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Functional Relationship of CRC-Associated Glycans with Malignant Phenotype and Transcriptome Changes

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Functional Relationship of CRC-Associated Glycans with Malignant Phenotype and Transcriptome Changes Alma Mater Studiorum – Università di Bologna DOTTORATO DI RICERCA IN Oncologia, Ematologia e Patologia Ciclo XXXI Settore Concorsuale: 06/A2 Settore Scientifico Disciplinare: MED04 Functional relationship of colorectal cancer- associated glycans with malignant phenotype and transcriptome changes Presentata da: Inês Isabel Gomes Ferreira Coordinatore Dottorato: Prof. Pier-Luigi Lollini Supervisore: Prof. Fabio Dall’Olio Esame finale anno 2019 Acknowledgements To the Marie Sklodowska Curie European committee for awarded me as one of the PhD students of the project H2020 GlyCoCan; To the Department of Experimental, Diagnostic and Specialty Medicine from Università di Bologna, for hosting me in this PhD project; To Professor Fabio Dall’Olio for accepting me as his PhD student in the Department of Experimental, Diagnostic and Specialty Medicine from Università di Bologna; for all the guidance and all knowledge passed to me during my period in his laboratory; To Professor Paula Videira from New University of Lisbon (Lisbon-Portugal) and Doctor Daniel Spencer from Ludger (Oxford-United Kingdom) for accepting me during my period aboard in their research laboratories; To Doctor Mariella Chiricolo and Doctor Nadia Malagolini for all the friendship, technical support and guidance during this PhD; To Doctor Francesco Vasuri from S.Orsola-Malpighi Hospital (Bologna-Italy) for all the work collaboration regarding the clinical samples; To Professor Manuela Ferracin from Università di Bologna for all the work collaboration regarding microarray analysis/TCGA database and for all the wise advices; To Professor Yoann Rombouts and Doctor Alexandre Stella from Institut de Pharmacologie et de Biologie Structurale (Toulouse-France) for the glycoproteomic analysis; To Doctor Rad Kozak from Ludger (Oxford-United Kingdom) for the help in glycomic data analysis; To LTTA microarray facility from University of Ferrara for all the technical support in the transcriptomic analysis; To my laboratory colleagues (Mariangela Catera, Giulia Venturi and Michella Pucci). More than colleagues, Friends! Thank you for all the moments; To all my department colleagues for the good environment, fun and sweet moments; To all my housemates at Bologna, for the great environment and all the friendship, with a special thanks to Carmen Santomauro for all laughs, friendship and craziness; To all my Portuguese friends specially my ever friends Susana Dias and Rita Martins; To my GlyCoCan family, thank you for these three crazy years. A group of 13 young students so different but at the same time, with such a great team spirit. Once a GlyCoCan, always GlyCocan; To all my family for all the personal support; To Garcez for all the love, kindness, patience and support during these years apart. Abstract Tumor-associated glycosylation alterations are both tumor markers and engines of cancer progression. Glycosyltransferases ST6GAL1 and B4GALNT2 (and their cognate antigens Sia6LacNAc and Sda, respectively) are associated with colorectal cancer (CRC) but it is not fully clear their biological and clinical significance. In this project, we explored the clinical relevance of both glycosyltransferases by interrogating The Cancer Genome Atlas (TCGA) database while the phenotypic/transcriptomic effects of ST6GAL1/B4GALNT2 overexpression were studied in genetically modified CRC cell lines. Transcriptomic data from CRC patients in TCGA database suggested a moderate impact of ST6GAL1 on CRC progression, although it was not possible to define a clear role as anti- or pro-tumoral effect. Transcriptomic analysis of ST6GAL1-transduced cell lines revealed a much deeper effect of ST6GAL1 on gene expression in SW948 than in SW48. Notably, no genes showed parallel modulation by ST6GAL1 in the two cell lines. The overexpression of ST6GAL1 induced opposite effects on growth in soft agar and wound healing in the two cell lines. These results indicate that the impact of a cancer-associated glycosyltransferase change on phenotype/transcriptome can be extremely variable, depending on the molecular context of the tumor cell. On the contrary, transcriptomic analysis of B4GALNT2-modified cell lines together with TCGA database survey demonstrated a strong impact of B4GALNT2 on the transcriptional activity of colon cancer cells, in particular its association with a better prognosis. We suggest an anti- tumoral role of this glycosyltransferase in CRC. We also investigated the glycan changes related to ST6GAL1 and B4GALNT2 expression in a small cohort of tissues/plasma samples as well as the N-glycomic profile of CRC, normal and polyp tissues. We found an increase of ST6GAL1 activity in CRC and inflammatory bowel disease plasma samples comparing with plasma from healthy donors. A different Sda protein carrier pattern was observed between healthy donors and CRC plasma samples. β-arrestin 1 is a possible candidate as the Sda carrier protein around 55kDa in plasma samples. Future studies are needed to validate this candidate which can be a potential useful biomarker to help a better CRC diagnosis. The alterations found in the N-glycan pattern among normal, cancer and polyp tissues highlight the importance of N-glycome as a molecular signature in cancer. Index Chapter I - Introduction ............................................................................................................. 1 1. Colorectal cancer .................................................................................................................. 1 1.1 Epidemiology .................................................................................................................. 1 1.2 Molecular pathogenesis ................................................................................................... 2 1.3 Aetiology and risk factors ................................................................................................ 4 1.4 Diagnosis, staging classification and treatment ................................................................ 5 2. Glycosylation ........................................................................................................................ 6 2.1 N-glycans ........................................................................................................................ 8 2.2 O-glycans ...................................................................................................................... 10 2.3 Glycosylation in cancer ................................................................................................. 11 2.4 Colorectal cancer associated carbohydrate antigens and enzymes ................................... 16 2.4.1. ST6GAL1 enzyme and Sia6LacNAc antigen ............................................................. 16 2.4.2. B4GALNT2 enzyme and Sda antigen ......................................................................... 20 3. Importance of “omics” in biomedical research ..................................................................... 23 4. Purpose of the work ............................................................................................................ 27 Chapter II - Material and Methods........................................................................................... 29 1. Cell lines ............................................................................................................................. 29 1.1 Total RNA extraction and reverse transcription to cDNA ............................................... 30 1.2 Transcriptomic data analysis.......................................................................................... 30 1.3 Wound healing assay ..................................................................................................... 31 1.4 Soft agar assay .............................................................................................................. 31 2. Biological samples .............................................................................................................. 32 2.1 Enzymatic activity assays .............................................................................................. 32 2.2 Total RNA extraction and reverse transcription to cDNA ............................................... 33 2.3 Real Time-PCR ............................................................................................................. 33 2.4 Western blotting ............................................................................................................ 34 2.5 Purification of plasma samples by affinity column purification ...................................... 35 2.6 Glycomic analysis ......................................................................................................... 35 3. TCGA database analysis - In silico study ............................................................................. 37 Chapter III - Results ................................................................................................................ 39 1. Transcriptomic and phenotypic impact of ST6GAL1 expression in colorectal cancer ........... 39 1.1 Survey of TCGA database ............................................................................................. 39 1.2 The impact of ST6GAL1 overexpression on the transcriptome is strongly cell-type specific ............................................................................................................................... 43 1.3 The phenotype of colon cancer cells is differentially
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