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Dive into the research topics where Julia Hoefer is active.

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Featured researches published by Julia Hoefer.


American Journal of Pathology | 2012

Epithelial-to-Mesenchymal Transition Leads to Docetaxel Resistance in Prostate Cancer and Is Mediated by Reduced Expression of miR-200c and miR-205

Martin Puhr; Julia Hoefer; Georg Schäfer; Holger H.H. Erb; Su Jung Oh; Helmut Klocker; Isabel Heidegger; Hannes Neuwirt; Zoran Culig

Docetaxel is a standard chemotherapy for patients with metastatic prostate cancer. However, the response is rather limited and not all of the patients benefit from this treatment. To uncover key mechanisms of docetaxel insensitivity in prostate cancer, we have established docetaxel-resistant sublines. In this study, we report that docetaxel-resistant cells underwent an epithelial-to-mesenchymal transition during the selection process, leading to diminished E-cadherin levels and up-regulation of mesenchymal markers. Screening for key regulators of an epithelial phenotype revealed a significantly reduced expression of microRNA (miR)-200c and miR-205 in docetaxel-resistant cells. Transfection of either microRNA (miRNA) resulted in re-expression of E-cadherin. Functional assays confirmed reduced adhesive and increased invasive and migratory abilities. Furthermore, we detected an increased subpopulation with stem cell-like properties in resistant cells. Tissue microarray analysis revealed a reduced E-cadherin expression in tumors after neoadjuvant chemotherapy. Low E-cadherin levels could be linked to tumor relapse. The present study uncovers epithelial-to-mesenchymal transition as a hallmark of docetaxel resistance. Therefore, we suggest that this mechanism is at least in part responsible for chemotherapy failure, with implications for the development of novel therapeutics.


American Journal of Pathology | 2012

PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21

Julia Hoefer; Georg Schäfer; Helmut Klocker; Holger H.H. Erb; Ian G. Mills; Ludger Hengst; Martin Puhr; Zoran Culig

Prostate cancer development and progression are associated with alterations in expression and function of elements of cytokine networks, some of which can activate multiple signaling pathways. Protein inhibitor of activated signal transducers and activators of transcription (PIAS)1, a regulator of cytokine signaling, may be implicated in the modulation of cellular events during carcinogenesis. This study was designed to investigate the functional significance of PIAS1 in models of human prostate cancer. We demonstrate for the first time that PIAS1 protein expression is significantly higher in malignant areas of clinical prostate cancer specimens than in normal tissues, thus suggesting a growth-promoting role for PIAS1. Expression of PIAS1 was observed in the majority of tested prostate cancer cell lines. In addition, we investigated the mechanism by which PIAS1 might promote prostate cancer and found that down-regulation of PIAS1 leads to decreased proliferation and colony formation ability of prostate cancer cell lines. This decrease correlates with cell cycle arrest in the G0/G1 phase, which is mediated by increased expression of p21(CIP1/WAF1). Furthermore, PIAS1 overexpression positively influences cell cycle progression and thereby stimulates proliferation, which can be mechanistically explained by a decrease in the levels of cellular p21. Taken together, our data reveal an important new role for PIAS1 in the regulation of cell proliferation in prostate cancer.


PLOS ONE | 2010

The Liver-Selective Thyromimetic T-0681 Influences Reverse Cholesterol Transport and Atherosclerosis Development in Mice

Ivan Tancevski; Egon Demetz; Philipp Eller; Kristina Duwensee; Julia Hoefer; Christiane Heim; Ursula Stanzl; Andreas Wehinger; Kristina Auer; Regina Karer; Julia M. Huber; Wilfried Schgoer; Miranda Van Eck; Jonathan Vanhoutte; Catherine Fievet; Frans Stellaard; Mats Rudling; Josef R. Patsch; Andreas Ritsch

Background Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice. Methodology/Principal Findings T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls. Conclusions/Significance The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans.


Endocrine-related Cancer | 2014

SOCS2 correlates with malignancy and exerts growth-promoting effects in prostate cancer.

Julia Hoefer; Johann Kern; Philipp Ofer; Iris E. Eder; Georg Schäfer; Dimo Dietrich; Glen Kristiansen; Stephan Geley; Johannes Rainer; Eberhard Gunsilius; Helmut Klocker; Zoran Culig; Martin Puhr

