Katharina Jonas

Medical University of Graz

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Martin Pichler

Medical University of Graz

Felix Prinz

Medical University of Graz

Christiane Klec

Medical University of Graz

Katarina Krajina

University Hospital Augsburg

Dominik A. Barth

Medical University of Graz

Manuela Ferracin

University of Bologna

Beate Rinner

Medical University of Graz

Barbara Pasculli

Istituti di Ricovero e Cura a Carattere Scientifico

Alexander Deutsch

Medical University of Graz

Andreas Prokesch

Medical University of Graz

Cooperative Institutions

Medical University of Graz

Istituti di Ricovero e Cura a Carattere Scientifico

Casa Sollievo della Sofferenza

University of Lausanne

University of Graz

BioTechMed-Graz

The University of Texas MD Anderson Cancer Center

Inserm

SIB Swiss Institute of Bioinformatics

Centre National de la Recherche Scientifique

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MicroRNA mimics can distort physiological microRNA effects on immune checkpoints by triggering an antiviral interferon response

RNA Biology (2022)

Felix Prinz Katharina Jonas Amar Balihodzic Christiane Klec Andreas Reicher

The microRNA-200 family has wide-ranging regulatory functions in cancer development and progression. Above all, it is strongly associated with the epithelial-to-mesenchymal transition (EMT), a process during which cells change their epithelial to a mesenchymal phenotype and acquire invasive characteristics. More recently, miR-200 family members have also been reported to impact the immune evasion of cancer cells by regulating the expression of immunoinhibitory immune checkpoints (ICs) like PD-L1. Therefore, we aimed to comprehensively characterize this miR-200 family as a regulatory interface between EMT and immune evasion mechanisms in biliary tract cancer. Initial correlation analyses and transient overexpression experiments using miRNA mimics suggested miR-200c-3p as a putative regulator of ICs including PD-L1, LGALS9, and IDO1. However, these effects could not be confirmed in stable miR-200c-3p overexpression cell lines, nor in cells transiently transfected with miR-200c-3p mimic from an independent manufacturer. By shifting our efforts towards dissecting the mechanisms leading to these disparate effects, we observed that the initially used miR-200c-3p mimic triggered a double-stranded (ds)RNA-dependent antiviral response. Besides upregulating the ICs, this had substantial cellular consequences including an induction of interferon type I and type III expression, increased levels of intracellular dsRNA sensors, and a significantly altered cellular growth and apoptotic activity.Our study highlights the capability of miRNA mimics to non-specifically induce a dsRNA-mediated antiviral interferon response. Consequently, phenotypic alterations crucially distort physiological miRNA functions and might result in a major misinterpretation of previous and future miRNA studies, especially in the context of IC regulation.

10.1080/15476286.2022.2152978

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Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

Non-Coding RNA (2020)

Dominik A. Barth Felix Prinz Julia Teppan Katharina Jonas Christiane Klec

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

Hypoxia-Inducible Factors

Hypoxia

Hypoxia-Inducible Factor 1

Tumor progression

10.3390/ncrna6030027

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MiR-4646-5p Acts as a Tumor-Suppressive Factor in Triple Negative Breast Cancer and Targets the Cholesterol Transport Protein GRAMD1B

Non-Coding RNA (2023)

Katharina Jonas Felix Prinz Manuela Ferracin Katarina Krajina Alexander Deutsch

MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression, and their deregulation contributes to many aspects of cancer development and progression. Thus, miRNAs provide insight into oncogenic mechanisms and represent promising targets for new therapeutic approaches. A type of cancer that is still in urgent need of improved treatment options is triple negative breast cancer (TNBC). Therefore, we aimed to characterize a novel miRNA with a potential role in TNBC. Based on a previous study, we selected miR-4646-5p, a miRNA with a still unknown function in breast cancer. We discovered that higher expression of miR-4646-5p in TNBC patients is associated with better survival. In vitro assays showed that miR-4646-5p overexpression reduces growth, proliferation, and migration of TNBC cell lines, whereas inhibition had the opposite effect. Furthermore, we found that miR-4646-5p inhibits the tube formation ability of endothelial cells, which may indicate anti-angiogenic properties. By whole transcriptome analysis, we not only observed that miR-4646-5p downregulates many oncogenic factors, like tumor-promoting cytokines and migration- and invasion-related genes, but were also able to identify a direct target, the GRAM domain-containing protein 1B (GRAMD1B). GRAMD1B is involved in cellular cholesterol transport and its knockdown phenocopied the growth-reducing effects of miR-4646-5p. We thus conclude that GRAMD1B may partly contribute to the diverse tumor-suppressive effects of miR-4646-5p in TNBC.

