Activated NOTCH2 is Overexpressed in Hepatoblastomas: An Immunohistochemical Study

Abstract

Hepatoblastoma is a pediatric malignancy characterized by the uncontrolled proliferation of immature hepatocytes (hepatoblasts). This disease is diagnosed primarily in children younger than 5 years and is disproportionately observed in former premature infants. Cytogenetically, hepatoblastoma is characterized by numerical aberrations, as well as unbalanced translocations involving the proximal region of chromosome 1q. The NOTCH2 gene has been mapped to this locus, and it is well established that the NOTCH gene family is an important regulator of several developmental pathways. Specifically, the NOTCH2 protein is known to delay hepatoblast maturation during early hepatic organogenesis, and the reduction of NOTCH2 expression correlates with the differentiation of hepatoblasts into hepatocytes and biliary cells in the developing liver. We hypothesized that NOTCH2 is involved in the pathogenesis of hepatoblastoma by maintaining a population of undifferentiated hepatoblasts. We studied the immunohistochemical expression of NOTCH2 and its isoforms NOTCH1, NOTCH3, and NOTCH4 and the NOTCH2 primary ligand JAGGED1 in hepatoblastomas. Compared with the normal liver, an increased level of NOTCH2 expression was seen in 22 of 24 (92%) hepatoblastomas. There was no significant staining for other NOTCH isoforms and JAGGED1 in hepatoblastomas. Therefore, we suggest that NOTCH2 expression and activation, independent of JAGGED1 expression, may contribute to the pathogenesis of hepatoblastoma. In the hepatoblastoma sinusoidal vasculature, we saw NOTCH3 and NOTCH1 expression. These observations have potential implications with regard to therapeutic targeting of the NOTCH signaling pathway in hepatoblastomas.

Therapeutic Innovations for Targeting Hepatoblastoma

“…More impressively, inhibiting this pathway with cyclopamine induced a striking growth inhibition of hepatoblastoma cells (54). On the other hand, when analysing Notch signaling by immunohistochemistry, Litten et al revealed an overexpression of the NOTCH2 receptor in 92% of the tumors compared to normal liver tissues (55). This result corroborates the idea that hepatoblastoma arises from immature precursors as NOTCH2 is known to repress hepatoblast differentiation during embryogenesis and sees its expression decrease with liver maturation (56).…”

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

“…Accordingly, Notch signal pathway has been considered as a crucial regulator of EMT (Espinoza and Miele, 2013; Ishida et al , 2013; Yuan et al , 2014; Zoni et al , 2015). Furthermore, the overexpression level and oncogenic role of Notch2 have been observed in numerous human cancer types, such as lung adenocarcinoma (Mimae et al , 2012), glioma (Yu et al , 2015), cervical cancer (Zhang et al , 2014), hepatoblastoma (Litten et al , 2011) and salivary adenoid cystic carcinoma (Qu et al , 2016). We have revealed that protein level of Notch2 was upregulated in ESCC cancerous cancer and it could promote the proliferation and survival ability of EC 9706 and Eca 109 (Wang et al , 2016b).…”

Pathology of Pediatric Gastrointestinal and Liver Disease

“…Mutations of beta-catenin lead to nuclear translocation, activation of diverse genes, and increased cell proliferation. NOTCH2 overexpression has been recently reported in HB (Litten et al 2011 ). Lopez-Terrada et al ( 2009 ) investigated the canonical Wnt signaling pathway in HBs and correlated the histologic subtype, beta-catenin immunostaining, and mutation status of the CTNNB1 gene ( Fig.…”