KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Mortezavi, Ashkan; Hermanns, Thomas; Seifert, Hans‐Helge; Baumgärtner, Martin; Provenzano, Maurizio; Sulser, Tullio; Burger, Maximilian; Montani, M.; Ikenberg, Kristian; Hofstädter, Ferdinand; Hartmann, Arndt; Jaggi, Rolf; Moch, Holger; Kristiansen, Glen; Wild, Peter J.

doi:10.1158/1078-0432.ccr-10-0081

Cited by 92 publications

(116 citation statements)

References 28 publications

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“…Although we do not have direct data showing the precise role of KPNA2 in glioma, based on the improved outcomes in patients exhibiting elevated expression of MIR517C, we hypothesize that KPNA2 may act as an oncogene in GBM. These findings are supported by a study by Gousias et al, 46 who show that patients with astrocytoma who exhibit higher expression of KPNA2 have poorer prognoses and increased resistance to chemotherapy, suggesting that KPNA2 may be a diagnostic and prognostic marker for astrocytoma.…”

Section: Discussionsupporting

confidence: 73%

“…As a member of the karyopherin family, KPNA2 has been investigated as a promising biomarker and prognostic factor in several types of solid tumors, including breast cancer, ovarian cancer, prostate cancer, and melanoma. [43][44][45][46] In our study, KPNA2 was found to be a direct target of MIR517C, and overexpression of KPNA2 blocked the function of MIR517C. Although we do not have direct data showing the precise role of KPNA2 in glioma, based on the improved outcomes in patients exhibiting elevated expression of MIR517C, we hypothesize that KPNA2 may act as an oncogene in GBM.…”

Section: Discussionmentioning

confidence: 51%

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MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Xiao

Liu

et al. 2015

Autophagy

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(2015) MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation, Autophagy, 11:12, 2213-2232, DOI: 10.1080/15548627.2015 LG, low glucose; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3B; MU, mutation; NC, negative control; NSC, neural stem cell; oe, overexpressing; OS, overall survival; PFS, progression-free survival; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; SNAI2, Slug (snail family zinc finger 2); SNAI1, snail (snail family zinc finger 1); TEM, transmission electron microscopy; TMZ, temozolomide; VIM, vimentin; WT, wild type; ZEB1, zinc finger E-box binding homeobox 1.The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53 +/+ and TP53 -/-HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 51%

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Xiao

Liu

et al. 2015

Autophagy

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“…Note that the expression loss of MAPK1 a contributing factor for cell-cycle progression (Brunet et al, 1995), decreased cell proliferation as expected, but did not cause full inhibition as found after a KPNA2 knockdown. In line with this, a KPNA2-silencingcaused reduction of cell proliferation was reported for prostate cancer cells as well (Mortezavi et al, 2011). Additionally, KPNA2 gene silencing increased significantly the apoptosis rate of malignant MCF7DKPNA2 cells, which could also explain the decreased viability of MCF7DKPNA2 cells during the migration experiment.…”

Section: Discussionsupporting

confidence: 72%

“…Furthermore, recent work identified KPNA2 as a potential prognostic marker for the progression of prostate cancer as well as therapy indicator for patients who underwent radical prostatectomy (Mortezavi et al, 2011).…”

mentioning

confidence: 99%

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

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Tumorigenesis and tumor progression are associated with dysfunction of the nuclear transport machinery at the level of import and export receptors (karyopherins). Recent studies have shown that the nuclear import factor karyopherin-a2 (KPNA2) is a novel prognostic marker for poor prognosis in human breast cancer. Based on the well-defined hallmarks of cancer progression, we performed a detailed in vitro characterization of the phenotypic effects caused by KPNA2 overexpression and KPNA2 silencing in benign and malignant human breast cells. KPNA2 overexpression clearly increased proliferation of MCF7 tumor cells and further led to a reduction of cell-matrix adhesion in benign MCF10A cells, whereas cell migration was significantly increased (Po0.0001) in both tumor models. Remarkably, these individual effects of KPNA2 overexpression on proliferation, cell-matrix adhesion and migration resulted in an increased colony spreading of benign MCF10A breast cells and malignant MCF7 tumor cells (Po0.001), which is a hallmark of cancer progression. Conversely, RNA interference-mediated KPNA2 silencing caused a complete inhibition of MCF7 tumor cell proliferation and migration (Po0.0001). In addition, in these experiments apoptosis was increased (Po0.05) and formation of tumor cell colonies was reduced (Po0.01). Thus, KPNA2 overexpression provoked increased aggressiveness of malignant MCF7 breast tumor cells and induced a shift in benign MCF10A breast cells toward a malignant breast cancer phenotype. In conclusion, we demonstrate for the first time in experimental tumor models that forced KPNA2 expression drives malignant features relevant for breast cancer progression, while its silencing is required for the remission of those progressive phenotypes. This study gives clear evidence that KPNA2 acts as a novel oncogenic factor in human breast cancer, in vitro.

