Publications by authors named "Andelko Hrzenjak"

41 Publications

Endothelial Lipase Modulates Paraoxonase 1 Content and Arylesterase Activity of HDL.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.

Endothelial lipase (EL) is a strong modulator of the high-density lipoprotein (HDL) structure, composition, and function. Here, we examined the impact of EL on HDL paraoxonase 1 (PON1) content and arylesterase (AE) activity in vitro and in vivo. The incubation of HDL with EL-overexpressing HepG2 cells decreased HDL size, PON1 content, and AE activity. The EL modification of HDL did not diminish the capacity of HDL to associate with PON1 when EL-modified HDL was incubated with PON1-overexpressing cells. The overexpression of EL in mice significantly decreased HDL serum levels but unexpectedly increased HDL PON1 content and HDL AE activity. Enzymatically inactive EL had no effect on the PON1 content of HDL in mice. In healthy subjects, EL serum levels were not significantly correlated with HDL levels. However, HDL PON1 content was positively associated with EL serum levels. The EL-induced changes in the HDL-lipid composition were not linked to the HDL PON1 content. We conclude that primarily, the interaction of enzymatically active EL with HDL, rather than EL-induced alterations in HDL size and composition, causes PON1 displacement from HDL in vitro. In vivo, the EL-mediated reduction of HDL serum levels and the consequently increased PON1-to-HDL ratio in serum increase HDL PON1 content and AE activity in mice. In humans, additional mechanisms appear to underlie the association of EL serum levels and HDL PON1 content.
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http://dx.doi.org/10.3390/ijms22020719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828365PMC
January 2021

Phospholipid dynamics in ex vivo lung cancer and normal lung explants.

Exp Mol Med 2021 Jan 6;53(1):81-90. Epub 2021 Jan 6.

Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036, Graz, Austria.

In cancer cells, metabolic pathways are reprogrammed to promote cell proliferation and growth. While the rewiring of central biosynthetic pathways is being extensively studied, the dynamics of phospholipids in cancer cells are still poorly understood. In our study, we sought to evaluate de novo biosynthesis of glycerophospholipids (GPLs) in ex vivo lung cancer explants and corresponding normal lung tissue from six patients by utilizing a stable isotopic labeling approach. Incorporation of fully C-labeled glucose into the backbone of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylinositol (PI) was analyzed by liquid chromatography/mass spectrometry. Lung cancer tissue showed significantly elevated isotopic enrichment within the glycerol backbone of PE, normalized to its incorporation into PI, compared to that in normal lung tissue; however, the size of the PE pool normalized to the size of the PI pool was smaller in tumor tissue. These findings indicate enhanced PE turnover in lung cancer tissue. Elevated biosynthesis of PE in lung cancer tissue was supported by enhanced expression of the PE biosynthesis genes ETNK2 and EPT1 and decreased expression of the PC and PI biosynthesis genes CHPT1 and CDS2, respectively, in different subtypes of lung cancer in publicly available datasets. Our study demonstrates that incorporation of glucose-derived carbons into the glycerol backbone of GPLs can be monitored to study phospholipid dynamics in tumor explants and shows that PE turnover is elevated in lung cancer tissue compared to normal lung tissue.
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http://dx.doi.org/10.1038/s12276-020-00547-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080582PMC
January 2021

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.

Mol Oncol 2020 11 1;14(11):2853-2867. Epub 2020 Sep 1.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria.

Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.
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http://dx.doi.org/10.1002/1878-0261.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607181PMC
November 2020

MicroRNA-182-5p regulates hedgehog signaling pathway and chemosensitivity of cisplatin-resistant lung adenocarcinoma cells via targeting GLI2.

Cancer Lett 2020 01 5;469:266-276. Epub 2019 Nov 5.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, 8036, Graz, Austria; Ludwig Boltzmann Institute for Lung Vascular Research, 8010, Graz, Austria. Electronic address:

Lung cancer is one of the deadliest cancers worldwide. Late diagnosis at an advanced, inoperable stage makes chemotherapy a treatment of choice, yet, with low response rates. The hedgehog signaling pathway (HHSP) is often reactivated in cancer. We identified miR-182-5p as a regulator of GLI2, a transcriptional regulator of the HHSP, and explored the role of the miR-182-5p/GLI2 axis in carcinogenesis and cisplatin resistance of lung adenocarcinoma (LADC). Expression of miRNAs and target genes was analyzed by RT-qPCR, expression of the GLI-protein family in LADC and adjacent lung tissue (n = 27 pairs) by immunohistochemistry. MiR-182-5p was manipulated, and data were generated by immunoblotting, immunofluorescence, apoptosis, proliferation/viability, dual-luciferase-, and colony forming assays. MiR-182-5p was down-regulated in cisplatin-resistant LADC cells and directly targeted GLI2. Interference with miR-182-5p or GLI2 silencing resulted in modulation of cell proliferation, clonogenic potential, and cisplatin-sensitivity. HHSP was markedly reactivated in LADC tissue compared to adjacent non-malignant lung tissue. Our results indicate that the miR-182-5p/GLI2 axis modulates tumorigenesis and cisplatin-resistance in LADC cells, by influencing the HHSP. Therefore, this axis might be considered as a potential biomarker and future therapeutic target in LADC patients.
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http://dx.doi.org/10.1016/j.canlet.2019.10.044DOI Listing
January 2020

Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension.

