Molecular Mechanisms of Hepatoblastoma

Abstract

Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations of several pathways, including Hippo, Hedgehog, NRF2/KEAP1, HGF/c-Met, NK-1R/SP, and PI3K/AKT/mTOR cascades and aberrant activation of c-MYC, n-MYC, and EZH2 proto-oncogenes, have been identified in HB, although their role requires additional investigation. Here, we summarize the current knowledge on HB molecular pathogenesis, the relevance of the preclinical findings for the human disease, and the innovative therapeutic strategies that could be beneficial for the treatment of HB patients.

Fig. 1

Scheme showing the distinct features of hepatoblastomas (HBs) depending on the type of β-catenin mutation. Details are reported in the main text.

Fig. 2

Mechanisms responsible for β-catenin activation in human hepatoblastoma (HB). (A) In quiescent hepatocytes, the β-catenin pathway is turned off (β-catenin OFF). Wild-type β-catenin (unstable β-catenin) is sequestered by a destruction complex consisting of adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK-3β), AXIN1, and casein kinase I α (CK1-α) and primed for proteolysis. (B) In HB, through somatic mutations (mutant β-catenin), β-catenin escapes proteasomal degradation and translocates into the nucleus, where it associates with T cell factor (TCF)/lymphoid enhancer 1 (LEF-1) transcription factors and induces the transcription (transcription ON) of target genes, including glutamine synthetase (GLUL), growth regulation by estrogen in breast cancer 1 (GREB1), leukocyte-cell-derived chemotaxin 2 (LECT2), cyclin D1, leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), c-Myc, etc. Alternatively, β-catenin degradation is suppressed by HB tumor cells via CAPRIN2-activating mutations. Mutant CAPRIN2 activates LDL-receptor-related protein 5 and 6 (LRP5/6) than in turn activates the adaptor protein Disheveled (DVL). Consequently, DVL triggers GSK-3β inactivation and disrupts the β-catenin destruction complex. Furthermore, c-Met receptor activation by hepatocyte growth factor (HGF) induces nuclear translocation of β-catenin via tyrosine phosphorylation. In quiescence, c-Met and β-catenin physically interact at the inner surface of the hepatocyte plasma membrane.

Fig. 3

Overview of various signaling pathways deregulated in human hepatoblastoma that might be therapeutically targeted. Only drugs either approved by the Food and Drug Administration or currently in clinical trials are shown. Details are reported in the main text. Stars attached to proteins indicate protein activation; blunted red arrows indicate inhibition.