| Abstract |
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ABSTRACT
p63 plays an important role in several intracellular processes
such as transcription activation and apoptosis. p63 has two Nterminal
isoforms, TAp63 and DNp63. TAp63 isoform has p53-like
functions, while DNp63 acts as a dominant negative inhibitor of the
p53 family and is considered oncogenic. Although p63 and its
isoforms are overexpressed in a wide variety of human malignancies
such as cervical, head and neck, and lung cancer, their role in
endometrial carcinoma has not been investigated.
We measured by quantitative real-time polymerase chain
reaction the mRNA expression of TAp63 and DNp63 in a series of 20
endometrioid adenocarcinomas paired with adjacent normal tissue.
TAp63 isoform exhibited 1.8-fold overexpression in malignant
samples, while DNp63 was 4.3-fold overexpressed in cancer
specimens. Further analysis revealed that the DN/TA isoform ratio
shifted from 0.5 in normal samples to 1.2 in tumor specimens.
Statistical analysis also revealed an association of TAp63 expression
with high body mass index (p = 0.034), late menopause (p =
0.020), and lower tumor grade (p = 0.034). DNp63 was also
correlated with grade I/II tumors (p = 0.044).
These results indicate that both p63 isoforms and especially
DNp63 play an important role in the development and progression of
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grade I/II endoπmetrial adenocarcinoma, especially in obese and
late-menopause women.
p73 plays an important role in several intracellular processes
such as transcription activation and apoptosis. Its promoters, P1 and
P2, produce two different classes of proteins: those containing the
transactivation domain (TAp73) and those lacking it (ΔNp73). TAisoforms
exhibit p53-like functions, while ΔΝ- isoforms act as
dominant negative inhibitors of both wild-type p53 and TAp73. p73
is overexpressed in a wide variety of human tumors such as breast,
lung, colon, bladder and ovarian cancer.
We investigated the role of p73 isoforms in endometrial
adenocarcinoma in a series of 20 tumor and adjacent normal tissue
samples. Mrna expression of TAp73 and ΔNp73 was measured by
realtime
PCR, while the methylation profile of promoters P1 and P2 was
examined by methylation-specific PCR (MSP).
Methylation analysis showed that P1 promoter was
unmethylated in all normal and malignant samples, while TAp73
expression levels were higher in 7/20 (35%), lower in 3/20 (15%)
and normal in 10/20 (50%) tumor specimens. On the contrary, P2
promoter was methylated in 10/20 (50%), unmethylated in 2/20
(10%) and unmethylated only in the tumor specimen in 6/20 (30%)
samples, respectively. This finding was in accordance with ΔNp73
mRNA expression, since ΔNp73 was not expressed in 10/20 (50%)
samples, while in 7/20 (35%) samples it was only expressed in the
tumor specimen.
From the above results we deduce that the demethylation of
P2 promoter and the subsequent expression of ΔΝp73 in tumor
specimens is a key event in the development and progression of
endometrial cancer.
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Μελέτη της έκφρασης και των μηχανισμών ρύθμισης των γονιδίων ρ63 και ρ73 στον καρκίνο του ενδομητρίου
