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P a r t i c i p a n t s :<br />
Gianluca Canettieri, Elisabetta Ferretti, professors; Enrico De<br />
Smaele, Lucia Di Marcotullio, Alessandra Ianari, researchers.<br />
Subversion of cerebellar neural progenitor cell development<br />
leads to neoplastic transformation into medulloblastoma,<br />
an aggressive brain malignancy with high<br />
incidence in childhood. Current treatment approaches<br />
have limited efficacy and severe side effects. Therefore,<br />
new risk-adapted therapeutic strategies based on<br />
molecular classification are required. A crucial master<br />
regulator of cerebellar neural progenitor cell development<br />
is represented by the Hedgehog pathway which<br />
displays, when deregulated, a critical role in the pathogenesis<br />
of medulloblastoma. Cross-regulation between<br />
Hedgehog signalling and several tumorigenic pathways<br />
(e.g. the oncogene products of the AP1/jun/fos complex)<br />
plays a role in cell development and tumorigenesis.<br />
Furthermore, deregulation of tumor suppressor<br />
gene function (i.e. Rb) is critical for the formation of<br />
Hedgehog-dependent medulloblastoma. We have investigated<br />
a number of molecular mechanisms involved in<br />
the formation of medulloblastoma (Gulino et al., J Clin<br />
Invest. 2009, in press; Gulino et al., Curr Opin Oncol.<br />
2008, 20:668-75; Gulino et al., Psychoneuroendocrinology<br />
2007, 32:S55-56; Farioli-Vecchioli et al., FASEB J. 2007,<br />
21:2215-25). We have also further dissected the molecular<br />
steps of the regulation of the Hedgehog pathway<br />
as well as of the control of the transcriptional function<br />
of AP1 and Rb proteins. Specific aspects of the<br />
research are described below.<br />
MicroRNA control of cerebellar neural<br />
progenitors and medulloblastoma cells via<br />
targeting of the Hedgehog pathway<br />
MicroRNAs are crucial post-transcriptional regulators<br />
of gene expression and control cell differentiation and<br />
proliferation. MicroRNA expression analysis has<br />
emerged as a powerful tool to identify candidate molecules<br />
playing an important role in a large number of<br />
malignancies. However little is known about their targeting<br />
of specific developmental pathways and, more<br />
specifically, no data are yet available on human primary<br />
medulloblastomas. We have performed a high through-<br />
Principal investigator: Alberto Gulino<br />
Professor of Molecular Pathology<br />
Dipartimento di Medicina Sperimentale<br />
Tel: (+39) 06 4464021; Fax: (+39) 06 4461974<br />
alberto.gulino@uniroma1.it<br />
55<br />
Molecular genetics of eukaryotes - AREA 3<br />
Regulation of the Hedgehog signaling in neural cell development<br />
and disease<br />
put microRNA expression profile analysis in human<br />
primary medulloblastoma specimens to investigate<br />
microRNA involvement in medulloblastoma carcinogenesis.<br />
We identified specific microRNA expression<br />
patterns which distinguish medulloblastoma differing<br />
in histotypes (anaplastic, classic and desmoplastic), in<br />
molecular features (ErbB2 or c-Myc over-expressing<br />
tumors) and in disease risk stratification. MicroRNAs<br />
expression profile clearly differentiates medulloblastoma<br />
from either adult or fetal normal cerebellar tissues.<br />
Only a few microRNAs displayed up-regulated<br />
expression, while most of them were downregulated in<br />
tumor samples, suggesting a tumor growth inhibitory<br />
function. This property has been addressed for miR-9<br />
and miR-125a whose rescued expression promoted<br />
medulloblastoma cell growth arrest and apoptosis<br />
while targeting the pro-proliferative truncated isoform<br />
of TrkC neurotrophin receptor (Ferretti et al., Int J<br />
Cancer 2009, 124:568-77; Laneve et al., Proc Natl Acad<br />
Sci USA 2007, 104:7957-62).<br />
Our microRNA high-throughput profile screening also<br />
revealed a downregulated microRNA signature in<br />
human medulloblastomas with high Hedgehog signaling.<br />
Specifically, we identify miR-125b and miR-326 as<br />
suppressors of the pathway activator Smoothened<br />
together with miR-324-5p which also targets the<br />
downstream transcription factor Gli1. Downregulation<br />
of these microRNAs allows high levels of Hedgehogdependent<br />
gene expression leading to tumor cell proliferation.<br />
Interestingly, the downregulation of miR-324-<br />
5p is genetically determined by medulloblastoma-associated<br />
deletion of chromosome 17p. Of note, we also<br />
<strong>report</strong> that while microRNA expression is downregulated<br />
in cerebellar neuronal progenitors, it increases<br />
along differentiation, thereby allowing cell maturation<br />
and growth inhibition. These findings identify a novel<br />
regulatory circuitry of the Hedgehog signaling pathway<br />
and suggest that misregulation of specific<br />
miRNAs, leading to its aberrant activation, sustains<br />
cancer development.<br />
In conclusion, specific microRNA deregulation signatures<br />
characterize medulloblastomas and discriminate<br />
tumor subsets with distinct properties thus representing<br />
potential targets for novel therapeutic strategies.