Abstract
Hepatoblastoma (HB) is the most common malignant liver neoplasm in children. Despite progress in HB therapy, outcomes for patients with metastatic disease remain poor. Dysregulation of miRNA expression is one of the potential epigenetic mechanisms associated with pathogenesis of HB. However, miRNA profiles related to the different stages of HB tissues and cells, in particular of lung metastatic tumor cells, are unknown. In the present study, using array-based miRNA expression and DNA methylation analysis on formalin-fixed paraffin-embedded tissues, we aimed to identify miRNA changes that can discriminate between lung metastatic tumors, primary tumors (fetal and embryonal subtypes), and nontumorous surrounding livers. Our analysis demonstrated that a large cluster of microRNAs and snoRNAs located within the 14q32.2 DLK1-DIO3 region showed a strikingly upregulated expression pattern in HB tumors, especially metastatic tumors, compared to normal liver tissues. This revealed dysregulation of miRNAs similar to that seen in a malignant stem-like subtype of hepatocellular carcinoma associated with poor prognosis. These findings in HB mirror similar findings made in multiple other cancer types. With further analysis this may in future allow stratification of different stages and types of HB tumors based on their miRNA profiles, which could lead to new approaches to diagnosis and treatment in progressive HB patients.
Highlights
Hepatoblastoma (HB) is the most common malignant neoplasm of the liver in children
The results of hierarchical clustering of the expression of these 73 miRNAs in the 44 tissue samples are presented in the heatmap diagram (Figure 1), showing that, with a few exceptions, almost all the nontumorous surrounding liver samples expressed most of the identified miRNAs at relatively low levels, and that these 73 miRNAs became upregulated in primary and metastatic tumors
These results suggest that by hierarchical clustering the identified differentially expressed miRNAs were able to discriminate between normal surrounding liver tissue and HB tumor tissue, but that clustering of the miRNA expression was unable to discriminate between metastatic tumors and the primary tumors of the two subtypes (Figure 1)
Summary
Hepatoblastoma (HB) is the most common malignant neoplasm of the liver in children. Despite progress in the therapy of HB, the outcome of patients with metastatic disease remains poor [1, 2]. One fifth of HB patients have pulmonary metastasis at diagnosis, and recurrence of HB most frequently occurs in the lung. Among those patients who had residual lung disease after induction chemotherapy, but were able to undergo complete resection of the liver tumor, the overall survival rates in those whose lung tumors were completely resected, and of those whose lung tumors were incompletely resected, were 63.6% and 41.8%, respectively [3]. The paucity of mutations has been reported in many pediatric tumors and may be correlated with their early age of onset [8].
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