Eur Respir J 2019 06 5;53(6). Epub 2019 Jun 5.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs).In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl current in PASMCs (n=9-10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6-10). Inhibition/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension.Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH.
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http://dx.doi.org/10.1183/13993003.00965-2018DOI Listing
June 2019

The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells.

Proc Natl Acad Sci U S A 2018 06 29;115(24):6225-6230. Epub 2018 May 29.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.

Cancer cells are reprogrammed to consume large amounts of glucose to support anabolic biosynthetic pathways. However, blood perfusion and consequently the supply with glucose are frequently inadequate in solid cancers. PEPCK-M (), the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK), has been shown by us and others to be functionally expressed and to mediate gluconeogenesis, the reverse pathway of glycolysis, in different cancer cells. Serine and ribose synthesis have been identified as downstream pathways fed by PEPCK in cancer cells. Here, we report that PEPCK-M-dependent glycerol phosphate formation from noncarbohydrate precursors (glyceroneogenesis) occurs in starved lung cancer cells and supports de novo glycerophospholipid synthesis. Using stable isotope-labeled glutamine and lactate, we show that PEPCK-M generates phosphoenolpyruvate and 3-phosphoglycerate, which are at least partially converted to glycerol phosphate and incorporated into glycerophospholipids (GPL) under glucose and serum starvation. This pathway is required to maintain levels of GPL, especially phosphatidylethanolamine (PE), as shown by stable shRNA-mediated silencing of PEPCK-M in H23 lung cancer cells. PEPCK-M shRNA led to reduced colony formation after starvation, and the effect was partially reversed by the addition of dioleyl-PE. Furthermore, PEPCK-M silencing abrogated cancer growth in a lung cancer cell xenograft model. In conclusion, glycerol phosphate formation for de novo GPL synthesis via glyceroneogenesis is a newly characterized anabolic pathway in cancer cells mediated by PEPCK-M under conditions of severe nutrient deprivation.
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http://dx.doi.org/10.1073/pnas.1719871115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004450PMC
June 2018

MicroRNAs as regulators of cisplatin-resistance in non-small cell lung carcinomas.

Oncotarget 2017 Dec 5;8(70):115754-115773. Epub 2017 Dec 5.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

With more than 80% of all diagnosed lung cancer cases, non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. Exact diagnosis is mostly very late and advanced-stage NSCLCs are inoperable at admission. Tailored therapies with tyrosine kinase inhibitors are only available for a minority of patients. Thus, chemotherapy is often the treatment of choice. As first-line chemotherapy for NSCLCs, platinum-based substances (e.g. cisplatin, CDDP) are mainly used. Unfortunately, the positive effects of CDDP are frequently diminished due to development of drug resistance and negative influence of microenvironmental factors like hypoxia. MicroRNAs (miRNAs) are small, non-coding molecules involved in the regulation of gene expression and modification of biological processes like cell proliferation, apoptosis and cell response to chemotherapeutics. Expression of miRNAs is often deregulated in lung cancer compared to corresponding non-malignant tissue. In this review we summarize the present knowledge about the effects of miRNAs on CDDP-resistance in NSCLCs. Further, we focus on miRNAs deregulated by hypoxia, which is an important factor in the development of CDDP-resistance in NSCLCs. This review will contribute to the general understanding of miRNA-regulated biological processes in NSCLC, with special focus on the role of miRNA in CDDP-resistance.
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http://dx.doi.org/10.18632/oncotarget.22975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777811PMC
December 2017

No erythropoietin-induced growth is observed in non-small cell lung cancer cells.

Int J Oncol 2018 Feb 12;52(2):518-526. Epub 2017 Dec 12.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Lung cancer patients have the highest incidence of anemia among patients with solid tumors. The use of recombinant human erythropoietin (Epo) has consistently been shown to reduce the need for blood transfusions and to increase hemoglobin levels in lung cancer patients with chemotherapy-induced anemia. However, clinical and preclinical studies have prompted concerns that Epo and the presence of its receptor, EpoR, in tumor cells may be responsible for adverse effects and, eventually, death. The question has been raised whether Epo promotes tumor growth and inhibits the death of cancer cells. In this study, we investigated the presence and functionality of EpoR, as well as the implications of Epo upon the proliferation and survival of lung cancer cells. Since the protein expression of both Epo and EpoR is induced by hypoxia, which is frequently present in lung cancer, the cells were treated with Epo under both normoxic and hypoxic conditions (1% O2). By using quantitative (real-time) PCR, western blot analysis, and immunocytochemical staining, three non-small cell lung cancer (NSCLC) cell lines (A427, A549 and NCI-H358) were analyzed for the expression of EpoR and its specific downstream signaling pathways [Janus kinase 2 (Jak2)-signal transducer and activator of transcription 5 (STAT5), phosphatidylinositol-3-kinase (PI3K)-Akt, mitogen-activated protein (MAP) kinase]. The effects of 100 U/ml Epo on cell proliferation and cisplatin-induced apoptosis were assessed. All NSCLC cell lines expressed EpoR mRNA and protein, while these levels differed considerably between the cell lines. We found the constitutive phosphorylation of EpoR and most of its downstream signaling pathways (STAT5, Akt and ERK1/2) independently of Epo administration. While Epo markedly enhanced the proliferation and reduced apoptosis of Epo-dependent UT-7/Epo leukemia cells, it did not affect tumor cell proliferation or the cisplatin-induced apoptosis of NSCLC cells. Thus, this in vitro study suggests that there are no tumor-promoting effects of Epo in the NSCLC cell lines studied, neither under normoxic nor under hypoxic conditions.
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http://dx.doi.org/10.3892/ijo.2017.4225DOI Listing
February 2018

Impact of Endothelial Lipase on Cholesterol Efflux Capacity of Serum and High-density Lipoprotein.

