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Purpose: To analyze rates of expression of karyopherin alpha 2 (KPNA2) in different prostate tissues and to evaluate the prognostic properties for patients with primary prostate cancer.Experimental Design: Tissue microarrays (TMA) contained 798 formalin-fixed, paraffin-embedded prostate tissue cores from two different institutes of pathology. TMAs were stained immunohistochemically for KPNA2 and NBS1. SiRNA technologies were used to inhibit KPNA2 expression in vitro, and the effect of this inhibition on cellular viability was determined. Efficiency of knockdown experiments was determined by Western blot analysis.Results: KPNA2 expression was significantly upregulated in carcinomas of the prostate, especially in metastatic and castration-resistant prostate cancer samples. Positive nuclear KPNA2 immunoreactivity was identified as a novel predictor of biochemical recurrence after radical prostatectomy (n = 348), and was independent of the well-established predictive factors preoperative PSA value, Gleason score, tumor stage, and surgical margin status. These results were validated by analyzing a second and independent prostate cancer cohort (n = 330). Further, in vitro experiments showed that the cell proliferation and viability of PC3 cells was significantly reduced when KPNA2 expression was inhibited. KPNA2 knockdown did not induce PARP cleavage as marker for apoptosis. No significantly increased sub-G1 fraction could be found by FACS analysis.Conclusions: KPNA2 is a novel independent prognostic marker for disease progression after radical prostatectomy. This allows to identify patients who need more aggressive treatment. It can moreover be speculated that patients not suited for surveillance regimens might be identified at initial biopsy by a positive KPNA2 immunohistochemistry. Clin Cancer Res; 17(5); 1111–21. ©2011 AACR.

Supplementary Figures S1-S3; Supplementary Table S1.

The receptor for advanced glycation end-products (RAGE) is known to act as a central driver of tumorigenesis by sustaining a chronic inflammatory tumor microenvironment. Until to date, RAGE has been exclusively described as a cell surface receptor being activated upon engagement with its various extra-cellular ligands, e.g. S100B, S100A8/A9, HMGB1, and others. This study aimed at elucidating the functional role of RAGE and its isoforms depending on their subcellular distribution in the context of melanoma development, growth and progression. Therefore, various in vitro models using melanoma cells or melanocytes and melanoma mouse models as well as tissue-microarrays representing human specimens of malignant melanoma and benign nevi were applied. The expression analyses revealed an overexpression of RAGE in melanoma cells compared to melanocytes/nevocytes. Moreover, RAGE protein was found to be localized primarily in the nucleus of melanocytes/nevocytes whereas a predominant cell surface/cytoplasmic localization of RAGE is observed in melanoma cells. Nuclear translocation of RAGE depends on the nuclear transport machinery and site-directed mutagenesis of predicted DNA binding sites within the RAGE protein was applied in order to study its functional role in the nucleus. Furthermore, knockdown of RAGE indicated its central function in apoptosis induction. In conclusion, RAGE and its isoforms are overexpressed and aberrantly localized in malignant melanoma cells compared to melanocytes/nevocytes. Our data point towards a novel tumor-protective function of RAGE in melanoma development depending on its nuclear localization. Citation Format: Maike Reith, Wolf-Henning Gebhardt, Kathrin Tarnanidis, Nikolaus B. Wagner, Kristian Ikenberg, Coretta Kehrel, Jochen Utikal, Christoffer Gebhardt. Subcellular distribution of RAGE affects its functions in melanoma growth and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 805. doi:10.1158/1538-7445.AM2015-805

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II carcinoma subtypes. The PI3K-Akt-mTOR signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, immunohistochemical analyses of 521 human endometrial carcinomas identified frequent mTOR pathway activation in type I as well as type II endometrial carcinoma subtypes and mTOR pathway activation and p53 expression each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the PI3K-mTOR pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and PI3K-mTOR pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3293. doi:1538-7445.AM2012-3293