[NF-kappaB subunit p65/RelA expression in ovarian carcinoma: prognostic impact and link to COX-2 overexpression].
OBJECTIVE
NF-kappaB has been demonstrated to activate proliferative, inflammatory, and angiogenic processes in ovarian cancer cells in vitro. To add translational information on the situation in vivo, we determined the expression pattern of p65, an important subunit of the classic NF-kappaB pathway, in ovarian carcinoma tissue, and investigated in vivo and in vitro whether this pathway is implicated in the known overexpression of cyclooxygenase-2 (COX-2).


METHODS
p65 siRNA, chemiluminescent NF-kappaB transcription factor assay, Taqman PCR, as well as immunoblotting were performed with OVCAR-3 ovarian cancer cells. 83 primary ovarian cancinomas as well as 17 cases of benign ovarian tissue were analyzed by p65 and COX-2 immunohistochemistry using a tissue microarray.


RESULTS
DNA-binding avtivity as well as COX-2 mRNA and protein expression were strongly inducible by IL-1beta treatment in OVCAR-3 cells, while p65 siRNA inhibited IL-1beta-dependent p65 activity (p = 0.037) as well as COX-2 expression on the mRNA (p < 0.03) and on the protein level. In human tumor tissue, p65 protein expression was significantly associated with COX-2 expression (p = 0.002) as well as tumor grading (p = 0.005). Furthermore, p65 expression was a significant prognostic indicator of a reduced patient survival both in univariate (p = 0.038) and in multivariate analysis (p = 0.014).


CONCLUSIONS
Our study indicates a deregulation of the classical NF-kappaB pathway in ovarian cancer, which results in the overexpression of the NF-kappaB target gene COX-2. Components of this pathway might constitute novel attractive targets for a specific therapy of advanced ovarian cancer.
Niesporek
S
S
Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Mitte
Weichert
W
W
Sinn
B
B
Röske
A
A
Noske
A
A
Buckendahl
A C
AC
Wirtz
R
R
Sehouli
J
J
Koensgen
D
D
Dietel
M
M
Denkert
C
C
D000970:Antineoplastic Agents / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis; D016019:Survival Analysis; D051996:Transcription Factor RelA / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2