Transcriptome Analysis of Wnt Signaling Pathway in Pediatric Hepatocellular Carcinoma

Abstract

Background: Pediatric hepatocellular carcinoma (HCC) is associated with high mortality partly due to the lack of effective chemotherapy. Therefore, identification of therapeutic targets is critical. While Wnt signaling has been widely implicated in adult HCC tumorgenesis, often with underlying cirrhosis, comparable studies in pediatric HCC, which typically occurs without cirrhosis, are lacking. We therefore sought to examine whether the Wnt pathway is also altered in pediatric HCC. Methods: Next-generation sequencing of mRNA from HCC tumor and non-neoplastic liver tissue from 3 pediatric patients(1.5, 13, and 13 years old) without underlying cirrhosis was performed. Sequenced reads were mapped to the human genome. Normalized expression levels were calculated and used to compare normal tissue to tumor. P-values were calculated by fitting the data to a negative binomial distribution and correcting for multiple hypothesis testing. Results: Transcriptome analysis demonstrated a statistically significant increase in the expression of key pro-proliferative proteins of the canonical Wnt pathway, including WNT1, WNT10B, and Wnt-receptor FZD10, in the tumor compared to non-neoplastic tissue. Additionally, there was a significant decrease in several pathway inhibitors including SFRP5, TBL1Y, and WNT11 (p-values < 1.0x10-4 ). Sequenced reads from one tumor sample also revealed a previously-reported gain-of-function p.S45F CTNNB1 mutation. Conclusion: Our results demonstrate a significant increase in the expression of pro-proliferative genes alongside a concomitant decrease in the expression of inhibitory genes of the canonical Wnt pathway in pediatric HCC tumors. These findings suggest that targeting the Wnt pathway may provide a potential therapeutic target for the treatment of pediatric HCC.