title: KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation.
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.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.forename: Nadejda
authors.initials: N
authors.lastname: Valtcheva
authors.forename: Simone
authors.initials: S
authors.lastname: Brandt
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhong
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wong
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.forename: Markus
authors.initials: M
authors.lastname: Rechsteiner
authors.forename: Jan H
authors.initials: JH
authors.lastname: Rueschoff
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Caduff
authors.forename: Athanassios
authors.initials: A
authors.lastname: Dellas
authors.forename: Ellen
authors.initials: E
authors.lastname: Obermann
authors.forename: Daniel
authors.initials: D
authors.lastname: Fink
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchs
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Frew
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D028901:alpha Karyopherins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C490630:KPNA2 protein, human; C490631:Kpna2 protein, mouse; D009687:Nuclear Proteins; D028901:alpha Karyopherins; D019869:Phosphatidylinositol 3-Kinases
keywords: EMT; KPNA2; Snail; biomarker; endometrial cancer; importin