Abstract
BackgroundASCL1 role in pancreatic endocrine tumourigenesis has not been established. Recently it was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist DKK1. Notch signalling regulates expression of TPH1, the rate limiting enzyme in the biosyntesis of serotonin. Understanding the development and proliferation of pancreatic endocrine tumours (PETs) is essential for the development of new therapies.MethodsASCL1 target genes in the pancreatic endocrine tumour cell line BON1 were identified by RNA interference and microarray expression analysis. Protein expressions of selected target genes in PETs were evaluated by immunohistochemistry.Results158 annotated ASCL1 target genes were identified in BON1 cells, among them DKK1 and TPH1 that were negatively regulated by ASCL1. An inverse relation of ASCL1 to DKK1 protein expression was observed for 15 out of 22 tumours (68%). Nine tumours displayed low ASCL1/high DKK1 and six tumours high ASCL1/low DKK1 expression. Remaining PETs showed high ASCL1/high DKK1 (n = 4) or low ASCL1/low DKK1 (n = 3) expression. Nine of twelve analysed PETs (75%) showed TPH1 expression with no relation to ASCL1.ConclusionA number of genes with potential importance for PET tumourigenesis have been identified. ASCL1 negatively regulated the Wnt signalling antagonist DKK1, and TPH1 expression in BON1 cells. In concordance with these findings DKK1 showed an inverse relation to ASCL1 expression in a subset of PETs, which may affect growth control by the Wnt signalling pathway.
Highlights
ASCL1 role in pancreatic endocrine tumourigenesis has not been established
We have recently reported that ASCL1 is invariably expressed in pancreatic endocrine tumours (PETs), and suggested that the observed lack of nuclear Hairy and enhancer of split 1 (HES1) might contribute to the expression of ASCL1 in these tumours [8]
Expression profiling in the pancreatic endocrine tumour cell line BON1 RNA interference and microarray expression analysis were employed in order to identify ASCL1 target genes in BON1 cells
Summary
ASCL1 role in pancreatic endocrine tumourigenesis has not been established. It was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist DKK1. Understanding the development and proliferation of pancreatic endocrine tumours (PETs) is essential for the development of new therapies. Understanding the molecular pathways that control PET development and proliferation are essential for possible development of novel therapies. Ascl is tightly controlled by the Notch signalling pathway in the developing pancreas and governs the exocrine versus endocrine cell fate decision [4]. The active form of Notch, NICD, induces the expression of Hairy and enhancer of split 1 (HES1) which in turn antagonises the expression of bHLH genes such as ASCL1, with subsequent inhibition of progenitor cell differentiation [7]
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