title: RAN nucleo-cytoplasmic transport and mitotic spindle assembly partners XPO7 and TPX2 are new prognostic biomarkers in serous epithelial ovarian cancer.
abstract: OBJECTIVE
  Epithelial ovarian cancer has the highest mortality rate of all gynecological malignancies. We have shown that high RAN expression strongly correlates with high-grade and poor patient survival in epithelial ovarian cancer. However, as RAN is a small GTPase involved in two main biological functions, nucleo-cytoplasmic transport and mitosis, it is still unknown which of these functions associate with poor prognosis.
  
  
  METHODS
  To examine the biomarker value of RAN network components in serous epithelial ovarian cancer, protein expression of six specific RAN partners was analyzed by immunohistochemistry using a tissue microarray representing 143 patients associated with clinical parameters. The RAN GDP/GTP cycle was evaluated by the expression of RANBP1 and RCC1, the mitotic function by TPX2 and IMPβ, and the nucleo-cytoplasmic trafficking function by XPO7, XPOT and IMPβ.
  
  
  RESULTS
  Based on Kaplan-Meier analyses, RAN, cytoplasmic XPO7 and TPX2 were significantly associated with poor overall patient survival, and RAN and TPX2 were associated with lower disease free survival in patients with high-grade serous carcinoma. Cox regression analysis revealed that RAN and TPX2 expression were independent prognostic factors for both overall and disease free survival, and that cytoplasmic XPO7 expression was a prognostic factor for overall patient survival.
  
  
  CONCLUSIONS
  In this systematic study, we show that RAN and two protein partners involved in its nucleo-cytoplasmic and mitotic functions (XPO7 and TPX2, respectively) can be used as biomarkers to stratify patients based on prognosis. In particular, we reported for the first time the clinical relevance of the exportin XPO7 and showed that TPX2 expression had the strongest prognostic value. These findings suggest that protein partners in each of RAN's functions can discriminate between different outcomes in high-grade serous epithelial ovarian cancer patients. Furthermore, these proteins point to cellular processes that may ultimately be targeted to improve the survival in serous epithelial ovarian cancer.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada; Institut du Cancer de Montréal, Montreal, Canada.
authors.forename: Katia Y
authors.initials: KY
authors.lastname: Cáceres-Gorriti
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada; Institut du Cancer de Montréal, Montreal, Canada.
authors.forename: Euridice
authors.initials: E
authors.lastname: Carmona
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada; Institut du Cancer de Montréal, Montreal, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Barrès
authors.affiliation: Department of Pathology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Canada.
authors.forename: Kurosh
authors.initials: K
authors.lastname: Rahimi
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada; Institut du Cancer de Montréal, Montreal, Canada.
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Létourneau
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada; Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada; Institut du Cancer de Montréal, Montreal, Canada; Department of Obstetric-Gynecology, Université de Montréal, Montreal, Canada; Department of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada; Institut du Cancer de Montréal, Montreal, Canada; Department of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D028884:Karyopherins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D008941:Spindle Apparatus / Q000378:metabolism; D046888:Tissue Array Analysis; D020931:ran GTP-Binding Protein / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D028884:Karyopherins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C120587:RAN protein, human; C122167:TPX2 protein, human; C000589007:XPO7 protein, human; D020931:ran GTP-Binding Protein