|
Etiology and Pathogenesis
>
Tumor
Biology / Tumorigenesis
|
|
Oncogene advance online publication 31 July 2006;
doi: 10.1038/sj.onc.1209716
|
|
|
|
|
Abstract |
|
|
|
Alternative
splicing of the ErbB-4 cytoplasmic domain and its regulation by
hedgehog signaling identify distinct medulloblastoma subsets
E Ferretti1,
L Di Marcotullio1, M Gessi2,
T Mattei1, A Greco1,
A Po1, E De Smaele1,
F Giangaspero1,3, R Riccardi4,
C Di Rocco5, S Pazzaglia6,
M Maroder1, M Alimandi1,
I Screpanti1,7 and A Gulino1,3
1Department
of Experimental Medicine and Pathology, University La Sapienza, Roma,
Italy. 2Division of Neuropathology,
National Neurological Institute 'C. Besta', Milano, Italy. 3Neuromed
Institute, Pozzilli, Isernia, Italy. 4Department
of Pediatrics, Catholic University, Rome, Italy. 5Neurosurgery
Institute, Catholic University, Rome, Italy. 6Biotechnology
Unit, ENEA-CR Casaccia, Roma, Italy. 7Pasteur
Institute, Cenci Bolognetti Foundation, Roma, Italy. --
Correspondence: Dr A Gulino, Department of Experimental Medicine and
Pathology, University La Sapienza, 324 Viale Regina Elena, Rome 00161,
Italy. E-mail: alberto.gulino@uniroma1.it. -- Received 13 December 2005;
Revised 24 April 2006; Accepted 27 April 2006;
Published online 31 July 2006.
|
|
|
|
|
Medulloblastoma (MB) results from aberrant
development of cerebellar neurons in which altered hedgehog (Hh)
signalling plays a major role.
We investigated the possible influence of
Hh signalling on ErbB-receptor expression in MB, in particular that of
the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing
of the cytoplasmic domain.
ErbB-4 expression was downregulated in Hh-induced
MBs from Patched-1+/- mice.
Hh signalling (reflected by enhanced
expression of the Gli1 transcription factor) inhibited ErbB-4
expression in mouse cerebellar granule progenitors and human MB
cells.
Analysis of 26 human primary MBs revealed
a subset of 11 tumors characterized by low Gli1 levels, upregulated
ErbB-4 expression and increased CYT-1:CYT-2 ratios.
Interestingly, CYT-1 and Gli1 levels were
inversely correlated.
ErbB-4 CYT-1 and CYT-2 had different
phenotypic effects in cultured MB cells: in response to neuregulin
treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1,
which includes a phosphatidylinositol 3-kinase (PI3K)-binding site
that is missing in CYT-2, enhanced resistance to starvation- and
etoposide-induced apoptosis by activating PI3K/Akt signalling.
CYT-1:CYT-2 ratios displayed correlation
with tumor histotype and ErbB-2 levels, which are established
prognostic indices for MB.
These findings demonstrate that low-level
Hh signalling in human MB is associated with the selective maintenance
of high ErbB-4 CYT-1 expression, an alteration that exerts
tumor-promoting effects.
Keywords:
medulloblastoma, ErbB-4, alternative splicing, hedgehog, Gli1
|
|
|
|
|
© 2006 Nature Publishing Group
|
|
|
Abstract
|
|
|
|
