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3. Functional antagonism between CagA and DLC1 in gastric cancer

Author

Hinsenkamp, Isabel, Köhler, Jan P., Flächsenhaar, Christoph, Hitkova, Ivana, Meessen, Sabine Eberhart, Gaiser, Timo, Wieland, Thomas, Weiss, Christel, Röcken, Christoph, Mowat, Michael, Quante, Michael, Taxauer, Karin, Mejias-Luque, Raquel, Gerhard, Markus, Vogelmann, Roger, Meindl-Beinker, Nadja, Ebert, Matthias, and Burgermeister, Elke

Published
2022
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4. A Comparative Assessment of Replication Stress Markers in the Context of Telomerase

Author

Meessen, Sabine, Najjar, Gregoire, Azoitei, Anca, Iben, Sebastian, Bolenz, Christian, Günes, Cagatay, and Horikawa, Izumi

Subjects
oncogene-induced replication stress, Cancer Research, DNS, Reaktive Sauerstoffspezies, Replikation, DNA replication, Aneuploidy, aneuploidy, reactive oxygen species, telomerase, phosho-RPA2, γ-H2AX, 53BP1, DDC 570 / Life sciences, Oncology, ddc:570, Aneuploidie, ddc:610, Reactive oxygen species, DDC 610 / Medicine & health, Telomerase
Abstract

Simple Summary Genetic alterations such as oncogenic- or aneuploidy-inducing mutations can induce replication stress as a tumor protection mechansim. Previous data indicated that telomerase may ameliorate the cellular responses that induce replication stress. However, the mechanisms how this may occur are still unclear. In order to address this question, the accurate evaluation of replication stress in the presence and absence of telomerase is crucial. Therefore, we used telomerase negative normal human fibroblasts, as well as their telomerase positive counterparts to compare the suitability of three protein markers (pRPA2, γ-H2AX and 53BP1), which were previously reported to accumulate in response to harmful conditions leading to replication stress in cells. In summary, we find that pRPA2 is the most consistent and reliable marker for the detection of replication stress. Further, we demonstrated that the inhibition of the DNA-damage activated ATM and ATR kinases by specific small compounds impaired the accumulation of pRPA2 foci in the absence of telomerase. These data suggest that telomerase rescues the cells from replication stress upon supression of DNA damage induction by modulating the ATM and ATR signaling pathways, and may therefore support tumor formation of genetically unstable cells. Abstract Aberrant replication stress (RS) is a source of genome instability and has serious implications for cell survival and tumourigenesis. Therefore, the detection of RS and the identification of the underlying molecular mechanisms are crucial for the understanding of tumourigenesis. Currently, three protein markers—p33-phosphorylated replication protein A2 (pRPA2), γ-phosphorylated H2AX (γ-H2AX), and Tumor Protein P53 Binding Protein 1 (53BP1)—are frequently used to detect RS. However, to our knowledge, there is no report that compares their suitability for the detection of different sources of RS. Therefore, in this study, we evaluate the suitability of pRPA2, γ-H2AX, and 53BP1 for the detection of RS caused by different sources of RS. In addition, we examine their suitability as markers of the telomerase-mediated alleviation of RS. For these purposes, we use here telomerase-negative human fibroblasts (BJ) and their telomerase-immortalized counterparts (BJ-hTERT). Replication stress was induced by the ectopic expression of the oncogenic RAS mutant RASG12V (OI-RS), by the knockdown of ploidy-control genes ORP3 or MAD2 (AI-RS), and by treatment with hydrogen peroxide (ROS-induced RS). The level of RS was determined by immunofluorescence staining for pRPA2, γ-H2AX, and 53BP1. Evaluation of the staining results revealed that pRPA2- and γ-H2AX provide a significant and reliable assessment of OI-RS and AI-RS compared to 53BP1. On the other hand, 53BP1 and pRPA2 proved to be superior to γ-H2AX for the evaluation of ROS-induced RS. Moreover, the data showed that among the tested markers, pRPA2 is best suited to evaluate the telomerase-mediated suppression of all three types of RS. In summary, the data indicate that the choice of marker is important for the evaluation of RS activated through different conditions., publishedVersion

