Year: 2021
Type: dissertation
Abstract: Hepatoblastoma (HB) is the most common pediatric liver malignancy with an annual incidence of 1.8 cases per million children. Most cases are sporadic, although certain genetic disorders such as Beckwith-Wiedemann syndrome and familial adenomatous polyposis are associated with increased risk of HB. Developmental pathways, such as WNT/β-catenin and Hedgehog signaling, are often aberrantly activated in HB cells. The overall mutation burden in HB is generally low, but the CTNNB1 gene encoding β-catenin is altered in over 60% of cases. Surgical resection of tumor is a mainstay of HB treatment, generally supported by pre- and post-operative chemotherapy. The survival rate of HB is over 80% if tumor is confined to liver but decreases dramatically when there is extrahepatic involvement, so new treatment options are needed. In this thesis we examined two key factors, GATA4 and neuropilin-2, in the pathobiology of HB. Additionally, we conducted in vitro experiments investigating the potential of chloroquine as a novel HB therapy. Transcription factor GATA4 is crucial for early liver development. We observed that most HB patient samples and cell lines express high levels of GATA4. Moreover, GATA4 expression was associated with mesenchymal-like and motile phenotype in HB cells. Neuropilins (NRP) are multifunctional receptors involved both in physiological and pathological processes. We noted high NRP1 and NRP2 expression in HB patient samples and six HB cell models. Utilizing siRNA transfection, we observed decreased viability and motility in NRP2 knockdown cells compared to cells with intact gene expression suggesting that NRP2 promotes aggressive behavior in HB cells. Chloroquine is a traditional anti-malarial which has demonstrated potential in cancer management. We observed a drastic decrease in HB spheroid viability after chloroquine treatment. Chloroquine treatment also modified the metabolic profile of HB cells with a remarkable decrease in NAD+ and aspartate concentrations. Additionally, we noticed significant decrease in PARP1/2 expression suggesting that chloroquine may have effect on DNA repair system in HB cells. In summary, this thesis shed new light on the molecular mechanisms of HB pathogenesis. In the future, these findings may be utilized in development of novel treatment approaches and diagnostics to improve survival and life quality of HB patients.
Source: Työväentutkimus Vuosikirja
Author: Katja Eloranta
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3165216268