Sci Rep 2017 10 2;7(1):12485. Epub 2017 Oct 2.

Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria.

Endothelial lipase (EL) is a potent modulator of the structural and functional properties of HDL. Impact of EL on cholesterol efflux capacity (CEC) of serum and isolated HDL is not well understood and apparently contradictory data were published. Here, we systematically examined the impact of EL on composition and CEC of serum and isolated HDL, in vitro and in vivo, using EL-overexpressing cells and EL-overexpressing mice. CEC was examined in a validated assay using H-cholesterol labelled J774 macrophages. In vitro EL-modification of serum resulted in complex alterations, including enrichment of serum with lipid-free/-poor apoA-I, decreased size of human (but not mouse) HDL and altered HDL lipid composition. EL-modification of serum increased CEC, in line with increased lipid-free/-poor apoA-I formation. In contrast, CEC of isolated HDL was decreased likely through altered lipid composition. In contrast to in vitro results, EL-overexpression in mice markedly decreased HDL-cholesterol and apolipoprotein A-I serum levels associated with a decreased CEC of serum. HDL lipid composition was altered, but HDL particle size and CEC were not affected. Our study highlights the multiple and complex effects of EL on HDL composition and function and may help to clarify the seemingly contradictory data found in published articles.
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http://dx.doi.org/10.1038/s41598-017-12882-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624901PMC
October 2017

TR3 is involved in hypoxia-induced apoptosis resistance in lung cancer cells downstream of HIF-1α.

Lung Cancer 2017 09 21;111:15-22. Epub 2017 Jun 21.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Institute of Physiology, Medical University of Graz, Graz, Austria. Electronic address:

Objectives: Lung cancer is the leading cause of cancer death worldwide. Like in all solid tumors, hypoxia is common in lung cancer and contributes to apoptosis, and thus chemotherapy resistance. However, the underlying mechanisms are not entirely clear. TR3 (NR4A1, Nur77) is an orphan nuclear receptor that induces apoptosis and may mediate chemotherapy-induced apoptosis in cancer cells.

Materials And Methods: We used A549, H23 and H1299 cell lines to investigate how TR3-mediated apoptosis is affected by hypoxia in non-small cell lung cancer (NSCLC) cells. Cell culture, western blot analysis, apoptosis assay, and siRNA-mediated gene silencing were performed in this study.

Results And Conclusion: The TR3 activator cytosporone B was used to investigate TR3-mediated apoptosis in NSCLC cells under normoxic and hypoxic conditions. Cytosporone B induced apoptosis in a concentration-dependent manner. Chronic moderate hypoxia induced a significant down-regulation of TR3. Accordingly, the cytosporone B effect was reduced under these conditions. Hypoxia-induced down-regulation of TR3 was mediated by hypoxia-inducible factor 1α. Our immunoblotting analysis and expression data from a public dataset suggest that TR3 is downregulated in NSCLC. In conclusion, our findings suggest that hypoxia-induced down-regulation of TR3 might play an important role for hypoxia-induced apoptosis resistance in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2017.06.013DOI Listing
September 2017

TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers.

PLoS One 2016 13;11(6):e0157453. Epub 2016 Jun 13.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Lung cancer is the leading cause of cancer deaths worldwide; survival times are poor despite therapy. The role of the two-pore domain K+ (K2P) channel TASK-1 (KCNK3) in lung cancer is at present unknown. We found that TASK-1 is expressed in non-small cell lung cancer (NSCLC) cell lines at variable levels. In a highly TASK-1 expressing NSCLC cell line, A549, a characteristic pH- and hypoxia-sensitive non-inactivating K+ current was measured, indicating the presence of functional TASK-1 channels. Inhibition of TASK-1 led to significant depolarization in these cells. Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. Na+-coupled nutrient transport across the cell membrane is functionally coupled to the efflux of K+ via K+ channels, thus TASK-1 may potentially influence Na+-coupled nutrient transport. In contrast to TASK-1, which was not differentially expressed in lung cancer vs. normal lung tissue, we found the Na+-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, transporters for myo-inositol, biotin and glutamine, respectively, to be significantly overexpressed in lung adenocarcinomas. In summary, we show for the first time that the TASK-1 channel regulates apoptosis and proliferation in a subset of NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157453PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905626PMC
July 2017

JAZF1/SUZ12 gene fusion in endometrial stromal sarcomas.

Authors:
Andelko Hrzenjak

Orphanet J Rare Dis 2016 Feb 16;11:15. Epub 2016 Feb 16.

Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Auenbruggerplatz 15, A-8036, Graz, Austria.