Published
2022
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5. Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma

Author

Zheng, Xi, primary, Wezel, Felix, additional, Azoitei, Anca, additional, Meessen, Sabine, additional, Wang, Wenya, additional, Najjar, Gregoire, additional, Wang, Xue, additional, Kraus, Johann M., additional, Kestler, Hans A., additional, John, Axel, additional, Zengerling, Friedemann, additional, Bolenz, Christian, additional, and Günes, Cagatay, additional

Published
2021
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7. Telomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells

Author

German Cancer Aid, German Research Foundation, The Hector Foundation, Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Ulm University, Walter, Karolin, Rodriguez-Aznar, Eva, Ventura Ferreira, Monica S., Frappart, Pierre-Olivier, Dittrich, Tabea, Tiwary, Kanishka, Meessen, Sabine, Lerma, L., Daiss, Nora, Schulte, Lucas-Alexander, Najafova, Zeynab, Arnold, Frank, Usachov, Valentyn, Azoitei, Ninel, Erkan, Mert M., Lechel, André, Brümmendorf, Tim H., Seufferlein, Thomas, Kleger, Alexander, Tabarés, E., German Cancer Aid, German Research Foundation, The Hector Foundation, Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Ulm University, Walter, Karolin, Rodriguez-Aznar, Eva, Ventura Ferreira, Monica S., Frappart, Pierre-Olivier, Dittrich, Tabea, Tiwary, Kanishka, Meessen, Sabine, Lerma, L., Daiss, Nora, Schulte, Lucas-Alexander, Najafova, Zeynab, Arnold, Frank, Usachov, Valentyn, Azoitei, Ninel, Erkan, Mert M., Lechel, André, Brümmendorf, Tim H., Seufferlein, Thomas, Kleger, Alexander, and Tabarés, E.

Abstract

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.

Published
2021

8. Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells

Author

Walter, Karolin, primary, Rodriguez-Aznar, Eva, additional, Ferreira, Monica S. Ventura, additional, Frappart, Pierre-Olivier, additional, Dittrich, Tabea, additional, Tiwary, Kanishka, additional, Meessen, Sabine, additional, Lerma, Laura, additional, Daiss, Nora, additional, Schulte, Lucas-Alexander, additional, Najafova, Zeynab, additional, Arnold, Frank, additional, Usachov, Valentyn, additional, Azoitei, Ninel, additional, Erkan, Mert, additional, Lechel, Andre, additional, Brümmendorf, Tim H., additional, Seufferlein, Thomas, additional, Kleger, Alexander, additional, Tabarés, Enrique, additional, Günes, Cagatay, additional, Johnsen, Steven A., additional, Beier, Fabian, additional, Sainz, Bruno, additional, and Hermann, Patrick C., additional

Published
2021
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10. The Role of Interleukin-1-Receptor-Antagonist in Bladder Cancer Cell Migration and Invasion

Author

Schneider, Lisa, primary, Liu, Junnan, additional, Zhang, Cheng, additional, Azoitei, Anca, additional, Meessen, Sabine, additional, Zheng, Xi, additional, Cremer, Catharina, additional, Gorzelanny, Christian, additional, Kempe-Gonzales, Sybille, additional, Brunner, Cornelia, additional, Wezel, Felix, additional, Bolenz, Christian, additional, Gunes, Cagatay, additional, and John, Axel, additional

Published
2021
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11. Grainyhead-Like 3 Influences Migration and Invasion of Urothelial Carcinoma Cells

Author

Wezel, Felix, primary, Lustig, Johannes, additional, Azoitei, Anca, additional, Liu, Junnan, additional, Meessen, Sabine, additional, Najjar, Gregoire, additional, Zehe, Viktor, additional, Faustmann, Philipp, additional, Zengerling, Friedemann, additional, John, Axel, additional, Martini, Thomas, additional, Bolenz, Christian, additional, and Günes, Cagatay, additional

