Περίληψη:
The p16-pRb and p53-MDM2 pathways represent vital cell cycle
checkpoints. Recent studies provide evidence that these pathways are
directly linked via MDM2-pRb interaction and p53 suppression of the RBI
gene. In the present study we investigated the alterations of this G1
phase protein network using immunohistochemical and molecular methods in
a series of 68 non-small-cell lung carcinomas (NSCLCs) and correlated
the findings with clinicopathological features and prognosis of the
patients. Aberrant expression (Ab) of p16 and pRb was observed in 33
(49%) and 27 (40%) of the carcinomas, respectively. Analysis of the
region that encodes for p16 by deletion mapping, a polymerase chain
reaction (PCR) based methylation assay and PCR single-strand
conformation polymorphism (SSCP) analysis revealed that deletions and
transcriptional silencing by methylation might represent the main
mechanisms of CDKN2/p16(ink4a) inactivation in NSCLCs, The results of
deletion mapping also suggest that other tumor suppressor genes may
reside at the 9p21-22 region, which encodes for CDKN2/MTS1/p16(ink4a),
r14(ARF), and MTS2/p15(ink4b), In addition, microsatellite instability
was observed with a frequency of 16% in the 9p21-22 chromosome area.
Overexpression (P) of p53 and MDM2 proteins was found in 39 (58%) and
47 (70%) of the cases, respectively, A highly significant association
was observed between p53 overexpression and p53 mutations (P = 0.006),
Statistical analysis of the expression patterns of the biologically
relevant molecules (p16/pRb, p53/MDM2, MDM2/pRb, and p53/pRb) showed
coincident overexpression of p53 and MDM2 (P = 0.04) and that abnormal
pRb was correlated with elevated levels of MDM2 (P = 0.013) and p53 (P =
0.01), respectively, We suggest that deregulated expression of these
molecules may act synergistically. An important finding of the study was
that multiple impairments (three and four molecules affected) of the
p16/pRb/p53/MDM2 network occurred in a large proportion (43%) of the
carcinomas, This finding in addition to the absence of correlation with
clinical stage of the tumors suggests that multiple hits of this network
may be a relatively early event in the development of a subset of
NSCLCs, The relationship between the factors examined in the present
study, clinicopathological features, and survival of the patients did
not reveal any significant correlations with the exception of smoking,
which was associated with microsatellite alterations (loss of
heterozygosity and microsatellite instability) at the 9p21-22 locus (P =
0.04) and the immunophenotypes p53(P)/MDM2(P) (P = 0.04) and
p16(Ab)/pRb(Ab)/p53(P)/MDM2(P) (P = 0.03), respectively. We suggest that
in a subset of NSCLCs, simultaneous deregulation of the members of this
network may represent one way of initiating the oncogenic procedure
whereas in other NSCLC subgroups alternative pathways may play this
role.
Συγγραφείς:
Gorgoulis, VG
Zacharatos, P
Kotsinas, A
Liloglou, T and
Kyroudi, A
Veslemes, M
Rassidakis, A
Halazonetis, TD and
Field, JK
Kittas, C