Endometrial stromal sarcomas (ESSs) belong to the rarest uterine malignancies (prevalence category <1-9/1,000,000). According to the new 2014 World Health Organisation (WHO) classification, they are separated into four categories; benign endometrial stromal nodules (ESNs), low grade endometrial stromal sarcomas (LG-ESSs), high-grade endometrial stromal sarcomas (HG-ESSs) and undifferentiated uterine sarcomas (UUSs). Due to heterogeneous histopathologic appearance these tumors still represent diagnostic challenge, even for experienced pathologists. ESSs are genetically very heterogeneous and several chromosomal translocations and gene fusions have so far been identified in these malignancies. To date the JAZF1/SUZ12 gene fusion is by far the most frequent and seems to be the cytogenetic hallmark of ESN and LG-ESS. Based on present literature data this gene fusion is present in approximately 75% of ESN, 50% of LG-ESS and 15% of HG-ESS cases. The frequency of JAZF1/SUZ12 appearance varies between classic ESS and different morphologic variants. This gene fusion is suggested to become a specific diagnostic tool, especially in difficult borderline cases. In combination with the recently described YWHAE/FAM22 gene fusion the JAZF1/SUZ12 fusion could be used to differentiate between LG-ESS and HG-ESS. The purpose of this review is to summarize literature data published in last two and a half decades about this gene fusion, as a contribution to our understanding of ESS genetics and pathogenesis.
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http://dx.doi.org/10.1186/s13023-016-0400-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754953PMC
February 2016

Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization.

Mol Cancer 2015 Jan 21;14. Epub 2015 Jan 21.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.

Background: Lung cancer is one of the most frequent cancer types and the leading cause of cancer death worldwide. Cisplatin is a widely used chemotherapeutic for non-small cell lung carcinoma (NSCLC), however, its positive effects are diminished under hypoxia. We wanted to determine if co-treatment with cisplatin and histone deacetalyse (HDAC) inhibitor panobinostat can reduce hypoxia-induced cisplatin resistance in NSCLC cells, and to elucidate mechanism involved.

Methods: Expression status of different HDACS was determined in two cell lines and in tumor tissue from 20 patients. Cells were treated with cisplatin, panobinostat, or with combination of both under normoxic and hypoxic (1% O(2)) conditions. Cell cycle, viability, acetylation of histones, and activation of apoptosis were determined. HIF-1α stability and its interaction with HDAC4 were analyzed.

Results: Most class I and II HDACs were expressed in NSCLC cells and tumor samples. Co-treatment of tumor cells with cisplatin and panobinostat decreased cell viability and increased apoptosis more efficiently than in primary, non-malignant bronchial epithelial cells. Co-treatment induced apoptosis by causing chromatin fragmentation, activation of caspases-3 and 7 and PARP cleavage. Toxic effects were more pronounced under hypoxic conditions. Co-treatment resulted in destabilization and degradation of HIF-1α and HDAC4, a protein responsible for acetylation and de/stabilization of HIF-1α. Direct interaction between HDAC4 and HIF-1α proteins in H23 cells was detected.

Conclusions: Here we show that hypoxia-induced cisplatin resistance can be overcome by combining cisplatin with panobinostat, a potent HDAC inhibitor. These findings may contribute to the development of a new therapeutic strategy for NSCLC.
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http://dx.doi.org/10.1186/1476-4598-14-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320451PMC
January 2015

Gluconeogenesis in cancer: door wide open.

Proc Natl Acad Sci U S A 2014 Oct 26;111(42):E4394. Epub 2014 Sep 26.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; and.

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http://dx.doi.org/10.1073/pnas.1415680111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210322PMC
October 2014

Molecular mechanisms of endometrial stromal sarcoma and undifferentiated endometrial sarcoma as premises for new therapeutic strategies.

Cancer Lett 2014 Nov 13;354(1):21-7. Epub 2014 Aug 13.

Institute of Pathology, Medical University of Graz, Graz, Austria.

Endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) are very rare gynecologic malignancies. Due to the rarity and heterogeneity of these tumors, little is known about their epidemiology, pathogenesis, and molecular pathology. Our previous studies have described deregulation of histone deacetylases expression in ESS/UES samples. Some of these enzymes can be inhibited by substances which are already approved for treatment of cutaneous T-cell lymphoma. On the basis of published data, they may also provide a therapeutic option for ESS/UES patients. Our review focuses on molecular mechanisms of ESS/UES. It describes various aspects with special emphasis on alteration of histone deacetylation and its possible relevance for novel therapies.
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http://dx.doi.org/10.1016/j.canlet.2014.08.013DOI Listing
November 2014

Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model - role of tumor stroma cells.

BMC Cancer 2014 Jan 25;14:40. Epub 2014 Jan 25.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 20, A-8036 Graz, Austria.

Background: Hypoxia-induced genes are potential targets in cancer therapy. Responses to hypoxia have been extensively studied in vitro, however, they may differ in vivo due to the specific tumor microenvironment. In this study gene expression profiles were obtained from fresh human lung cancer tissue fragments cultured ex vivo under different oxygen concentrations in order to study responses to hypoxia in a model that mimics human lung cancer in vivo.