Published
2021
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12. A feedback-loop between telomerase activity and stemness factors regulates PDAC stem cells

Author

Walter, Karolin, primary, Rodriguez-Aznar, Eva, additional, Ventura Ferreira, Monica S., additional, Frappart, Pierre-Olivier, additional, Dittrich, Tabea, additional, Tiwary, Kanishka, additional, Meessen, Sabine, additional, Lerma, Laura, additional, Daiss, Nora, additional, Schulte, Lucas-Alexander, additional, Arnold, Frank, additional, Usachov, Valentyn, additional, Azoitei, Ninel, additional, Erkan, Mert, additional, Lechel, Andre, additional, Brümmendorf, Tim H., additional, Seufferlein, Thomas, additional, Kleger, Alexander, additional, Tabarés, Enrique, additional, Günes, Cagatay, additional, Beier, Fabian, additional, Sainz, Bruno, additional, and Hermann, Patrick C., additional

Published
2020
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14. Downregulation of ORP3 Correlates with Reduced Survival of Colon Cancer Patients with Advanced Nodal Metastasis and of Female Patients with Grade 3 Colon Cancer

Author

Xu, Pengfei, primary, Richter, Julia, additional, Blatz, Annette, additional, Gärtner, Fabian, additional, Alberts, Roland, additional, Azoitei, Anca, additional, Makori, Wycliffe Arika, additional, Meessen, Sabine, additional, Knippschild, Uwe, additional, and Günes, Cagatay, additional

Published
2020
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15. A Novel Tissue and Stem Cell Specific TERF1 Splice Variant Is Downregulated in Tumour Cells

Author

Morcos, Yousef Ashraf Tawfik, primary, Najjar, Gregoire, additional, Meessen, Sabine, additional, Witt, Britta, additional, Azoitei, Anca, additional, Kumar, Mukesh, additional, Wakileh, Gamal, additional, Schwarz, Klaus, additional, Schrezenmeier, Hubert, additional, Zengerling, Friedemann, additional, Bolenz, Christian, additional, and Günes, Cagatay, additional

Published
2019
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16. A Novel Tissue and Stem Cell Specific TERF1 Splice Variant Is Downregulated in Tumour Cells.

Author

Morcos, Yousef Ashraf Tawfik, Najjar, Gregoire, Meessen, Sabine, Witt, Britta, Azoitei, Anca, Kumar, Mukesh, Wakileh, Gamal, Schwarz, Klaus, Schrezenmeier, Hubert, Zengerling, Friedemann, Bolenz, Christian, and Günes, Cagatay

Subjects
STEM cells, HEMATOPOIETIC stem cells, CELL nuclei, RNA splicing, CANCER cells, RNA analysis
Abstract

In this study, we describe the identification of a novel splice variant of TERF1/PIN2, one of the main components of the telomeric shelterin complex. This new splice variant is identical to TERF1, apart from a 30 amino acid internal insertion near to the C-terminus of TERF1. Based on genome comparison analyses and RNA expression data, we show that this splice variant is conserved among hominidae but absent from all other species. RNA expression and histological analyses show specific expression in human spermatogonial and hematopoietic stem cells (HSCs), while all other analyzed tissues lack the expression of this TERF1-isoform, hence the name TERF1-tsi (TERF1-tissue-specific-isoform). In addition, we could not detect any expression in primary human cells and established cancer cell lines. Immunohistochemistry results involving two new rabbit polyclonal antibodies, generated against TERF1-tsi specific peptides, indicate nuclear localization of TERF1-tsi in a subset of spermatogonial stem cells. In line with this observation, immunofluorescence analyzes in various cell lines consistently revealed that ectopic TERF1-tsi localizes to the cell nucleus, mainly but not exclusively at telomeres. In a first attempt to evaluate the impact of TERF1-tsi in the testis, we have tested its expression in normal testis samples versus matched tumor samples from the same patients. Both RT-PCR and IHC show a specific downregulation of TERF1-tsi in tumor samples while the expression of TERF1 and PIN2 remains unchanged. [ABSTRACT FROM AUTHOR]

Published
2020
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