Activated NOTCH2 is overexpressed in hepatoblastomas: An immunohistochemical study

Jason B. Litten, Tina T L Chen, Roger Schultz, Karl Herman, Jessica Comstock, Joshua Schiffman, Gail E. Tomlinson, Dinesh Rakheja

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)378-383
Number of pages6
JournalPediatric and Developmental Pathology
Issue number5
StatePublished - 2011


  • Hepatoblastoma
  • Immunohistochemistry
  • Liver
  • NOTCH2

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine


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