Role of Lamin A/C in neuroblastoma differentiation: therapeutic implications
Author(s)
Maresca, Giovanna
Date Issued
February 8, 2011
Type
Doctoral Thesis
Abstract
Neuroblastoma is one of the most aggressive solid tumors in childhood. The degree of its
differentiation can influence patient outcome since high differentiated tumors have been correlated
to favourable prognosis. Most neuroblastoma cells maintain the ability to differentiate in vitro in the
presence of various agents, rendering them a good model to study the differentiation potential of
these tumors.
Nuclear lamins are type V intermediate-filament proteins that form a scaffoldlike meshwork
underlying the inner nuclear membrane and have many different and not completely known
functions. Among lamins, the A-type ones are expressed in differentiated tissues and are involved in
the differentiation processes during the embryonal development. Their expression is reduced or
absent in different human malignancies even though their role in the tumorigenesis is not yet
characterized.
Our aim was to investigate the role of Lamin A/C, belonging to A-type lamins, in the
differentiation and tumorigenesis of neuroblastoma cells. We have also studied whether Lamin A/C
could represent a marker of drug sensitivity, which could contribute to develop therapeutic
strategies based on the molecular profile of the individual tumor.
As cellular model we employed a neuroblastoma cell line able to differentiate in vitro and
showing high expression levels of Lamin A/C, the SHSY5Y cell line. As differentiating stimulus
we used the all-trans retinoic acid (RA), the most effective compound which has been shown to
induce differentiation in neuroblastoma cells and that is employed as biological agent in clinics to
improve patients’ survival.
Silencing of Lamin A/C blocked the differentiation processes activated by the RA in SHSY5Y
cells, thus preventing the formation of neurites and inhibiting the expression of the tyrosine
hydroxylase differentiation marker. The genome-wide gene-expression profiling of SHSY5Y cells
silenced for LMNA gene (miRL cells), in the presence or not of the differentiating stimulus
confirmed that miRL cells have down-regulated those genes necessary for the differentiation
program. As well an increase of tumor progression related genes shifted the SHSY5Y cells
phenotype towards a more aggressive one, with a higher resistance elicited versus some
chemoterapic agents, thus demonstrating that Lamin A/C could represent a good marker of
neuroblastoma tumor progression and of response to antitumoral therapeutics.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
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