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Unnatural MUC1 based glycopeptides in early stage breast cancer biomarkers discovery

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Please use this identifier to cite or link to this item:https://doi.org/10.14943/doctoral.k14391
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Title: Unnatural MUC1 based glycopeptides in early stage breast cancer biomarkers discovery
Other Titles: 非天然型 MUC1糖ペプチドによる乳がん早期バイオマーカーの探索
Authors: Guillén Poza, Pablo Adrián Browse this author
Issue Date: 25-Mar-2021
Publisher: Hokkaido University
Abstract: Mucin 1 (MUC1) is a highly glycosylated O-glycoprotein that experiences alterations in cancer cells and assists the tumor progression. In many human carcinomas and, in particular in breast cancer, MUC1 is overexpressed and aberrantly glycosylated. As a consequence, previously covered antigens are now exposed and accessible to the immune system. This results in the production of antibodies towards these neoepitopes, providing an exploitable divergence between healthy individuals and cancer patients antibody profiles. In order to properly differentiate and develop specific diagnostic tools for early breast cancer detection, we require of the appropriate chemical probes. In this thesis, we have focused on the MUC1 tumor-associated carbohydrate Tn antigen (α-O-GalNAc-Ser/Thr) because of its tumor high specificity, well-defined chemical structure and starting point role for more complex tumor antigens. Previous studies report the use of autoantibodies as potential cancer biosensors. With the intention of developing a more effective and robust sensing device we considered the substitution of GalNAc monosaccharides by stable glycomimic units. To investigate our hypothesis, two different glycopeptide libraries presenting the natural Tn antigen or the sp2-iminosugar-derived unnatural analog were produced through microwave assisted solid-phase peptide synthesis. The whole glycopeptide collection was then evaluated with anti-MUC1 (SM3, VU-3C6, and VU-11E2) monoclonal antibodies (mAbs) in a microarray platform. The most promising candidates were tested with healthy, stage I and stage IV breast cancer sera with the aim of discovering serological autoantibodies (autoAbs) as stage-dependent breast cancer diagnostic biomarkers. Despite the variability between mAbs, the suitability of the glycopeptides bearing the unnatural sp2-iminosugar-based Tn antigen mimic to detect anti-MUC1 antibodies was demonstrated. The present results also revealed that the glycopeptide mimic-antibody interactions are glycosylation pattern-specific and underlined the crucial contribution of the PDTR epitope embedded in the glycopeptide backbone to mAbs binding. Furthermore, stage I breast cancer serum experiments clearly showed autoAbs binding with a specific sp2-iminosugar glycopeptide with almost no interaction with healthy serum, results which will promote further studies on their function as early cancer biomarkers.
Description: 担当:理学部図書室
Conffering University: 北海道大学
Degree Report Number: 甲第14391号
Degree Level: 博士
Degree Discipline: 生命科学
Examination Committee Members: (主査) 教授 西村 紳一郎, 教授 門出 健次, 教授 比能 洋, 客員准教授 Garcia Martin Fayna Maria(先端生命科学研究院)
Degree Affiliation: 生命科学院(生命科学専攻)
Type: theses (doctoral)
URI: http://hdl.handle.net/2115/82016
Appears in Collections:課程博士 (Doctorate by way of Advanced Course) > 生命科学院(Graduate School of Life Science)
学位論文 (Theses) > 博士 (生命科学)

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