Triple-negative breast cancer

Tumor progression

10.3390/ncrna10010002

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Citations (1)

Zum Verhältnis von Interesse und Lebensweltbezug bei Lernaufgaben im Unterrichtsfach Geschichte

Katharina Jonas

Die geschichtsdidaktische wie allgemeindidaktische Theorie postulieren Lebensweltbezuge als interessenforderliches Merkmal von Unterricht und Lernaufgaben (Gautschi 2011; WaldisB Bergmann 2002; Kleinknecht et al. 2012). In der Studie wird zunachst das theoretische Konzept des Lebensweltbezugs im Kontext des historischen Lernens diskutiert und fur die Hypothesenprufung operationalisiert. Fur die empirische Untersuchung der Wirksamkeitsannahmen des Lebensweltbezugs von Geschichtsaufgaben wird das situationale Interesse als zweidimensionales Konstrukt bestehend aus Aufgabeninteressantheit und subjektiver Bedeutsamkeit der Aufgabe (vgl. auch HidiR DurikH Mitchell 1993) konzeptualisiert. Dabei wird davon ausgegangen, dass sich Merkmale der Aufgabe auf beide Komponenten des situationalen Interesses unterschiedlich auswirken konnen. Zusatzlich wird ein Einfluss des individuellen Fachinteresses an Geschichte auf die Aufgabenwahrnehmung angenommen. Eine differenzielle Betrachtung des Interesses (Fachinteresse und situationales Interesse) fur das Fach Geschichte stellt bislang ein Desiderat dar. Sowohl auf Aufgaben- wie auch auf Individualebene liegen hierzu nur wenige Befunde fur das historische Lernen vor (Bracke et al. 2014). Ebenso lasst sich die interessenforderliche Wirkung des Lebensweltbezugs fur Geschichte bislang nur unzureichend empirisch belegen. Fur die Studie wurden insgesamt 34 Aufgaben zu drei Themengebieten des Geschichtsunterrichts der 9. Jahrgangsstufe inhaltsanalytisch hinsichtlich ihres Lebensweltbezugs untersucht sowie 801 Schuler/innen bayerischer Realschulen hinsichtlich der wahrgenommenen Interessantheit und Bedeutsamkeit der Aufgaben befragt. Die Wirkung des jeweiligen Lebensweltbezugs sowie des individuellen Fachinteresses auf die wahrgenommene subjektive Bedeutsamkeit und Interessantheit der Aufgaben wurde mittels Cross-Classified Mulitlevel Analysen mit dem Statistikprogramm MPlus (Muthen und Muthen 2012) uberpruft. Die Analysen zeigten, dass grundsatzlich das bereits bestehende Fachinteresses Geschichte eines Menschen die wahrgenommene Interessantheit und Bedeutsamkeit der Aufgabe pradiziert, unabhangig von den Merkmalen der Aufgabe. Die differenzielle Wirkung von Aufgabenmerkmalen auf die beiden Komponenten des situationalen Interesses kann den Ergebnissen gemas bestatigt werden. Insgesamt gesehen wirkt der Lebensweltbezug einer Aufgabe insbesondere auf die subjektive Bedeutsamkeit und nicht auf die Aufgabeninteressantheit. Es wird diskutiert, dass das Fachinteresse an Geschichte als Pradiktorvariable eine wichtige Einflussgrose auf die Aufgabenwahrnehmung darstellt. Zugleich ist das situationale Interesse, das beim Lernen geweckt wird, eine wichtige Voraussetzung dafur, dass sich dauerhaft ein stabiles individuelles Fachinteresse ausbilden kann (Ferdinand 2014). In der geschichtsdidaktischen Forschung wurde den motivationalen Bedingungen des historischen Lernens insgesamt bislang nur wenig Aufmerksamkeit beigemessen. Die Ergebnisse der Studie legen nahe, dass eine intensivere Erforschung einer interessenforderlicher Unterrichts- und Aufgabengestaltung, die sowohl die situationale Interessantheit als auch die subjektive Bedeutsamkeit anregt, einen wertvollen Beitrag zur Erweiterung des empirischen Forschungsfeldes in der Geschichtsdidaktik leisten kann.

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MicroRNAs as regulators of tumor metabolism

Endocrine Related Cancer (2023)

Francesca Ruggieri Katharina Jonas Manuela Ferracin Michael A. Dengler V. Jäger

Cancer cells reprogram their metabolism to support their growth. Since the discovery of the Warburg effect, several other metabolic alterations and metabolites have been described in cancer cells, including lactate, glutamine, and lipid metabolism reprogramming. Together these alterations provide rapidly dividing tumor cells with metabolic intermediates needed for nucleotide, protein, and fatty acid biosynthesis. MicroRNAs are a class of small non-coding RNAs involved in the regulation of virtually all biological pathways. Altered microRNA expression patterns are associated with the onset and development of several diseases, including cancer. Tumor suppressor microRNAs targeting molecules involved in tumor metabolism are frequently downregulated in cancers. Therefore, microRNAs can serve as potential tumor biomarkers and also represent interesting therapeutic targets. This review summarizes recent findings about microRNAs involved in the regulation of tumor metabolism.

