Περίληψη:
Numerous upstream stimulatory and inhibitory signals converge to the
pRb/E2F pathway, which governs cell-cycle progression, but the
information concerning alterations of E2F-1 in primary malignancies is
very limited. Several in vitro studies report that E2F-1 can act either
as an oncoprotein or as a tumour suppressor protein. In view of this
dichotomy in its functions and its critical role in cell cycle control,
this study examined the following four aspects of E2F-1 in a panel of 87
non-small cell lung carcinomas (NSCLCs), previously analysed for defects
in the pRb-p53-MDM2 network: firstly, the status of E2F-1 at the
protein, mRNA and DNA levels; secondly, its relationship with the
kinetic parameters and genomic instability of the tumours; thirdly, its
association with the status of its transcriptional co-activator CBP,
downstream target PCNA and main cell cycle regulatory and
E2F-1-interacting molecules pRb, p53 and MDM2; and fourthly, its impact
on clinical outcome. The protein levels of E2F-1 and its co-activator
CBP were significantly higher in the tumour area than in the
corresponding normal epithelium (p < 0.001). E2F-1 overexpression was
associated with increased E2F-1 mRNA levels in 82% of the cases
examined. The latter finding, along with the low frequency of E2F-1 gene
amplification observed (9%), suggests that the main mechanism of E2F-1
protein overexpression in NSCLCs is deregulation at the transcriptional
level. Mutational analysis revealed only one sample with a somatic
mutation at codon 371 (Glu –> Asp) and one carrying a polymorphism at
codon 393 (Gly –> Ser). Carcinomas with increased E2F-1 positivity
demonstrated a significant increase in their growth indexes (r = 0.402,
p = 0.001) and were associated with adverse prognosis (P = 0.033 by Cox
regression analysis). The main determinant of the positive association
with growth was the parallel increase between E2F-1 staining and
proliferation (r = 0.746, p < 0.001), whereas apoptosis was not
influenced by the status of E2F-1. Moreover, correlation with the status
of the pRb-p53-MDM2 network showed that the cases with aberrant pRb
expression displayed significantly higher E2F-1 indexes (p = 0.033),
while a similar association was noticed in the group of carcinomas with
deregulation of the p53-MDM2 feedback loop. In conclusion, the results
suggest that E2F-1 overexpression may contribute to the development of
NSCLCs by promoting proliferation and provide evidence that this role is
further enhanced in a genetic background with deregulated pRb-p53-MDM2
circuitry. Copyright (C) 2002 John Wiley & Sons, Ltd.
Συγγραφείς:
Gorgoulis, VG
Zacharatos, P
Mariatos, G
Kotsinas, A and
Bouda, M
Kletsas, D
Asimacopoulos, PJ
Agnantis, N and
Kittas, C
Papavassiliou, AG
