Περίληψη:
Background: Down-regulation or overexpression of the cyclin-dependent
kinase inhibitor p27 have been observed in a range of malignancies,
including lung cancer. To further elucidate the role of the molecule in
tumor growth regulation, we evaluated p27 expression in a series of
non-small cell lung carcinomas (NSCLCs), and examined its relation with
histology, kinetic parameters, ploidy, and overall survival. We extended
our investigation into the association of p27 levels with the presence
of Ki-ras mutations, as well as with the expression status of p53 and
pRb in tumor cells.
Material and Methods: p27, p53, and pRb status were
immunohistochemically evaluated in a total of 69 NSCLCs. In situ assays
were employed to assess the kinetic parameters (Ki-67
immunohistochemistry for proliferation index, Tdt-mediated dUTP nick end
labeling assay for apoptotic index). The ploidy status of the tumors was
assessed after staining nuclei with the Feulgen procedure, and the
presence of Ki-ras mutations was examined by restriction fragment length
polymorphisms. All possible associations were assessed with a series of
statistical methods.
Results: Immunoreactivity for p27 was observed in the entire series of
specimens, with the mean percentage of positive cells being 33%.
Adenocarcinomas (AdCs) exhibited higher p27 levels compared to squamous
cell carcinomas (SqCCs) (p < 0.01). An inverse correlation was
established between p27 expression and proliferation index (PI) (r =
-0.834, p < 0.01) but not with apoptotic index (AI), whereas aneuploid
tumors were characterized by lower p27 levels than diploid ones (p <
0.01). No difference in p27 immunostaining was observed with regard to
the presence of Ki-ras mutations, whereas aberrant p53 and/or pRb
expression patterns were associated with p27 underexpression (p < 0.01
for p53 status, p < 0.05 regarding pRb levels, and p < 0.01 for a
combined deregulation of both proteins). Two or more alterations in the
p27/p53/pRb protein network (i.e., p27 levels lower than the estimated
mean value, overexpressed p53, and/or aberrant pRb) were associated with
increased PI and aneuploidy (p < 0.001 and p < 0.01, respectively). A
powerful trend was found between p27 expression and overall survival (p
= 0.066).
Conclusions: Our findings confirm the heterogeneity between AdCs and
SqCCs, and are suggestive of an increased proliferative activity in
NSCLCs underexpressing p27. Furthermore, our analysis supports the
concept of p27 forming a functionally compact network with p53 and pRb,
which is actively involved in the regulation of cellular proliferation
and chromosomal stability.
Συγγραφείς:
Tsoli, E
Gorgoulis, VG
Zacharatos, P
Kotsinas, A and
Mariatos, G
Kastrinakis, NG
Kokotas, S
Kanavaros, P and
Asimacopoulos, P
Bramis, J
Kletsas, D
Papavassiliou, AG and
Kittas, C