Methods: Non-small cell lung cancer (NSCLC) fragments from altogether 70 patients were maintained ex vivo in normoxia or hypoxia in short-term culture. Viability, apoptosis rates and tissue hypoxia were assessed. Gene expression profiles were studied using Affymetrix GeneChip 1.0 ST microarrays.

Results: Apoptosis rates were comparable in normoxia and hypoxia despite different oxygenation levels, suggesting adaptation of tumor cells to hypoxia. Gene expression profiles in hypoxic compared to normoxic fragments largely overlapped with published hypoxia-signatures. While most of these genes were up-regulated by hypoxia also in NSCLC cell lines, membrane metallo-endopeptidase (MME, neprilysin, CD10) expression was not increased in hypoxia in NSCLC cell lines, but in carcinoma-associated fibroblasts isolated from non-small cell lung cancers. High MME expression was significantly associated with poor overall survival in 342 NSCLC patients in a meta-analysis of published microarray datasets.

Conclusions: The novel ex vivo model allowed for the first time to analyze hypoxia-regulated gene expression in preserved human lung cancer tissue. Gene expression profiles in human hypoxic lung cancer tissue overlapped with hypoxia-signatures from cancer cell lines, however, the elastase MME was identified as a novel hypoxia-induced gene in lung cancer. Due to the lack of hypoxia effects on MME expression in NSCLC cell lines in contrast to carcinoma-associated fibroblasts, a direct up-regulation of stroma fibroblast MME expression under hypoxia might contribute to enhanced aggressiveness of hypoxic cancers.
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http://dx.doi.org/10.1186/1471-2407-14-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905926PMC
January 2014

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries.

Eur Respir J 2013 Jan 20;41(1):85-95. Epub 2012 Apr 20.

Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, Austria.

The potassium channel TWIK-related acid sensitive potassium (TASK)-1 channel, together with other potassium channels, controls the low resting tone of pulmonary arteries. The Src family tyrosine kinase (SrcTK) may control potassium channel function in human pulmonary artery smooth muscle cells (hPASMCs) in response to changes in oxygen tension and the clinical use of a SrcTK inhibitor has resulted in partly reversible pulmonary hypertension. This study aimed to determine the role of SrcTK in hypoxia-induced inhibition of potassium channels in hPASMCs. We show that SrcTK is co-localised with the TASK-1 channel. Inhibition of SrcTK decreases potassium current density and results in considerable depolarisation, while activation of SrcTK increases potassium current in patch-clamp recordings. Moderate hypoxia and the SrcTK inhibitor decrease the tyrosine phosphorylation state of the TASK-1 channel. Hypoxia also decreases the level of phospho-SrcTK (tyr419) and reduces the co-localisation of the TASK-1 channel and phospho-SrcTK. Corresponding to this, hypoxia reduces TASK-1 currents before but not after SrcTK inhibition and, in the isolated perfused mouse lung, SrcTK inhibitors increase pulmonary arterial pressure. We propose that the SrcTK is a crucial factor controlling potassium channels, acting as a cofactor for setting a negative resting membrane potential in hPASMCs and a low resting pulmonary vascular tone.
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http://dx.doi.org/10.1183/09031936.00211811DOI Listing
January 2013

Origin of neomuscularized vessels in mice exposed to chronic hypoxia.

Respir Physiol Neurobiol 2011 Dec 1;179(2-3):342-5. Epub 2011 Oct 1.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

Exposure of mice to chronic hypoxia is one of the most often used animal models to study pulmonary hypertension. Hypoxia exposure leads to vascular remodeling and muscularization of the small parenchymal vessels in the lung. Due to the anatomical differences between mice and humans, it is not possible to determine whether the remodeled vessels originate from the arterial or venous side of the vasculature. By applying antibodies against specific marker molecules expressed by arterial (ephrinB2) and venous (EphB4) endothelial cells, we could show that remodeled parenchymal vessels in hypoxia-exposed mice are mostly of arterial origin with slight venous involvement. Using these tools, it is possible to further characterize remodeled vessels in other small animal models, such as transgenic or knockout mice. Particularly useful applications would include selection of parenchymal vessels for laser microdissection studies.
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http://dx.doi.org/10.1016/j.resp.2011.09.016DOI Listing
December 2011

Hypoxia-induced cisplatin resistance is reversible and growth rate independent in lung cancer cells.

Cancer Lett 2011 Sep 12;308(2):134-43. Epub 2011 Jun 12.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria.

Hypoxia frequently occurs in solid tumors and is known to contribute to chemotherapy resistance. However, the mechanisms leading to chemotherapy resistance are not entirely known. We investigated hypoxia-induced resistance to cisplatin in NSCLC cell lines. We show that chronic moderate hypoxia induced resistance to cisplatin in NSCLC cells without involvement of selection pressure. Our data suggest that stabilization of the hypoxia-inducible factor 1 alpha and down-regulation of the pro-apoptotic protein BAX play a role in this process. Furthermore, we provide evidence that hypoxia-induced resistance to cisplatin is not due to the reduced growth rate of cancer cells under hypoxic conditions.
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http://dx.doi.org/10.1016/j.canlet.2011.03.014DOI Listing
September 2011

Endothelial lipase (EL) and EL-generated lysophosphatidylcholines promote IL-8 expression in endothelial cells.

Atherosclerosis 2011 Feb 13;214(2):338-44. Epub 2010 Nov 13.

