GATA transcription factors are required for the normal differentiation of various tissues, including liver, but their expression is low in normal postnatal hepatocytes. Aberrant expression of GATA factors has been connected to several human diseases. Hepatoblastoma (HB) is a rare liver malignancy of small children, with a largely unknown molecular pathology, histologically resembling fetal liver tissue. Biliary atresia (BA) is a neonatal cholestatic condition caused by fibroinflammatory obstruction of the extrahepatic bile ducts, with subsequent histological changes in liver. This thesis work demonstrates that GATA4 is frequently overexpressed in childhood HBs. The effects of GATA4 in HB cell malignancy were studied in vitro utilizing a human HB cell line. The changes in cell function and gene expression caused by modification of GATA4 levels were analyzed. We found that GATA4 1) protects HB cells from the commonly used cytostatic drug doxorubicin by regulating the intrinsic apoptotic pathway, and 2) shifts the transcriptomic profile of HB cells to more mesenchymal-type and enhances their migration. A second focus of this thesis is the role of GATA6 transcription factor in BA pathogenesis. We found that GATA6, normally restricted to biliary epithelium in postnatal liver, is highly expressed in the hepatocytes undergoing ductal metaplasia in livers of BA patients. GATA6 expression correlates to known prognostic markers, including bile ductule expansion and age at portoenterostomy. The expression of GATA6 decreases significantly after resolution of cholestasis by successful portoenterostomy. Analogously to its increased expression in BA, GATA6 is also upregulated in the hepatocytes of two mouse models with biliary obstruction. Furthermore, forced expression of GATA6 in two human hepatocyte cell models drives their gene expression towards cholangiocyte lineage. Taken together, transcription factors GATA4 and GATA6 are essential for the initial differentiation of hepatoblasts and for liver organogenesis. Compared to normal postnatal liver, their expression is upregulated in these two pediatric diseases of the liver. GATA4 and GATA6 are here demonstrated as putative drivers of hepatocyte neoplasia and metaplasia.
|Tilldelningsdatum||7 sep 2018|
|Status||Publicerad - 2018|
|MoE-publikationstyp||G5 Doktorsavhandling (artikel)|
Bibliografisk informationM1 - 77 s. + liitteet
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