.
- MeSH
- buňky Hep G2 MeSH
- chronická hepatitida B virologie MeSH
- cytokiny metabolismus MeSH
- hepatocyty virologie MeSH
- interferon alfa metabolismus MeSH
- kruhová DNA metabolismus MeSH
- kultivační média speciální farmakologie MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé MeSH
- přirozená imunita účinky léků MeSH
- replikace viru účinky léků MeSH
- systémy cílené aplikace léků MeSH
- toll-like receptory agonisté metabolismus MeSH
- virus hepatitidy B fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytokiny MeSH
- interferon alfa MeSH
- kruhová DNA MeSH
- kultivační média speciální MeSH
- toll-like receptory MeSH