Deregulation of cytokine and growth factor signaling due to an altered expression of endogenous regulators is well recognized in prostate cancer (PCa) and other cancers. Suppressor of cytokine signaling 2 (SOCS2) is a key regulator of the GH, IGF, and prolactin signaling pathways that have been implicated in carcinogenesis. In this study, we evaluated the expression patterns and functional significance of SOCS2 in PCa. Protein expression analysis employing tissue microarrays from two independent patient cohorts revealed a significantly enhanced expression in tumor tissue compared with benign tissue as well as association with Gleason score and disease progression. In vitro and in vivo assays uncovered the involvement of SOCS2 in the regulation of cell growth and apoptosis. Functionally, SOCS2 knockdown inhibited PCa cell proliferation and xenograft growth in a CAM assay. Decreased cell growth after SOCS2 downregulation was associated with cell-cycle arrest and apoptosis. In addition, we proved that SOCS2 expression is significantly elevated upon androgenic stimulation in androgen receptor (AR)-positive cell lines, providing a possible mechanistic explanation for high SOCS2 levels in PCa tissue. Consequently, SOCS2 expression correlated with AR expression in the malignant tissue of patients. On the whole, our study linked increased SOCS2 expression in PCa with a pro-proliferative role in vitro and in vivo.


The Journal of Urology | 2011

Soluble gp130 Regulates Prostate Cancer Invasion and Progression in an Interleukin-6 Dependent and Independent Manner

Shahrokh F. Shariat; Thomas F. Chromecki; Julia Hoefer; Christopher E. Barbieri; Douglas S. Scherr; Pierre I. Karakiewicz; Claus G. Roehrborn; Francesco Montorsi; Zoran Culig; Ilaria T. Cavarretta

PURPOSE Soluble gp130 is a regulator of interleukin-6/soluble interleukin-6 receptor signaling that influences prostate cancer progression. We determined the association of soluble gp130 with prostate cancer prognosis, invasiveness and epithelial-to-mesenchymal transition. MATERIALS AND METHODS A total of 423 preoperative and 206 postoperative blood samples were available from patients treated with radical prostatectomy for clinically localized prostate cancer. Prostate cancer cell lines were used for in vitro studies. Plasma soluble gp130, interleukin-6 and soluble interleukin-6 receptor levels were measured using enzyme immunoassay. In vitro invasion assays and quantification of E-cadherin expression were done using modified Boyden chambers and Western blot, respectively. RESULTS In patients treated with radical prostatectomy higher preoperative plasma soluble gp130 was significantly associated with higher biopsy and pathological Gleason sum, extraprostatic extension, seminal vesicle invasion, lymph node metastasis and biochemical recurrence. In a subset of 206 patients postoperative soluble gp130 levels were 18% lower than preoperative levels (p = 0.037). Soluble gp130 levels weakly correlated with preoperative plasma interleukin-6 and soluble interleukin-6 receptor levels. In vitro soluble gp130 alone increased the invasiveness of androgen responsive prostate cancer cells and induced a significant decrease in E-cadherin. In patients higher plasma soluble gp130 was associated with features of biologically aggressive prostate cancer. The decrease in postoperative plasma soluble gp130 after surgery suggests that the higher blood levels of soluble gp130 are produced by tumor cells. CONCLUSIONS Data suggest that soluble gp130 has a role in prostate cancer invasion in an interleukin-6 dependent and independent manner.


Oncotarget | 2016

Critical role of androgen receptor level in prostate cancer cell resistance to new generation antiandrogen enzalutamide

Julia Hoefer; Mohammady Akbor; Florian Handle; Philipp Ofer; Martin Puhr; Walther Parson; Zoran Culig; Helmut Klocker; Isabel Heidegger

Enzalutamide is an androgen receptor (AR) inhibitor approved for therapy of metastatic castration resistant prostate cancer. However, clinical application revealed that 30 to 40% of patients acquire resistance after a short period of treatment. Currently, the molecular mechanisms underlying such resistances are not completely understood, partly due to a lack of model systems. In the present study we established three different cellular models of enzalutamide resistance including a cell line with wild type AR (LAPC4), DuCaP cells which overexpress wild-type AR, as well as a cell which has been adapted to long term androgen ablation (LNCaP Abl) and harbors the AR T878A mutation. After 10 months of cultivation, sustained growth in the presence of enzalutamide was achieved. When compared to controls, resistant cells exhibit significantly decreased sensitivity to enzalutamide as measured with 3[H]thymidine incorporation and WST assay. Moreover, these cell models exhibit partly re-activated AR signaling despite presence of enzalutamide. In addition, we show that enzalutamide resistant cells are insensitive to bicalutamide but retain considerable sensitivity to abiraterone. Mechanistically, enzalutamide resistance was accompanied by increased AR and AR-V7 mRNA and protein expression as well as AR gene amplification, while no additional AR mutations have been identified.


Embo Molecular Medicine | 2014

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2.

Ivan Tancevski; Manfred Nairz; Kristina Duwensee; Kristina Auer; Andrea Schroll; Christiane Heim; Clemens Feistritzer; Julia Hoefer; Romana R. Gerner; Alexander R. Moschen; Ingrid Heller; Petra Pallweber; Xiaorong Li; Markus Theurl; Egon Demetz; Anna Maria Wolf; Dominik Wolf; Philipp Eller; Andreas Ritsch; Guenter Weiss

Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate‐mediated early control of infection, the systemic inflammatory response was repressed in fibrate‐treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS‐induced phosphorylation of ERK. This results in a decrease of G protein‐coupled receptor kinase‐2 expression, thereby inhibiting the LPS‐mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.