Warburg Effect

Nucleic acid metabolism

Reprogramming

10.1530/erc-22-0267

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MiR-4649-5p acts as a tumor-suppressive microRNA in triple negative breast cancer by direct interaction with PIP5K1C, thereby potentiating growth-inhibitory effects of the AKT inhibitor capivasertib

Breast Cancer Research (2023)

Katharina Jonas Felix Prinz Manuela Ferracin Katarina Krajina Barbara Pasculli

Abstract Background Triple negative breast cancer (TNBC) is a particularly aggressive and difficult-to-treat subtype of breast cancer that requires the development of novel therapeutic strategies. To pave the way for such developments it is essential to characterize new molecular players in TNBC. MicroRNAs (miRNAs) constitute interesting candidates in this regard as they are frequently deregulated in cancer and contribute to numerous aspects of carcinogenesis. Methods and results Here, we discovered that miR-4649-5p, a miRNA yet uncharacterized in breast cancer, is associated with better overall survival of TNBC patients. Ectopic upregulation of the otherwise very low endogenous expression levels of miR-4646-5p significantly decreased the growth, proliferation, and migration of TNBC cells. By performing whole transcriptome analysis and physical interaction assays, we were able to identify the phosphatidylinositol phosphate kinase PIP5K1C as a direct target of miR-4649-5p. Downregulation or pharmacologic inhibition of PIP5K1C phenocopied the growth-reducing effects of miR-4649-5p. PIP5K1C is known to play an important role in migration and cell adhesion, and we could furthermore confirm its impact on downstream PI3K/AKT signaling. Combinations of miR-4649-5p upregulation and PIP5K1C or AKT inhibition, using the pharmacologic inhibitors UNC3230 and capivasertib, respectively, showed additive growth-reducing effects in TNBC cells. Conclusion In summary, miR-4649-5p exerts broad tumor-suppressive effects in TNBC and shows potential for combined therapeutic approaches targeting the PIP5K1C/PI3K/AKT signaling axis.

Surgical oncology

10.1186/s13058-023-01716-2

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Tumor Suppressor miR-27a-5p and Its Significance for Breast Cancer

Biomedicines (2024)

Paola Parrella Raffaela Barbano Katharina Jonas Andrea Fontana Serena Barile

MicroRNAs are well established as master regulators of carcinogenesis and potential biomarkers in breast cancer (BC). In a preliminary effort, we found miR-27a-5p to be significantly downregulated in experimentally derived mammospheres and BC patients from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) dataset.

10.3390/biomedicines12112625

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ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform

Cellular and Molecular Life Sciences (2022)

Christiane Klec Erik Knutsen Daniela Schwarzenbacher Katharina Jonas Barbara Pasculli

Abstract The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 promoter region to enhance the global NEAT1 transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of NEAT1 , as well as by direct binding and stabilization of the short isoform of NEAT1, ALYREF selectively fine-tunes the expression of the short NEAT1 isoform. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of NEAT1 .

Phenocopy

10.1007/s00018-022-04402-2

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MiR-200c-3p Modulates Cisplatin Resistance in Biliary Tract Cancer by ZEB1-Independent Mechanisms

Cancers (2021)

Florian Posch Felix Prinz Amar Balihodzic Christian Mayr Tobias Kiesslich

Biliary tract cancer is a major global health issue in cancer-related mortality. Therapeutic options are limited, and cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategies. Although the gain of survival by the addition of cisplatin to gemcitabine is moderate, acquired cisplatin resistance frequently leads to treatment failures with mechanisms that are still poorly understood. Epithelial–mesenchymal transition (EMT) is a dynamic process that changes the shape, function, and gene expression pattern of biliary tract cancer cells. In this study, we explored the influence of the EMT-regulating miR-200c-3p on cisplatin sensitivity in biliary tract cancer cells. Using gain of function experiments, we demonstrated that miR-200c-3p regulates epithelial cell markers through the downregulation of the transcription factor ZEB1. MiR-200c-3p upregulation led to a decreased sensitivity against cisplatin, as observed in transient overexpression models as well as in cell lines stably overexpressing miR-200c-3p. The underlying mechanism seems to be independent of miR-200c-3p’s influence on ZEB1 expression, as ZEB1 knockdown resulted in the opposite effect on cisplatin resistance, which was abolished when ZEB1 knockdown and miR-200c-3p overexpression occurred in parallel. Using a gene panel of 40 genes that were previously associated with cisplatin resistance, two (Dual Specificity Phosphatase 16 (DUSP16) and Stratifin (SFN)) were identified as significantly (>2 fold, p-value < 0.05) up-regulated in miR-200c-3p overexpressing cells. In conclusion, miR-200c-3p might be an important contributor to cisplatin resistance in biliary tract cancer, independently of its interaction with ZEB1.

10.3390/cancers13163996

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RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

International Journal of Molecular Sciences (2020)

Katharina Jonas George A. Călin Martin Pichler

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments.

Tristetraprolin

Post-transcriptional regulation

10.3390/ijms21082969

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Citations (110)