MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cells

Solari, Valeria
MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cells. PhD thesis, University of Liverpool.

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Neuroblastoma (NBL) is the most common type of cancer diagnosed in the first year of life. It is a complex and heterogeneous disease that arises from the developing sympathetic nervous system. Despite numerous advances and the well-demonstrated role of MYCN in the pathogenesis of neuroblastoma, the mechanisms underlying its oncogenic function are not entirely understood and there is evidence that its function is, in part, dependent on the tumour microenvironment (TME). New and improved therapeutic targets are urgently required for this often lethal tumour. Heparan sulfate proteoglycans (HSPG) play a critical role in the interactions between tumour cells and the TME and their activities are dependent on the sulfation pattern, that is controlled by sulfotransferases, which add sulfate groups to the repeating disaccharide units, and sulfatases (SULFs), which selectively remove 6-O-sulfates. In this work an analysis of the expression of these enzymes in human neuroblastoma revealed higher levels of SULF2 specifically when the MYCN oncogene was amplified. Loss of expression of SULF2 in MYCN-amplified (A) cell lines was associated with a marked decrease in survival and an increase in apoptosis. Evidence is presented that SULF2 is a direct downstream target of MYCN since overexpression of MYCN in neuroblastoma cells increases SULF2 expression whereas a down regulation reduced SULF2 expression. Underlying the importance of SULF2 in neuroblastoma cell survival independently of MYCN, it is demonstrated that overexpression of SULF2 in MYCN-NA cells increases cell viability without increasing MYCN expression. Analysis of SULF2 protein expression in a large cohort of primary human neuroblastoma tumours also indicated a high level of expression in MYCN-A tumours and an almost complete absence of expression in MYCN-non A (NA) tumours. The data identify SULF2 as a new downstream target of MYCN and a key contributor to its oncogenic function in human neuroblastoma, which might have future implications for clinical therapies for high-risk NBL.

Item Type: Thesis (PhD)
Additional Information: Date: 2014-07 (completed)
Depositing User: Symplectic Admin
Date Deposited: 06 May 2015 14:17
Last Modified: 17 Dec 2022 01:33
DOI: 10.17638/02003528