Molecular Cancer Research | 2016

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Florian Handle; Holger H.H. Erb; Birgit Luef; Julia Hoefer; Dimo Dietrich; Walther Parson; Glen Kristiansen; Frédéric R. Santer; Zoran Culig

The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor–positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor–mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment. Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines. Mol Cancer Res; 14(6); 574–85. ©2016 AACR.


Clinical Cancer Research | 2017

The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Martin Puhr; Julia Hoefer; Andrea Eigentler; Christian Ploner; Florian Handle; Georg Schaefer; Jan Kroon; Angela Leo; Isabel Heidegger; Iris E. Eder; Zoran Culig; Gabri van der Pluijm; Helmut Klocker

Purpose: The major obstacle in the management of advanced prostate cancer is the occurrence of resistance to endocrine therapy. Although the androgen receptor (AR) has been linked to therapy failure, the underlying escape mechanisms have not been fully clarified. Being closely related to the AR, the glucocorticoid receptor (GR) has been suggested to play a role in enzalutamide and docetaxel resistance. Given that glucocorticoids are frequently applied to prostate cancer patients, it is essential to unravel the exact role of the GR in prostate cancer progression. Experimental Design: Assessment of GR expression and functional significance in tissues from 177 prostate cancer patients, including 14 lymph node metastases, as well as in several human prostate cancer models, including androgen-dependent, androgen-independent, and long-term antiandrogen-treated cell lines. Results: Although GR expression is reduced in primary prostate cancer tissue, it is restored in metastatic lesions. Relapse patients with high GR experience shortened progression-free survival. GR is significantly increased upon long-term abiraterone or enzalutamide treatment in the majority of preclinical models, thus identifying GR upregulation as an underlying mechanism for cells to bypass AR blockade. Importantly, GR inhibition by RNAi or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines. Conclusions: GR upregulation seems to be a common mechanism during antiandrogen treatment and supports the notion that targeting the GR pathway combined with antiandrogen medication may further improve prostate cancer therapy. Clin Cancer Res; 24(4); 927–38. ©2017 AACR.


Frontiers in Aging Neuroscience | 2017

The “Aging Factor” Eotaxin-1 (CCL11) Is Detectable in Transfusion Blood Products and Increases with the Donor’s Age

Julia Hoefer; Markus F. Luger; Christian Dal-Pont; Zoran Culig; Harald Schennach; Stefan Jochberger

Background: High blood levels of the chemokine eotaxin-1 (CCL11) have recently been associated with aging and dementia, as well as impaired memory and learning in humans. Importantly, eotaxin-1 was shown to pass the blood-brain-barrier (BBB) and has been identified as crucial mediator of decreased neurogenesis and cognitive impairment in young mice after being surgically connected to the vessel system of old animals in a parabiosis model. It thus has to be assumed that differences in eotaxin-1 levels between blood donors and recipients might influence cognitive functions also in humans. However, it is unknown if eotaxin-1 is stable during processing and storage of transfusion blood components. This study assesses eotaxin-1 concentrations in fresh-frozen plasma (FFP), erythrocyte concentrate (EC), and platelet concentrate (PC) in dependence of storage time as well as the donor’s age and gender. Methods: Eotaxin-1 was measured in FFP (n = 168), EC (n = 160) and PC (n = 8) ready-to-use for transfusion employing a Q-Plex immunoassay for eotaxin-1. Absolute quantification of eotaxin-1 was performed with Q-view software. Results: Eotaxin-1 was consistently detected at a physiological level in FFP and EC but not PC. Eotaxin-1 levels were comparable in male and female donors but increased significantly with rising age of donors in both, FFP and EC. Furthermore, eotaxin-1 was not influenced by storage time of either blood component. Finally, eotaxin-1 is subject to only minor fluctuations within one donor over a longer period of time. Conclusion: Eotaxin-1 is detectable and stable in FFP and EC and increases with donor’s age. Considering the presumed involvement in aging and cognitive malfunction, differences in donor- and recipient eotaxin-1 levels might affect mental factors after blood transfusion.

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Zoran Culig

Innsbruck Medical University

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Martin Puhr

Innsbruck Medical University

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Helmut Klocker

Innsbruck Medical University

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Holger H.H. Erb

Innsbruck Medical University

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Florian Handle

Innsbruck Medical University

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Isabel Heidegger

Innsbruck Medical University

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Georg Schäfer

Innsbruck Medical University

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Walther Parson

Innsbruck Medical University

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Andreas Ritsch

Innsbruck Medical University

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Egon Demetz

Innsbruck Medical University

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