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

Ikenberg, Kristian and Valtcheva, Nadejda and Brandt, Simone and Zhong, Qing and Wong, Christine E. and Noske, Aurelia and Rechsteiner, Markus and Rueschoff, Jan H. and Caduff, Rosmarie and Dellas, Athanassios and Obermann, Ellen and Fink, Daniel and Fuchs, Thomas J. and Krek, Wilhelm and Moch, Holger and Frew, Ian J. and Wild, Peter J. (2014) KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation. Journal of Pathology, 234 (2). pp. 239-252. ISSN 0022-3417. https://resolver.caltech.edu/CaltechAUTHORS:20141110-091539565

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/path.4390DOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/path.4390/abstractAuthorArticle
Additional Information:© 2014 Pathological Society of Great Britain and Ireland. Received 16 April 2014; Revised 2 June 2014; Accepted 10 June 2014. We thank Silvia Behnke, Martina Storz, Susanne Dettwiler, Annette Bohnert, Sonja Brun-Schmid, Dr Adriana von Teichman, Nicole Neumann, André Fitsche, and Marcel Glönkler for excellent technical assistance and Simone Holdermann for critical reading of the manuscript. This work was supported by an SNF Förderungsprofessur grant to IJF and a Baugarten Foundation grant to PJW.
Funders:
Funding AgencyGrant Number
SNF FörderungsprofessurUNSPECIFIED
Baugarten FoundationUNSPECIFIED
Subject Keywords:KPNA2; importin; endometrial cancer; biomarker; EMT; Snail
Issue or Number:2
Record Number:CaltechAUTHORS:20141110-091539565
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141110-091539565
Official Citation:Ikenberg, K., Valtcheva, N., Brandt, S., Zhong, Q., Wong, C. E., Noske, A., Rechsteiner, M., Rueschoff, J. H., Caduff, R., Dellas, A., Obermann, E., Fink, D., Fuchs, T., Krek, W., Moch, H., Frew, I. J. and Wild, P. J. (2014), KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation. J. Pathol., 234: 239–252. doi: 10.1002/path.4390
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:51484
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:11 Nov 2014 00:31
Last Modified:03 Oct 2019 07:33

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