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A Balancing Act: Role of HNF4α and β ‐catenin in Hepatobiliary Development and Cholangiocarcinoma Pathogenesis
Author(s) -
Walesky Chad,
Goessling Wolfram
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.56.4
Subject(s) - wnt signaling pathway , zebrafish , biology , cholangiocyte , context (archaeology) , cancer research , population , pathogenesis , progenitor cell , bioinformatics , endocrinology , medicine , immunology , stem cell , microbiology and biotechnology , signal transduction , genetics , gene , paleontology , environmental health
Cholangiocarcinoma (CC) is among the deadliest cancers worldwide, with a five‐year survival rate of ~15% in intrahepatic cholangiocarcinoma (ICC) and ~30% in extrahepatic cholangiocarcinoma (ECC). It is a rare cancer, affecting ~8,500 patients in the U.S. each year. The incidence of CC has increased, and there are few effective strategies for prevention, diagnosis, or treatment, indicating a significant unmet medical need. Often, altered developmental signaling can shed light on pathways that may also be altered during cancer pathogenesis. Therefore, our strategy is to understand mechanisms that are important in hepatobiliary development and examine these pathways in the context of CC pathogenesis in hopes of discovering novel therapeutic targets. We have recently shown that loss of hepatocyte nuclear factor 4 alpha (HNF4α) contributes to the pathogenesis of CC. Further, Wnt/β‐catenin has recently been shown to be upregulated in patients with CC. Therefore, we hypothesized that an HNF4α/β‐catenin interaction may be important in the context of CC pathogenesis. Hepatocytes and cholangiocytes are thought to originate from a bipotent progenitor cell population called hepatoblasts (Prox1‐positive). In the current study we have demonstrated the importance of proper HNF4α/β‐catenin signaling in the development of both hepatocytes and cholangiocytes within the zebrafish liver. HNF4α knockdown results in a loss of the hepatoblast marker Prox1. Interestingly, zebrafish maintain development of cholangiocytes following a loss of the Prox1‐positive hepatoblast population. Further, genetic or chemical increase in β‐catenin (APC‐/‐ ; Wnt agonist) results in a loss of HNF4α, Prox1, and a maintenance of cholangiocyte differentiation. Therefore, we hypothesize that over‐activation of β‐catenin results in a loss of HNF4α, causing hepatoblasts to preferentially differentiate into cholangiocytes. These studies demonstrate that HNF4α/β‐catenin signaling are directly linked to regulate hepatobiliary development. Further investigation into the mechanisms by which these pathways interact can provide valuable knowledge in understanding hepatobiliary development and how alterations in these pathways may contribute to cholangiocarcinoma pathogenesis. Support or Funding Information Supported by a research fellowship from the Cholangiocarcinoma Foundation