Institute of Molecular Biology and Biochemistry, Harrachgasse 21/III, Medical University Graz, 8010 Graz, Austria.

Objective: Previously we identified palmitoyl-lysophosphatidylcholine (LPC 16:0), as well as linoleoyl-, arachidonoyl- and oleoyl-LPC (LPC 18:2, 20:4 and 18:1) as the most prominent LPC species generated by the action of endothelial lipase (EL) on high-density lipoprotein (HDL). In the present study, the impact of EL and EL-generated LPC on interleukin-8 (IL-8) synthesis was examined in vitro in primary human aortic endothelial cells (HAEC) and in mice.

Methods And Results: Adenovirus-mediated overexpression of the catalytically active EL, but not its inactive mutant, increased endothelial synthesis of IL-8 mRNA and protein in a time- and HDL-concentration-dependent manner. While LPC 18:2 was inactive, LPC 16:0, 18:1 and 20:4 promoted IL-8 mRNA- and protein-synthesis, differing in potencies and kinetics. The effects of all tested LPC on IL-8 synthesis were completely abrogated by addition of BSA and chelation of intracellular Ca(2+). Underlying signaling pathways also included NFkB, p38-MAPK, ERK, PKC and PKA. In mice, adenovirus-mediated overexpression of EL caused an elevation in the plasma levels of MIP-2 (murine IL-8 analogue) accompanied by a markedly increased plasma LPC/PC ratio. Intravenously injected LPC also raised MIP-2 plasma concentration, however to a lesser extent than EL overexpression.

Conclusion: Our results indicate that EL and EL-generated LPC, except of LPC 18:2, promote endothelial IL-8 synthesis, with different efficacy and kinetics, related to acyl-chain length and degree of saturation. Accordingly, due to its capacity to modulate the availability of the pro-inflammatory and pro-adhesive chemokine IL-8, EL should be considered an important player in the development of atherosclerosis.
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http://dx.doi.org/10.1016/j.atherosclerosis.2010.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034026PMC
February 2011

Acyl chain-dependent effect of lysophosphatidylcholine on endothelial prostacyclin production.

J Lipid Res 2010 Oct 7;51(10):2957-66. Epub 2010 Jul 7.

Institute of Molecular Biology and Biochemistry, University of Helsinki, Helsinki, Finland.

Previously we identified palmitoyl-lysophosphatidylcholine (16:0 LPC), linoleoyl-LPC (18:2 LPC), arachidonoyl-LPC (20:4 LPC), and oleoyl-LPC (18:1 LPC) as the most prominent LPC species generated by the action of endothelial lipase (EL) on high-density lipoprotein. In the present study, the impact of those LPC on prostacyclin (PGI(2)) production was examined in vitro in primary human aortic endothelial cells (HAEC) and in vivo in mice. Although 18:2 LPC was inactive, 16:0, 18:1, and 20:4 LPC induced PGI(2) production in HAEC by 1.4-, 3-, and 8.3-fold, respectively. LPC-elicited 6-keto PGF1α formation depended on both cyclooxygenase (COX)-1 and COX-2 and on the activity of cytosolic phospholipase type IVA (cPLA2). The LPC-induced, cPLA2-dependent (14)C-arachidonic acid (AA) release was increased 4.5-fold with 16:0, 2-fold with 18:1, and 2.7-fold with 20:4 LPC, respectively, and related to the ability of LPC to increase cytosolic Ca(2+) concentration. In vivo, LPC increased 6-keto PGF(1α) concentration in mouse plasma with a similar order of potency as found in HAEC. Our results indicate that the tested LPC species are capable of eliciting production of PGI(2), whereby the efficacy and the relative contribution of underlying mechanisms are strongly related to acyl-chain length and degree of saturation.
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http://dx.doi.org/10.1194/jlr.M006536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936763PMC
October 2010

Hypochlorite modification of sphingomyelin generates chlorinated lipid species that induce apoptosis and proteome alterations in dopaminergic PC12 neurons in vitro.

Free Radic Biol Med 2010 Jun 11;48(12):1588-600. Epub 2010 Mar 11.

Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.

Recent observations link myeloperoxidase (MPO) activation to neurodegeneration. In multiple sclerosis MPO is present in areas of active demyelination where the potent oxidant hypochlorous acid (HOCl), formed by MPO from H(2)O(2) and chloride ions, could oxidatively damage myelin-associated lipids. The purpose of this study was (i) to characterize reaction products of sphingomyelin (SM) formed in response to modification by HOCl, (ii) to define the impact of exogenously added SM and HOCl-modified SM (HOCl-SM) on viability parameters of a neuronal cell line (PC12), and (iii) to study alterations in the PC12 cell proteome in response to SM and HOCl-SM. MALDI-TOF-MS analyses revealed that HOCl, added as reagent or generated enzymatically, transforms SM into chlorinated species. On the cellular level HOCl-SM but not SM induced the formation of reactive oxygen species. HOCl-SM induced severely impaired cell viability, dissipation of the mitochondrial membrane potential, and activation of caspase-3 and DNA damage. Proteome analyses identified differential expression of specific subsets of proteins in response to SM and HOCl-SM. Our results demonstrate that HOCl modification of SM results in the generation of chlorinated lipid species with potent neurotoxic properties. Given the emerging connections between the MPO-H(2)O(2)-chloride axis and neurodegeneration, this chlorinating pathway might be implicated in neuropathogenesis.
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http://dx.doi.org/10.1016/j.freeradbiomed.2010.02.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061462PMC
June 2010

Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo.

