Down-regulation of proteasomal subunit MB1 is an independent predictor of improved survival in ovarian cancer.
OBJECTIVE
To investigate the expression and to determine the prognostic impact of components of the antigen processing and presentation pathway (APPP) in ovarian cancer.


METHODS
Expression of MB1, LMP7, TAP1, TAP2, ERp57, ERAP1, beta(2)-microglobulin and the alpha-chains, HLA-B/C and HLA-A, of the MHC class I molecules was evaluated on tissue microarrays containing primary tumor samples from 232 FIGO stages I-IV ovarian cancer patients. Expression levels were correlated to clinicopathological data and disease specific (DSS) survival.


RESULTS
Patients with expression of all components of the MHC class I complex, i.e. HLA-A(+)-beta(2)-m(+) and HLA-B/C(+)-beta(2)-m(+) patients, more often had expression of LMP7, a component of the immunoproteasome than patients with other phenotypes (p<0.001). These patients were also more prone to loss of MB1, part of the constitutive multicatalytic proteasome (p<0.05). Nuclear MB1 expression was an independent predictor of worse DSS (HR 1.94, 95% CI 1.16-3.26, p=0.012). The HLA-B/C(+)-beta(2)-m(+) phenotype was an independent predictor of a better prognosis (HR 0.63, 95% CI 0.40-0.99, p=0.047). Median DSS was longer for patients with normal nuclear expression of LMP7 (57.4 vs. 31.0 months, p=0.029).


CONCLUSIONS
The prognostic influence of the proteasomal subunit MB1 and the MHC class I complex in ovarian cancer provides a rationale for targeting these specific APPP components in ovarian cancer.
Leffers
Ninke
N
Department of Gynecological Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Gooden
Marloes J M
MJ
Mokhova
Anna A
AA
Kast
W Martin
WM
Boezen
H Marike
HM
Ten Hoor
Klaske A
KA
Hollema
Harry
H
Daemen
Toos
T
van der Zee
Ate G J
AG
Nijman
Hans W
HW
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000276:immunology; D000626:Aminopeptidases / Q000096:biosynthesis / Q000276:immunology; D017951:Antigen Presentation; D051925:CD79 Antigens / Q000096:biosynthesis* / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000276:immunology; D015235:HLA-B Antigens / Q000096:biosynthesis / Q000276:immunology; D015236:HLA-C Antigens / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000276:immunology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000276:immunology; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D051925:CD79 Antigens; C497881:CD79A protein, human; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; C073119:TAP1 protein, human; C071692:TAP2 protein, human; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human