Verena Stiegelbauer
Medical University of Graz
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Publication
Featured researches published by Verena Stiegelbauer.
British Journal of Cancer | 2014
M Pichler; Anna Lena Ress; Elke Winter; Verena Stiegelbauer; Michael Karbiener; Daniela Schwarzenbacher; Marcel Scheideler; Cristina Ivan; Stephan Jahn; Tobias Kiesslich; Armin Gerger; Thomas Bauernhofer; George A. Calin; Gerald Hoefler
Background:MicroRNAs (miRNAs) regulate the biological properties of colorectal cancer (CRC) cells and might serve as potential prognostic factors and therapeutic targets. In this study, we therefore globally profiled miRNAs associated with E-cadherin expression in CRC cells in an attempt to identify miRNAs that are associated with aggressive clinical course in CRC patients.Methods:Two CRC cell lines (Caco-2 and HRT-18) with different E-cadherin expression pattern were profiled for differences in abundance for more than 1000 human miRNAs using microarray technology. One of the most differentially expressed miRNAs, miR-200a was evaluated for its prognostic role in a cohort of 111 patients and independently validated in 217 patients of the Cancer Genome Atlas data set. To further characterise the biological role of miR-200a expression in CRC, in vitro miR-200a inhibition and overexpression were performed and the effects on cellular growth, apoptosis and epithelial–mesenchymal transition (EMT)-related gene expression were explored.Results:In situ hybridisation specifically localised miR-200a in CRC cells. In both cohorts, a low miR-200a expression was associated with poor survival (P<0.05). Multivariate Cox regression analysis identified low levels of miR-200a expression as an independent prognostic factor with respect to cancer-specific survival (HR=2.04, CI=1.28–3.25, P<0.002). Gain and loss of function assays for miR-200a in vitro led to a significantly differential and converse expression of EMT-related genes (P<0.001.) A low expression of miR-200a was also observed in cancer stem cell-enriched spheroid growth conditions (P<0.05).Conclusions:In conclusion, our data suggest that low miR-200a expression is associated with poor prognosis in CRC patients. MiR-200a has a regulatory effect on EMT and is associated with cancer stem cell properties in CRC.
Gut | 2016
Hui Ling; Karen Pickard; Cristina Ivan; Claudio Isella; Mariko Ikuo; Richard Mitter; Riccardo Spizzo; Marc D. Bullock; Cornelia Braicu; Valentina Pileczki; Kimberly Vincent; Martin Pichler; Verena Stiegelbauer; Gerald Hoefler; Maria Inês Almeida; Annie Hsiao; Xinna Zhang; John Primrose; Graham Packham; Kevin Liu; Krishna Bojja; Roberta Gafà; Lianchun Xiao; Simona Rossi; Jian H. Song; Ivan Vannini; Francesca Fanini; Scott Kopetz; Patrick A. Zweidler-McKay; Xuemei Wang
Objective MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. Design We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan–Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. Results MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=−0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175). Conclusions MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.
World Journal of Gastroenterology | 2014
Verena Stiegelbauer; Samantha Perakis; Alexander Deutsch; Hui Ling; Armin Gerger; Martin Pichler
Colorectal cancer (CRC) is the third most common cancer in western countries. Despite significant improvement in available treatment options, CRC still remains the second leading cause of cancer-related death. Traditionally, 5-fluorouracil has been used as the main chemotherapy drug for treatment of metastatic CRC (mCRC). However, during the last two decades more effective chemotherapeutic agents such as oxaliplatin, irinotecan and the monoclonal antibodies cetuximab, panitumumab and bevacizumab have been used in clinical practice. More recently, the therapeutic armamentarium has been supplemented by the monoclonal antibodies bevacizumab, cetuximab and panitumumab as well as the protein-trap aflibercept and the small molecule multi-kinase inhibitor regorafenib. One of the major problems for the management of CRC is the inherent or acquired resistance to therapeutic approaches. The discovery of microRNAs (miRNAs), a class of small, endogenous, non-coding, single-stranded RNAs that play a role as post-transcriptional regulators, has added new dimensions to the diagnosis and treatment of cancer. Because miRNAs are important regulators of carcinogenesis, progression, invasion, angiogenesis and metastases in CRC, they might serve as potential predictive and prognostic factors and even as therapeutic targets themselves. Several miRNAs are already known to be dysregulated in CRCs and have been linked to biological processes involved in tumor progression and response to anti-cancer therapies. This review summarizes current therapeutic approaches for treating CRC and highlights the role of miRNAs as novel predictive biomarkers and potential drug targets in CRC patients.