Mol Cancer 2010 Mar 4;9:49. Epub 2010 Mar 4.

Lore Saldow Research Unit for Molecular Pathology of Gynecologic Tumors, Department of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.

Background: Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC) inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat) on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21(WAF1) and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo.

Results: Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 microM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 microM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3) as well as class II (HDAC7) were preferentially affected by this treatment. Vorinostat significantly increased p21(WAF1) expression and apoptosis. Nude mice injected with 5 x 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice.

Conclusions: Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.
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http://dx.doi.org/10.1186/1476-4598-9-49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843655PMC
March 2010

Plasma-advanced oxidation protein products are potent high-density lipoprotein receptor antagonists in vivo.

Circ Res 2009 Mar 29;104(6):750-7. Epub 2009 Jan 29.

Center of Theoretical-Clinical Medicine II, Medical University Graz, Universitätsplatz 4, 8010 Graz, Austria.

Advanced oxidation protein products (AOPPs) are carried by oxidized plasma proteins, especially albumin and accumulate in subjects with renal disease and coronary artery disease. AOPPs represent an excellent novel marker of oxidative stress and their roles in the development of cardiovascular disease might be of great importance. Here, we show that in vitro-generated AOPP-albumin binds with high affinity to the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI). Already an equimolar concentration of AOPP-albumin to HDL blocked HDL association to SR-BI and effectively inhibited SR-BI-mediated cholesterol ester (CE) uptake. Interestingly, albumin extensively modified by advanced glycation end products (AGE-albumin), which is an established SR-BI ligand known to accumulate in renal disease, only weakly interfered with HDL binding to SR-BI. Furthermore, AOPP-albumin administration increased the plasma half-life of [3H]CE-HDL in control mice 1.6-fold (P=0.01) and 8-fold (P=0.0003) in mice infected with adenoviral vectors encoding human SR-BI. Moreover, albumin isolated from hemodialysis patients, but not albumin isolated from healthy controls, markedly inhibited SR-BI-mediated HDL-CE transfer in vitro dependent on the AOPP content of albumin. These results indicate that AOPP-albumin effectively blocks SR-BI in vitro and in vivo. Thus, depressed plasma clearance of HDL-cholesterol may contribute to the abnormal composition of HDL and the high cardiovascular risk observed in patients with chronic renal failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.108.193169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375477PMC
March 2009

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer.

Mod Pathol 2008 May 8;21(5):639-46. Epub 2008 Feb 8.

Department of Pathology, Medical University of Graz, Graz, Austria.

Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12 mastectomy specimens showing invasive ductal carcinomas. In each case, morphologically normal epidermis and dermis, carcinoma, normal stroma close to carcinoma, and stroma at a distant from carcinoma were microdissected. Metastatic-free lymphatic tissues from lymph nodes served as a control. Using PCR, DNA extracts were examined with 11 microsatellite markers known for a high frequency of allelic imbalances in breast cancer. Losses of heterozygosity and/or microsatellite instability were detected in 83% of the skin samples occurring either concurrently with or independently from the cancerous tissues. In 80% of these cases at least one microsatellite marker displayed loss of heterozygosity or microsatellite instability in the skin, which was absent in carcinoma. A total of 41% of samples showed alterations of certain loci observed exclusively in the carcinoma but not in the skin compartments. Our study suggests that breast cancer is not just a localized genetic disorder, but rather part of a larger field of genetic alterations/instabilities affecting multiple cell populations in the organ with various cellular elements, ultimately contributing to the manifestation of the more 'localized' carcinoma. These data indicate that more global assessment of tumor micro- and macro-environment is crucial for our understanding of breast carcinogenesis.
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http://dx.doi.org/10.1038/modpathol.2008.28DOI Listing
May 2008

The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling.

Blood 2007 Nov 9;110(9):3374-83. Epub 2007 Aug 9.

Klinische Abteilung für Hämatologie, Universitätsklinik für Innere Medizin, Medizinische, Universität Graz, Auenbruggerplatz 38, A-8036 Graz, Austria.

Anaplastic large cell lymphomas (ALCLs) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in approximately 50% of ALCLs, and among these, 80% have the t(2;5) translocation with NPM-ALK expression. We report greater activity of JunB in NPM-ALK-positive than in NPM-ALK-negative ALCLs. Specific knockdown of JUNB mRNA using small interfering RNA and small hairpin RNA in NPM-ALK-expressing cells decreases cellular proliferation as evidenced by a reduced cell count in the G2/M phase of the cell cycle. Expression of NPM-ALK results in ERK1/2 activation and transcriptional up-regulation of JUNB. Both NPM-ALK-positive and -negative ALCL tumors demonstrate active ERK1/2 signaling. In contrast to NPM-ALK-negative ALCL, the mTOR pathway is active in NPM-ALK-positive lymphomas. Pharmacological inhibition of mTOR in NPM-ALK-positive cells down-regulates JunB protein levels by shifting JUNB mRNA translation from large polysomes to monosomes and ribonucleic particles (RNPs), and decreases cellular proliferation. Thus, JunB is a critical target of mTOR and is translationally regulated in NPM-ALK-positive lymphomas. This is the first study demonstrating translational control of AP-1 transcription factors in human neoplasia. In conjunction with NPM-ALK, JunB enhances cell cycle progression and may therefore represent a therapeutic target.
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http://dx.doi.org/10.1182/blood-2007-02-071258DOI Listing
November 2007

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells.

