Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer.
BACKGROUND
The human nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 (CRM1) mediates the nuclear export of proteins and messenger RNAs and, thus, is an important regulator of subcellular distribution of key molecules. Whereas cell-biologic studies have suggested a fundamental role for CRM1 in the regulation of mitosis, the expression of this protein in human tumor tissue has not been investigated to date.


METHODS
In this study, the expression of CRM1 was analyzed in a cohort of 88 ovarian tumors and 12 ovarian cell lines for the first time to the authors' knowledge.


RESULTS
Immunohistochemistry revealed increased nuclear (52.7%) and cytoplasmic (56.8%) expression of CRM1 in 74 carcinomas compared with the expression revealed in borderline tumors and benign lesions. Similarly, CRM1 expression was increased in ovarian cancer cell lines compared with human ovarian surface epithelial cells. Cytoplasmic CRM1 expression was related significantly to advanced tumor stage (P= .043), poorly differentiated carcinomas (P= .011), and higher mitotic rate (P= .008). Nuclear CRM1 was associated significantly with cyclooxygenase-2 (COX-2) expression (P= .002) and poor overall survival (P= .01). Because it was demonstrated previously that blocking of CRM1 by leptomycin B (LMB) contributes to the inhibition of nuclear export, the authors used a set of mechanistic assays to study the effects of CRM1 inhibition in cancer cells. Treatment of OVCAR-3 cells with LMB revealed a significant reduction of cell proliferation and increased apoptosis as well as suppressed interleukin-1beta-induced COX-2 expression.


CONCLUSIONS
The current results indicated that CRM1 is expressed in a subpopulation of ovarian carcinomas with aggressive behavior and is related to poor patient outcome. A correlation also was demonstrated between CRM1 and COX-2 expression in ovarian cancer tissue. Furthermore, the treatment of ovarian cancer cells with LMB revealed a reduction in COX-2 expression. Therefore, the authors suggest that CRM1 may be an interesting biomarker for the assessment of patient prognosis and a molecular target for anticancer treatment.
Noske
Aurelia
A
Institute of Pathology, Charité University Hospital, Berlin, Germany. aurelia.noske@charite.de
Weichert
Wilko
W
Niesporek
Silvia
S
Röske
Annika
A
Buckendahl
Ann-Christin
AC
Koch
Ines
I
Sehouli
Jalid
J
Dietel
Manfred
M
Denkert
Carsten
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000032:analysis; D003593:Cytoplasm / Q000648:ultrastructure; D004847:Epithelial Cells / Q000473:pathology; D005231:Fatty Acids, Unsaturated / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000187:drug effects; D028884:Karyopherins / Q000032:analysis* / Q000187:drug effects; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000473:pathology*; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis* / Q000187:drug effects; D015996:Survival Rate; D000097606:Exportin 1 Protein
D000903:Antibiotics, Antineoplastic; D051546:Cyclooxygenase 2; D005231:Fatty Acids, Unsaturated; D053583:Interleukin-1beta; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C496540:PTGS2 protein, human; C038753:leptomycin B