Clinical Cancer Research | 2017
Martin Pichler; Verena Stiegelbauer; Petra Vychytilova-Faltejskova; Cristina Ivan; Hui Ling; Elke Winter; Xinna Zhang; Matthew Goblirsch; Annika Wulf-Goldenberg; Masahisa Ohtsuka; Johannes Haybaeck; Marek Svoboda; Yoshinaga Okugawa; Armin Gerger; Gerald Hoefler; Ajay Goel; Ondrej Slaby; George A. Calin
Purpose: Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568–10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107–2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. Clin Cancer Res; 23(5); 1323–33. ©2016 AACR.
Molecular Carcinogenesis | 2015
Anna Lena Ress; Verena Stiegelbauer; Elke Winter; Daniela Schwarzenbacher; Tobias Kiesslich; Sigurd Lax; Stefan Jahn; Alexander Deutsch; Thomas Bauernhofer; Hui Ling; Hellmut Samonigg; Armin Gerger; Gerald Hoefler; Martin Pichler
Expression of miR‐96‐5p is frequently altered in various types of cancer and the KRAS oncogene has been identified as one of its potential targets. However, the biological role of miR‐96‐5p expression in colorectal cancer (CRC) and its ability to predict the clinical course of patients have not been investigated yet. In this study, we explored miR‐96‐5p expression in 80 CRC patients and evaluated the impact on clinical outcome by Kaplan‐Meier curves and multivariate Cox proportional models. In vitro miR‐96‐5p inhibition and overexpression were performed in CRC cells and the effects on cellular growth, anchorage‐independent growth, apoptosis, and epithelial‐mesenchymal transition (EMT)‐related gene expression were explored. Low miR‐96‐5p expression levels in tumor tissue were associated with distant metastasis (P = 0.025) and multivariate Cox regression analysis identified low levels of miR‐96‐5p as an independent prognostic factor with respect to cancer‐specific survival (hazard ratio = 1.78, 95%CI = 1.03‐3.03, P < 0.038). In vitro overexpression of miR‐96‐5p led to a reduced cellular growth rate (P < 0.05), reduced colonies in soft agar (P < 0.05), corroborated by a decreased cyclin D1 and increased p27‐CDKN1A expression (P < 0.05). Forced expression of miR‐96‐5p in CRC cells entailed no effects on apoptosis or EMT‐related genes but decreased the expression levels of the KRAS oncogene (P < 0.05). Despite regulating KRAS expression, there was no significant association in miR‐96‐5p expression levels and response rates to EGFR‐targeting agents. In conclusion, our data suggest that miR‐96‐5p influences cellular growth of CRC cells and low expression of miR‐96‐5p seems to be associated with poor clinical outcome in CRC patients.
EBioMedicine | 2016
Masahisa Ohtsuka; Hui Ling; Cristina Ivan; Martin Pichler; Daisuke Matsushita; Matthew Goblirsch; Verena Stiegelbauer; Kunitoshi Shigeyasu; Xinna Zhang; Meng Chen; Fnu Vidhu; Geoffrey Bartholomeusz; Yuji Toiyama; Masato Kusunoki; Yuichiro Doki; Masaki Mori; Shumei Song; Jillian R. Gunther; Sunil Krishnan; Ondrej Slaby; Ajay Goel; Jaffer A. Ajani; Milan Radovich; George A. Calin
Highlights • High H19 expression in primary tumors is an independent predictor of short overall survival in CRC patients.• RB1-E2F and CDK8-β-catenin signaling are essential in mediating the oncogenic activity of H19 in CRC.• Combined analysis of H19 and its targets further improved the prediction power on overall survival of CRC patients. Long noncoding RNAs (lncRNAs) are transcripts at least 200 nucleotides long that do not code for proteins. The clinical relevance of lncRNAs in colorectal cancer (CRC) is largely unknown. Here we identified that H19 expression in primary tumors is an independent prognostic predictor of poor prognosis of CRC patients and further proved its oncogenic role. To characterize the mechanisms, we profiled gene expression changes following H19 modulation in CRC cell lines and analyzed gene expression association in clinical datasets. Our data revealed important cancer-signaling pathways, including the RB1-E2F and the CDK8-β-catenin signaling, underlying H19 function.