Mol Cancer Ther 2006 Sep;5(9):2203-10

Department of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.

Covalent modifications of histone proteins, in particular deacetylation of lysine residues, are important for the regulation of gene transcription both in normal and malignant cells. These processes are controlled by histone acetyltransferases and histone deacetylases (HDAC) and have up to now not been described in solid mesenchymal tumors. The present study shows differences in the HDAC1 and HDAC2 expression in endometrial stromal sarcomas (ESS) and a cognate cell line (ESS-1) compared with nonneoplastic endometrial stroma. We show for the first time that HDAC2 expression is consistently increased in ESS. In contrast, HDAC1 expression is generally lower than HDAC2 both in nonneoplastic stroma and in ESS, suggesting that these two proteins, although closely related, are regulated in different ways. In vitro experiments with an ESS cell line showed that valproate, an inhibitor of the class I HDACs, led to significant HDAC2 decrease and to cell differentiation. HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G1-S transition and influencing expression of p21WAF1 and cyclin D1. Moreover, in ESS-1 cells, increased expression of the p21WAF1 was associated with reduction of HDAC2 expression after transfection with small interfering RNA directed against HDAC2. Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS.
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http://dx.doi.org/10.1158/1535-7163.MCT-05-0480DOI Listing
September 2006

Expression of serum amyloid A transcripts in human trophoblast and fetal-derived trophoblast-like choriocarcinoma cells.

FEBS Lett 2006 Jan 6;580(1):161-7. Epub 2005 Dec 6.

Medical University Graz, Center of Molecular Medicine, Institute of Molecular Biology and Biochemistry, A-8010 Graz, Austria.

The placenta comprises a highly specialized trophoblast layer, which arises from the embryo and differentiates during embryonic development to perform specialized functions, e.g., synthesis of pregnancy-associated hormones, growth factors and cytokines. As there is no evidence of maternal acute-phase protein transplacental transfer and trophoblast plays an important role in regulating immune responses at the feto-maternal interface, the expression of acute-phase serum amyloid A (A-SAA) was investigated in human first trimester trophoblast and trophoblast-like JAR and Jeg-3 choriocarcinoma cells. We here show expression of cytokine receptors and cytokine-dependent induction of A-SAA in JAR and Jeg-3 cells. While interleukin-1alpha/beta is a major agonist for A-SAA expression in JAR, tumor necrosis factor-alpha is the predominant agonist in Jeg-3. First trimester trophoblast and JAR/Jeg-3 cells further express the human homolog of SAA-activating factor-1, a transcription factor involved in cytokine-mediated induction of A-SAA genes. A-SAA1 and A-SAA2 transcripts were increased in first trimester trophoblast during pregnancy weeks 10 and 12 suggesting that A-SAA plays a role during early fetal development.
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http://dx.doi.org/10.1016/j.febslet.2005.11.067DOI Listing
January 2006

Ovarian granulosa cell tumors frequently express EGFR (Her-1), Her-3, and Her-4: An immunohistochemical study.

Gynecol Oncol 2006 Apr 5;101(1):18-23. Epub 2005 Dec 5.

Department of Pathology, Medical University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria.

Objective: Up to 50% of patients with ovarian granulosa cell tumors (GCTs) will develop recurrences; some of these recurrences can be seen as late as 30 years following the initial surgical treatment. Combined chemotherapy and radiotherapy are currently used for patients with advanced or recurrent disease. The aim of this study was to investigate the possible eligibility of patients with GCTs for anti-Her therapy.

Methods: The immunohistochemical expression of EGFR (Her-1), Her-2, Her-3, and Her-4 was analyzed in a group of ovarian GCTs encompassing 38 adult type and 2 juvenile type.

Results: Thirty-one cases (77.5%) were positive for at least one of the receptors EGFR (Her-1), Her-3, and Her-4. Twenty-six out of 40 (65%) GCTs showed positive reaction for EGFR (Her-1). Eight tumors (20%) were exclusively positive for EGFR (Her-1). None of 40 cases showed a positive reaction for Her-2. Positive reactions for Her-3 and Her-4 were observed in 18 (45%) and 23 (57.5%) tumors. Only one case (2.5%) was exclusively positive for Her-4. Four tumors (10%) showed positivity for Her-3 and Her-4 but were negative for EGFR (HER-1). While one of the two JGCTs was negative for all members of the Her-family, one showed reactivity for EGFR (Her-1), Her-3, and Her-4.

Conclusion: In this study, most of the ovarian GCTs express at least one of the receptors EGFR (Her-1), Her-3, and Her-4. These findings provide some evidence to further explore the potential use of agents targeting these receptors (particularly EGFR) in the treatment of ovarian GCTs.
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http://dx.doi.org/10.1016/j.ygyno.2005.10.009DOI Listing
April 2006