RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

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Abstract

Purpose

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.

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Most cited references 39

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A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2.

Rohit Mahajan, Christian Delphin, Tinglu Guan … (1997)

We have found that the mammalian Ran GTPase-activating protein RanGAP1 is highly concentrated at the cytoplasmic periphery of the nuclear pore complex (NPC), where it associates with the 358-kDa Ran-GTP-binding protein RanBP2. This interaction requires the ATP-dependent posttranslational conjugation of RanGAP1 with SUMO-1 (for small ubiquitin-related modifier), a novel protein of 101 amino acids that contains low but significant homology to ubiquitin. SUMO-1 appears to represent the prototype for a novel family of ubiquitin-related protein modifiers. Inhibition of nuclear protein import resulting from antibodies directed at NPC-associated RanGAP1 cannot be overcome by soluble cytosolic RanGAP1, indicating that GTP hydrolysis by Ran at RanBP2 is required for nuclear protein import.

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A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex

G Blobel (1996)

Ran is a nuclear Ras-like GTPase that is required for the bidirectional transport of proteins and ribnucleoproteins across the nuclear pore complex (NPC). A key regulator of the Ran GTP/GDP cycle is the 70-kD Ran-GTPase-activating protein RanGAP1. Here, we report the identification and localization of a novel form of RanGAP1. Using peptide sequence analysis and specific mAbs, RanGAP1 was found to be modified by conjugation to a ubiquitin-like protein. Immunoblot analysis and immunolocalization by light and EM demonstrated that the 70-kD unmodified from of RanGAP1 is exclusively cytoplasmic, whereas the 90-kD modified form of RanGAP1 is associated with the cytoplasmic fibers of the NPC. The modified form of RanGAP1 also appeared to associated with the mitotic spindle apparatus during mitosis. These findings have specific implications for Ran function and broad implications for protein regulation by ubiquitin-like modifications. Moreover, the variety and function of ubiquitin-like protein modifications in the cell may be more diverse than previously realized.

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Ovarian surface epithelium: biology, endocrinology, and pathology.

N Auersperg, S. Kang, K. Choi … (2001)

The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

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Author and article information

Contributors

Eric Asselin: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 13 March 2014

Volume: 9

Issue: 3

Electronic Location Identifier: e91000

Affiliations

[1 ]Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Canada

[2 ]Institut du Cancer de Montréal, Montreal, Canada

[3 ]Department of Pathology, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, Canada

[4 ]The Research Institute of the McGill University Health Centre, Montreal, Canada

[5 ]Department of Human Genetics, McGill University, Montreal, Canada

[6 ]Department of Medicine, McGill University, Montreal, Canada

[7 ]Department of Obstetric-Gynecology, Université de Montréal, Montreal, Canada

[8 ]Department of Medicine, Université de Montréal, Montreal, Canada

University of Quebec at Trois-Rivieres, Canada

Author notes

* E-mail: anne-marie.mes-masson@ 123456umontreal.ca

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: KYCG AMMM VB. Performed the experiments: KYCG VB KR IJL. Analyzed the data: KYCG KR EC. Contributed reagents/materials/analysis tools: DP AMMM PNT. Wrote the paper: KYCG AMMM EC.

Article

Publisher ID: PONE-D-13-30998

DOI: 10.1371/journal.pone.0091000

PMC ID: 3953127

PubMed ID: 24625450

SO-VID: 0e465f77-7a3e-4f42-a309-109b46725d88

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 July 2013

Date accepted : 6 February 2014

Page count

Pages: 12

Funding

This work was supported by a grant (MOP #36056) from the Canadian Institutes of Health Research (CIHR) to A-MM-M, PNT and DP. Tumor banking was supported by the Banque de tissus et données of the Réseau de recherche sur le cancer of the Fond de recherche du Québec – Santé (FRQS), associated with the Canadian Tumor Repository Network (CTRNet). KYC-G was supported in part by studentships from the Carole Epstein Foundation and the Canderel fund of the Institut du cancer de Montréal. IJL was supported by a FRQS postdoctoral training award. A-MM-M and DMP are researchers of the Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM) and PNT is a researcher at the Research Institute of the McGill University Health Centre (MUHC), both of which receive support from the FRQS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

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Most cited references 39

A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2.

A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex

Ovarian surface epithelium: biology, endocrinology, and pathology.

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