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KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation
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KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation

Author: Kristian Ikenberg Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, SwitzerlandNadejda Valtcheva Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, SwitzerlandSimone Brandt Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, SwitzerlandQing Zhong Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, SwitzerlandChristine E Wong Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; et al; All authors
Edition/Format: Article Article : English
Publication:The Journal of Pathology, v234 n2 (October 2014): 239-252
Summary:
Endometrial cancer is the most frequently occurring malignancy of the female genital tract in Western countries. Although in many cases surgically curable, about 30% of the tumours represent an aggressive and untreatable disease. In an attempt to establish a reliable prognostic marker for endometrial carcinomas disregarding their histological diversity, we investigated the expression of KPNA2, a mediator of  Read more...
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Document Type: Article
All Authors / Contributors: Kristian Ikenberg Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Nadejda Valtcheva Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Simone Brandt Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Qing Zhong Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Christine E Wong Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Aurelia Noske Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Markus Rechsteiner Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Jan H Rueschoff Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Rosmarie Caduff Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Athanassios Dellas Affiliation: Krebsliga beider Basel, Basel, Switzerland; Ellen Obermann Affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland; Daniel Fink Affiliation: Department of Gynecology, University Hospital Zurich, Zurich, Switzerland; Thomas Fuchs Affiliation: Department of Electrical Engineering, California Institute of Technology, PasadenaCA, USA; Wilhelm Krek Affiliation: Institute of Cell Biology, ETH Zurich, Zurich, Switzerland; Holger Moch Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Ian J Frew Affiliation: Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Peter J Wild Affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; et al
ISSN:0022-3417
Language Note: English
Unique Identifier: 5627115038
Notes: Correspondence to: Peter J Wild, Institute of Surgical Pathology, Schmelzbergstrasse 12, 8091 Zurich, Switzerland. e-mail: peter.wild@usz.ch
Awards:
Other Titles: High KPNA2 expression promotes endometrial cancer
Responsibility: K Ikenberg et al

Abstract:

Endometrial cancer is the most frequently occurring malignancy of the female genital tract in Western countries. Although in many cases surgically curable, about 30% of the tumours represent an aggressive and untreatable disease. In an attempt to establish a reliable prognostic marker for endometrial carcinomas disregarding their histological diversity, we investigated the expression of KPNA2, a mediator of nucleocytoplasmic transport, and other cell proliferation-associated proteins and their correlation with cancer progression. We analysed patient tissue microarrays (TMAs) assembled from 527 endometrial cancer tissue specimens and uterus samples from a Trp53 knockout mouse model of endometrial cancer. Our data show that KPNA2 expression was significantly up-regulated in human endometrial carcinomas and associated with higher tumour grade (p = 0.026), higher FIGO stage (p = 0.027), p53 overexpression (p < 0.001), activation of the PI3K/AKT pathway, and epithelial-mesenchymal transition. Increased nuclear KPNA2 immunoreactivity was identified as a novel predictor of overall survival, independent of well-established prognostic factors in Cox regression analyses (hazard ratio 1.7, 95% CI 1.13-2.56, p = 0.01). No significant association between KPNA2 expression and endometrial cancer subtype was detected. In the mouse model, KPNA2 showed increased expression levels from precancerous (EmgD, EIC) to far-advanced invasive lesions. We further investigated the cell proliferation capacity after siRNA-mediated KPNA2 knockdown in the human endometrial cancer cell line MFE-296. KPNA2 silencing led to decreased proliferation of the cancer cells, suggesting interplay of the protein with the cell cycle. Taken together, increased expression of KPNA2 is an independent prognostic marker for poor survival. The mechanism of enhanced nucleocytoplasmic transport by KPNA2 overexpression seems a common event in aggressive cancers since we have shown a significant correlation of KPNA2 expression and tumour aggressiveness in a large variety of other solid tumour entities. Introducing KPNA2 immunohistochemistry in routine diagnostics may allow for the identification of patients who need more aggressive treatment regimens. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

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