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“…16 A relevant biological role of NBS1 in prostate cancer is further supported by immunohistochemical studies describing higher NBS1 expression in cancer as compared to non-neoplastic prostate epithelium. 19 To further evaluate the potential biological and clinical role of NBS1 in prostate cancer, and to search for possible associations with molecularly defined cancer subgroups, a preexisting tissue microarray (TMA) containing 11,152 prostate cancer specimens with follow-up data and attached molecular information was analyzed for NBS1 immunostaining. Our data demonstrate a link of NBS1 immunostaining with morphological and molecular cancer features as well as with PSA recurrence, which is largely driven by KPNA2 expression.…”

mentioning

confidence: 99%

The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG‐negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression

Grupp

Boumesli

Koop

et al. 2014

Intl Journal of Cancer

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The Nijmegen breakage syndrome (NBS1) gene was suggested as a prostate cancer susceptibility gene. This study was undertaken to determine, whether NBS1 expression is linked to clinically or molecularly relevant subgroups of prostate cancer. NBS1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. NBS1 expression was absent or only weakly detectable in benign prostate. In prostate cancers, NBS1 expression was found in 81.3% of interpretable tumors and was considered strong in 41.3% of cases. NBS1 upregulation was tightly linked to ERG-positive cancers (p < 0.0001). Within ERG-negative cancers, strong NBS1 immunostaining was linked to advanced pathological tumor stage, high Gleason grade, and positive nodal status (p < 0.0001 each), while high NBS1 immunostaining was only weakly associated with advanced pathological tumor stage in ERG-positive cancers (p 5 0.0099). A comparison with chromosomal deletions revealed a strong NBS1 upregulation in PTEN-deleted cancers, while deletions of 3p13, 5q21 and 6q15 did not affect NBS1 expression. High NBS1 expression was linked to biochemical recurrence in ERG-negative and PTEN nondeleted cancers (p < 0.0001), which was largely driven by high KPNA2 karyopherin alpha 2 expression. In conclusion, our study identifies an association of NBS1 expression with surrogates of genomic instability in prostate cancer including TMPRSS2-ERG rearrangements and PTEN deletion. The prognostic impact of NBS1 expression in ERG-negative, PTEN nondeleted cancers was dependent of the expression status of its interaction partner KPNA2.Prostate cancer is the most frequent cancer in men in developed countries and a leading cause of cancer-related death. It is estimated that about 5 to 10% of prostate cancers are hereditary in nature.1 Several genes have recently been identified or suggested as hereditary prostate cancer genes but the relevant genes are still unknown for most hereditary cancers. The high prevalence of sporadic prostate cancer is one of the causes rendering the search for hereditary prostate cancer genes complicated, especially in societies where large families are often small. More than 60% of men older than 60 carry prostate cancer but most of these patients will never face clinical consequences of their disease. The established pre-treatment prognostic parameters Gleason grade, tumor extent on biopsies, preoperative PSA and clinical parameters are statistically powerfull but still insufficent for optimal individual treatment decisions. The identification of these prostate cancers requiring therapy is thus another major need in prostate cancer research.Cancer development and progression is often caused by situations increasing a cell's risk to develop genomic alterations or its ability to repair such DNA alterations. Genes involved in DNA repair mechanisms are thus optimal candidates for affecting cancer progression and have also been identified as the cause for hereditary cancer syndromes such as in hereditary non-polypos...

show abstract

KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Cited by 92 publications

References 28 publications

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG‐negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression

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