Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer

Abstract

BACKGROUNDThe 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.METHODSIn 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.RESULTSImmunohistochemistry 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‐1β‐induced COX‐2 expression.CONCLUSIONSThe 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. Cancer 2008. © 2008 American Cancer Society.

Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway

“…These results are in agreement with previous findings, including Noske's report on CRM1 expression in EOC patients. 41 It is noteworthy that there is a positive correlation of increased CRM1 and mTOR expression in EOC tissues. We suggest that tissue expressions of CRM1 and mTOR may be interesting prognostic predictors and therapeutic targets in EOC patients.…”

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

“…Mechanistically, overexpression of XPO1 enhances export of nuclear tumor suppressor proteins such as p53, BRCA1, allophycocyanin, and NMP1, resulting in drug resistance. 33 Overexpression of XPO1 has also been associated with drug resistance and poor outcome in many solid tumors such as glioblastoma, cervical and ovarian cancer, [35][36][37] and various hematologic malignancies, including myeloma, 38 chronic lymphocytic leukemia, 26 T-cell acute lymphoblastic leukemia, acute myeloid leukemia, [39][40][41] and BCR-ABL1-driven blastic transformation. 19,42 In the shRNA library screen, shRAN-infected cells were depleted by fourfold in K562 R compared with K562 S cells (supplemental Table 4) following 9 days in culture.…”

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

“…Overexpression of XPO1 has been observed in many types of human solid tumors and hematologic malignancies (35)(36)(37)(38). Importantly, XPO1 overexpression has usually been correlated with higher tumor grade, more advanced tumor stage, and poor prognosis (34,37,39), suggesting its involvement in tumorigenesis.…”