Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma

Abstract

Hepatoblastoma is a malignant tumor in the liver of children that generally occurs at the age of 2–3 years. There have been ample evidence from the preclinical as well as clinical studies suggesting the activation of Wnt/β-catenin signaling in hepatoblastoma, which is mainly attributed to the somatic mutations in the exon 3 of β-catenin gene. There is increased translocation of β-catenin protein from the cell surface to cytoplasm and nucleus and intracellular accumulation is directly linked to the severity of the cancer. Accordingly, the alterations in β-catenin and its target genes may be used as markers in the diagnosis and prognosis of pediatric live tumors. Furthermore, scientists have reported the therapeutic usefulness of inhibition of Wnt/β-catenin signaling in hepatoblastoma and this inhibition of signaling has been done using different methods including short interfering RNA (siRNA), miRNA and pharmacological agents. Wnt/β-catenin works in association with other signaling pathways to induce the development of hepatoblastoma including Yes-associated protein (YAP)1 (YAP-1), mammalian target of rapamycin (mTOR) 1 (mTOR-1), SLC38A1, glypican 3 (GPC3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-kB), epidermal growth factor receptor, ERK1/2, tumor necrosis factor-α (TNF-α), regenerating islet-derived 1 and 3 α (REG1A and 3A), substance P (SP)/neurokinin-1 receptor and PARP-1. The present review describes the key role of Wnt/β-catenin signaling in the development of hepatoblastoma. Moreover, the role of other signaling pathways in hepatoblastoma in association with Wnt/β-catenin has also been described.

Focal Adhesion Kinase (FAK) Over-Expression and Prognostic Implication in Pediatric Hepatocellular Carcinoma

“…Profiling expression of β-Catenin protein (β-Cat), its downstream target glutamine synthetase (GS), and its interactor Glypican-3 (GPC3) could be helpful in the identification of altered Wnt/β-Cat pathways. Thus, immunohistochemical co-expression of β-Cat, GS, and GPC3 observed in HCC suggests that GPC3-induced activation of the Wnt/β-Cat pathway is responsible for the development of malignant hepatocellular tumors [ 5 ].…”

MiR-125b-5p Inhibited The Progression of Hepatoblastoma As A Shared miRNA of The lncRNA NEAT1 and YES1

“…Yes-associated protein (YAP)1 has been reported to be related to tumor development and it cooperates with other signaling pathways. It has been reported that Wnt/βcatenin works in association with Hippo/YAP to induce the development of hepatoblastoma 33,34 . We suspect that miR-125b-5p targets and regulates YES1, causing changes in related signaling pathways that are involved in the progression of HB.…”

RNA Splicing: A Versatile Regulatory Mechanism in Pediatric Liver Diseases

“…In addition, several research groups have proposed the therapeutic effects of HB by specific inhibition of Wnt/β-catenin pathway, through a number of post-transcriptional measures such as short interfering miRNA, RNAs (siRNA), and bioactive small molecules. Hence, the Wnt/β-catenin signaling pathway is a valuable target for the development of therapeutic measures of HB ( Koch et al, 1999 ; Takayasu et al, 2001 ; Koch et al, 2005 ; Cairo et al, 2008 ; Eichenmüller et al, 2014 ; Sumazin et al, 2017 ; Sha et al, 2019 ). However, HB has the lowest mutation burden among all known cancer types, and the genetic determinants of HB remain to be further investigated ( Gröbner et al, 2018 ).…”

“…However, several genes, including IGF2, fibronectin, DLK1, TGFb1, MALAT1, and MIG6, were overexpressed in HB versus HCC. HB is genetically characterized by abnormal activation of the Wnt/β-catenin signaling pathway (Sha et al, 2019). Generally, extensive evidence has suggested that mutations in the β-catenin gene exon 3 are responsible for the activation of the Wnt/β-catenin signal transduction pathway in HB.…”