Clinical Cancer Research | 2017
Verena Stiegelbauer; Petra Vychytilova-Faltejskova; Michael Karbiener; Anna Maria Pehserl; Andreas Reicher; Margit Resel; Ellen Heitzer; Cristina Ivan; Marc D. Bullock; Hui Ling; Alexander Deutsch; Annika Wulf-Goldenberg; Jan Basri Adiprasito; Herbert Stoeger; Johannes Haybaeck; Marek Svoboda; Michael Stotz; Gerald Hoefler; Ondrej Slaby; George A. Calin; Armin Gerger; Martin Pichler
Purpose: miR-196b-5p has been previously implicated in malignant transformation; however, its role in colorectal cancer has not been fully explored. In this study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in colorectal cancer. Experimental Design: miR-196b-5p expression was quantitated by qRT-PCR in 2 independent cohorts composed of 292 patients with colorectal cancer in total, to explore its biomarker potential. Transient and stable gain- and loss-of-function experiments were conducted in a panel of colorectal cancer cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemosensitivity, migration/invasion, and metastases formation in vitro and in vivo. The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in silico target prediction tools, luciferase interaction assays, and phenocopy/rescue gene knockdown experiments. Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in 2 independent colorectal cancer patient cohorts (P < 0.05, log-rank test). miR-196b-5p inhibition led to significantly increased colorectal cancer cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulated colorectal cancer cell migration. Conclusions: The association of low levels of miR-196b-5p and poor prognosis in patients with colorectal cancer can be explained by its influence on cancer cell migration and metastases formation. miR-196b-5p has an impact on colorectal cancer progression pathways through direct interaction with genes involved in cancer cell migration. Clin Cancer Res; 23(17); 5255–66. ©2017 AACR.
Pediatric and Developmental Pathology | 2014
Karin Koller; Martin Pichler; Karin Koch; Martina Zandl; Verena Stiegelbauer; Ivo Leuschner; Gerald Hoefler; Barbara Guertl
By comparing several studies we identified a possible deregulation of the transcription factors PBX2 (pre–B-cell leukemia homeobox 2) and one of its binding partners, MEIS1 (Meis homeobox 1) in nephroblastomas. The regulation of MEIS1 is complex, and its expression is known to be influenced by changes of promoter methylation and binding of microRNA-204 (miR-204). Therefore, in our study, we assessed the expression of MEIS1 and PBX2 and the factors regulating expression of MEIS1 in nephroblastomas. MEIS1 and PBX2 messenger RNA (mRNA) and protein levels were investigated by quantitative real-time-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Promoter methylation of MEIS1 was evaluated using a methylation-specific PCR assay. Expression levels of miR-204 were examined by qRT-PCR. Eighteen of 21 nephroblastomas showed a high level of MEIS1 mRNA, and 22 of 26 samples had a specific nuclear protein expression. MicroRNA-204 had a statistically significantly lower expression in all nephroblastomas investigated compared with renal parenchyma, but no change of MEIS1 promoter methylation status was noted. Eleven of 23 nephroblastomas had a high expression of PBX2 mRNA, and 15 of 23 samples had a specific nuclear protein expression was noted. In our study, we demonstrated an expression of MEIS1 and its binding partner PBX2 in most nephroblastomas. The statistically significantly lower expression of miR-204 in all nephroblastomas investigated might point to an involvement of miR-204 in the regulation of MEIS1 in nephroblastomas.
International Journal of Molecular Sciences | 2016
Anna-Maria Pehserl; Anna Lena Ress; Stefanie Stanzer; Margit Resel; Michael Karbiener; Elke Stadelmeyer; Verena Stiegelbauer; Armin Gerger; Christian Mayr; Marcel Scheideler; Georg C. Hutterer; Thomas Bauernhofer; Tobias Kiesslich; Martin Pichler
MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies.
PLOS ONE | 2017
Georg Richtig; Ariane Aigelsreiter; Daniela Schwarzenbacher; Anna Lena Ress; Jan Basri Adiprasito; Verena Stiegelbauer; Gerald Hoefler; Silvia Schauer; Tobias Kiesslich; Peter Kornprat; Thomas Winder; Florian Eisner; Armin Gerger; Herbert Stoeger; Rudolf E. Stauber; Carolin Lackner; Martin Pichler
SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor.