Nuclear expression of apurinic/apyrimidinic endonuclease increases with progression of ovarian carcinomas.
OBJECTIVE
Apurinic/apyrimidinic endonuclease (APE alias Ref-1) is a key enzyme in the base excision repair pathway. Besides its function in DNA repair, APE serves to maintain several transcription factors in an active reduced state such as c-Fos, c-Jun, NF-kappaB, p53 and HIF-1alpha, all of which have been shown to play a role in tumorigenesis. Because of the importance of APE in maintaining genomic stability and gene regulation, we examined whether APE expression is associated with survival and histopathological parameters of patients with ovarian cancer.


METHODS
Tissue sections of primary epithelial ovarian carcinomas from 141 patients were immunostained using a monoclonal antibody directed against APE.


RESULTS
Nuclear expression of APE was clearly associated with progression of ovarian carcinomas. Patients with Federation of Gynecology and Obstetrics (FIGO) stages III and IV showed a higher nuclear APE expression level than patients with FIGO stages I and II (P < 0.0001). Similarly, nuclear APE expression was associated with histological grading (grade 1 vs. 2 vs. 3; P = 0.025). In contrast, cytoplasmic and stromal APE expression were not associated with progression. The fraction of APE-positive nuclei (P = 0.0185), the intensity of nuclear staining (P = 0.0496) and a combination of both (P = 0.0070) were associated with survival of ovarian cancer patients, as evidenced by a univariable proportional hazards model.


CONCLUSIONS
Multivariable analysis, adjusted to FIGO stage, histological grade and type as well as residual tumor after surgery showed that APE is not independent from "classical" prognostic factors of ovarian cancer. An unexpected observation was the inverse correlation between nuclear and cytoplasmic expression of APE. Tumors with strong cytoplasmic APE reactivity showed a higher fraction of APE-negative nuclei than tumors with weak or negative cytoplasmic APE expression (P = 0.045). This suggests that nuclear translocation of APE is impaired during ovarian carcinogenesis. In conclusion, we have shown that nuclear APE expression increases during tumor progression. This suggests that increased base excision repair capacity and/or APE-mediated activation of transcription factors may contribute to more aggressive proliferation of ovarian carcinomas.
Tanner
Berno
B
Department of Gynecology and Obstetrics, University of Mainz, Mainz, Germany. tanner@mail.uni-mainz.de
Grimme
Stephan
S
Schiffer
Ilka
I
Heimerdinger
Carolin
C
Schmidt
Markus
M
Dutkowski
Philipp
P
Neubert
Susanne
S
Oesch
Franz
F
Franzen
Arno
A
Kölbl
Heinz
H
Fritz
Gerhard
G
Kaina
Bernd
B
Hengstler
Jan Georg
JG
D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002467:Cell Nucleus / Q000201:enzymology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D015996:Survival Rate
D014408:Biomarkers, Tumor; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase