Molecular Mechanisms in the Pathogenesis of Hepatoblastoma

Cancer;Liver;genetics;Molecular Biology;paediatrics;miRNA;signalling

Purcell, Rachel Violet ; Sullivan, Michael ; Hale, Tracy ; Kennedy, Martin

University of Otago

关键词: Cancer;    Liver;    genetics;    Molecular Biology;    paediatrics;    miRNA;    signalling;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/1841/1/PurcellRachel2004PhD.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Hepatoblastoma accounts for 1% of new cancer diagnoses in childhood and is the most common childhood liver cancer. While most cases of hepatoblastoma (HB) are sporadic and its aetiology is unknown, there is a close association of HB with developmental syndromes such as the Beckwith-Wiedemann Syndrome (BWS) and Familial Adenomatous Polyposis (FAP). Clinical staging and histologic classification are complex and the current approach to risk stratification of these patients is based on clinical features such as the tumour stage, and the extent of liver involvement. Although treatment of HB with platinum-based chemotherapy followed by resection is highly successful there remains >15 % of HB that suffer from relapse. These relapse patients are often refractive to conventional chemotherapy and have a poor prognosis. The International Society of Paediatric Oncology liver tumour strategy group (SIOPEL) has conducted a series of clinical trials, with the aim of improving the overall clinical outcome of HB. In this study we accessed 94 formalin-fixed paraffin-embedded (FFPE) tumour samples from patients registered with SIOPEL. Corresponding clinical, histologic and survival data was available for all samples. We created a tissue microarray from these samples and examined the expression of E-cadherin, Cyclin D1, Ki67 AFP and β-catenin using immunohistochemistry. Statistical analysis revealed that Cyclin D1 and Ki67 expression were significantly associated with outcome in our HB cohort. This has revealed two potential biomarkers that may aid in prognostication. Activation of β-catenin is a hallmark of hepatoblastoma and appears to play a crucial role in its pathogenesis. However, while aberrant accumulation of β-catenin is a common event in HB, the high frequency of protein expression cannot always be accounted for by mutations or deletions in CTNNB1, the β-catenin gene. 87% of this HB cohort showed aberrant accumulation of the β-catenin protein but only 15% had mutations in the β-catenin gene by sequence analysis. In this study we also investigated alternative activation of β-catenin by HGF/c-MET signalling in our large cohort of HB patients. Activation of the HGF/c-Met pathway leads to tyrosine phosphorylation on residue 654 of β-catenin resulting in nuclear localization and downstream signalling. Immunohistochemical analysis revealed a large subset of HB, 83%, with cytoplasmic localization of tyrosine654-phosphorylated β-catenin with 30% showing additional nuclear accumulation. Statistical analysis revealed an association between nuclear expression of c-MET activated β-catenin and wild type CTNNB1. Our analysis identifies a significant subset of hepatoblastoma patients for whom targeting of the c-MET pathway with TRK inhibitors may be a treatment option. To investigate potential epigenetic regulation of HB pathogenesis we examined microRNA profiles from a number of tumours using microarrays. No differential expression was found between wild type and mutant CTNNB1 tumours or between relapse and non-relapse patients. However particular miRNAs appear to be upregulated/down-regulated in HB when compared to published data on normal liver miRNA profiles, including miRNAs known to be involved in cancer.