Altered microRNA Expression Patterns in Hepatoblastoma Patients

Abstract

Liver cancers in children are rare representing only 1.1% of malignancies, with an annual incidence rate of 1.5 cases per million. Hepatoblastoma and hepatocellular carcinomas are the most common malignancies of the liver occurring in young people aged 15 years or younger. Molecular basis of both tumors are still unclear, and common markers (i.e., CTNNB1, APC, IGF-2) are not always useful in the characterization of sporadic forms; in this respect, microRNA recently associated with carcinogenesis could play a pivotal role in their onset. CTNNB1 and APC were analyzed by sequencing, and IGF-2 promoter methylation status was assessed by methylation-specific polymerase chain reaction. MicroRNA expression was assayed by microarray and quantitative reverse transcription-polymerase chain reaction in hepatoblastoma samples. Although few genomic alterations were detected in ours samples, an altered expression of somemicroRNA in hepatoblastoma was observed. Unsupervised clustering shows that microRNA profile can distinguish tumor from nontumor tissues. Further analyses of microRNA contents in hepatoblastoma compared with hepatocellular carcinoma highlighted four upregulated microRNA (miR-214, miR-199a, miR-150 [P < .01], and miR-125a [P < .05]) and one downregulated microRNA (miR-148a [P < .01]). In conclusion, although our samples were poorly informative from a genetic point of view, they showed a peculiar microRNA expression pattern compared with nontumor tissues and hepatocellular carcinoma. MicroRNA could represent valid markers for the classification of pediatric liver tumors.

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

“…Contrarily, miR‐624‐5p, let‐7i‐3p, miR‐885‐5p, and miR‐449b‐3p were significantly down‐regulated in tumors (Fig. 3A), supporting previous results for miR‐885‐5p 14. Relating miRNA expression to the clinical information, we noticed that low expression of miR‐885‐5p was correlated with the presence of multiple nodules and an advanced stage of the disease (Fig.…”

“…This decrease was previously reported for miR‐885‐5p,14 and we further found that an miR‐885‐5p decrease is associated with advanced HBL (Fig. 3B) and inversely correlates with beta‐catenin mRNA in CTNNB1 ‐deleted HBL tumors.…”

“…1B,C; Supporting Table S2). This selection comprised miR‐885‐5p, which is decreased in HBL tumors,14 and miR‐483‐3p, which regulates beta‐catenin 18. In a second step, we studied the targeting preference of the 26 candidates for the beta‐catenin 5′‐ and/or 3′‐UTR using Tomato‐positive cells expressing GFP with specific UTRs (Fig.…”

“…As miR‐885‐5p down‐regulation has been described in HBL,14 we focused on a novel miRNA, miR‐624‐5p, whose implication had never been described in cancer. Moreover, miR‐624‐5p was the only beta‐catenin‐regulating miRNA to induce HBL cell senescence.…”

“…They guide the association of the RNA‐induced silencing complex with target messenger RNAs (mRNAs), mostly through interactions with the 3′‐untranslated region (UTR), resulting in translational repression and/or mRNA destabilization 11, 12. Deregulation of miRNA biogenesis and expression is a hallmark of cancer12 and has been reported in HBL 13, 14, 15. Unlike small interfering RNAs (siRNAs), miRNAs can simultaneously target multiple genes involved in the same cellular pathways.…”