cell lung cancer.23 Also, overexpression of CDK2 has been
observed for oral and laryngeal squamous cell carcino-
ma.24,25 In addition, proliferating Schwann cells estab-
lished in culture from rat sciatic nerves showed higher
CDK2 protein expression than nonproliferating cells.26
Taken together, our results suggest that decreased ex-
pression of CDK2 in vestibular schwannomas may relate
to the slow growth rate of the tumor.
The cyclin-dependent kinase inhibitor p27 has been
assigned to chromosome 12p12, a region often mutated in
childhood acute lymphoblastic leukemia (ALL).27 Consis-
tently, we found that three vestibular schwannomas
showed p27 downregulation. In contrast, overexpression
of p27 in non-Hodgkin’s lymphoma has been shown to be
of prognostic value.28 Other authors have also reported
that high expression of p27 and inhibition of cyclin
E/CDK2 may favor survival of small cell lung carcinoma
cells by preventing apoptosis in an environment that is
not favorable for cell proliferation.29
The Rb-related protein p130 can be phosphorylated in a
CDK2 dependent fashion resulting in the activation of E2F-4
and E2F-5 transcription factors.30 It is likely that deregula-
tion of E2F transcription factors would interrupt normal cell
cycle progression. DP-1 associates with E2F transcription
factors. The functional significance of underexpression of
E2F-4, E2F-5, and their associated protein DP-1 in some
vestibular schwannomas is currently unknown.
One important consideration that should be pointed
out in our analysis is the use of the paired normal vestib-
ular nerve as the control tissue. Experiments using cul-
tured Schwann cells may yield data for direct comparison
with schwannoma tissue. However, the drawback of using
such a cell culture is that culture conditions could alter
gene expression patterns. Studies with colon cancer have
revealed that normal colon tissue, colon carcinoma tissue,
and colon carcinoma cell culture yield distinctly different
expression profiles.10 In addition, limited division, as well
as growth arrest, has been commonly observed with cul-
tured human VS cells, and a stable human Schwann cell
line has not been established. Nevertheless, a direct com-
parison of protein expression (CDK2) in tissue section,
together with quantitative real-time PCR analysis,
yielded results consistent with cDNA microarray data
when schwannoma tumors were compared with the nor-
mal vestibular nerve.
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CONCLUSION
Approximately 0.5% of genes expressed in vestibular
schwannomas showed deregulation compared with those
in the normal vestibular nerve. Among deregulated genes,
several members of the pRb-CDK pathway, including
Rb-1; cyclin D1, D2, and E; and CDK2, CDK6, p27, E2F,
and DP-1, were found. In particular, CDK2 expression
was downregulated in seven of the eight vestibular
schwannomas studied. Further collaboration with other
centers and investigation in vitro and in vivo into the
regulatory mechanisms governing CDK2 expression may
lead to a better understanding of VS tumorigenesis.
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Laryngoscope 112: September 2002
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Lasak et al.: Vestibular Schwannomas