Activated NOTCH2 is Overexpressed in Hepatoblastomas: An Immunohistochemical Study

• Published in: Pediatric and developmental pathology 2011-09, Vol.14 (5), p.378-383
• Main Authors: Litten, Jason B., Chen, Tina T.-L., Schultz, Roger, Herman, Karl, Comstock, Jessica, Schiffman, Joshua, Tomlinson, Gail E., Rakheja, Dinesh
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - metabolism; Calcium-Binding Proteins - metabolism; Cell Differentiation; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cell Proliferation; Child; Child, Preschool; Cytoplasm - metabolism; Cytoplasm - pathology; Female; Hepatoblastoma - blood supply; Hepatoblastoma - metabolism; Hepatoblastoma - pathology; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Immunohistochemistry - methods; Infant; Infant, Newborn; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Liver Neoplasms - blood supply; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Membrane Proteins - metabolism; Receptor, Notch2 - metabolism; Serrate-Jagged Proteins; Signal Transduction
• ISSN: 1093-5266; 1615-5742
• DOI: 10.2350/10-09-0900-OA.1

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 increasedlevelofNOTCH2expressionwasseenin22of 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.