| Přispěvatelé: |
University of Helsinki, Faculty of Medicine, Medicum, Biochemistry and Developmental Biology, Translational Cancer Biology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsingin yliopisto, lääketieteellinen tiedekunta, Medicum, Helsingfors universitet, medicinska fakulteten, Medicum, Nilsen, Hilde, Holmberg-Still, Carina |
| Popis: |
The ubiquitin-proteasome system (UPS) is the major cellular pathway for controlled protein degradation, and, together with the autophagy-lysosome pathway, it is a central player in maintaining protein homeostasis. The catalytic core of the UPS is the proteasome, a complex holoenzyme composed of multiple different subunits with varying functions. Disruptions in the UPS are associated with many pathological conditions, including aging-related neurological diseases (such as Alzheimer's, Parkinson's, or Huntington's disease), as well as different cancers. Proteasome inhibitors (e.g. Bortezomib) are in use as cancer therapeutics (e.g. in refractory multiple myeloma and mantle cell lymphoma), but dose-limiting toxicities, drug-resistance and other adverse side-effects have created an acute need for identifying alternative targets that modulate the UPS. Yet, despite its wide-ranging importance, it remains to be defined how UPS is regulated, especially in vivo. The purpose of this thesis was to provide new information on UPS modulation in a living, multicellular organism, with the help of the model organism Caenorhabditis elegans. Further, the aim was to investigate the potential role of an identified proteasome regulator UCHL5/UBH-4 as a biomarker in three gastrointestinal cancers: colorectal cancer (CRC), gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC). In the first part of the study, it was established that UCHL5/UBH-4, a proteasome-associated deubiquitinating enzyme (DUB), modulates proteasome activity in C. elegans, and additionally increases the degradation of proteotoxic proteins in human cancer cells. In C. elegans, UBH-4 expression was demonstrated to be regulated by the ageing-regulating Insulin/IGF-1 signaling (IIS) pathway through the transcription factor DAF-16 in a tissue-specific manner. Further, minor knockdown of ubh-4 resulted in a short lifespan extension without affecting progeny amounts. In the second part of the study, the role of UCHL5 was investigated in various gastrointestinal cancers. UCHL5 tumorexpression was scored with immunohistochemistry from representative patient tumor samples in CRC, GC and PDAC. UCHL5-immunoexpression correlated with increased survival in the subgroup of patients with lymph node-positive (Dukes C/stage III) rectal cancer. In addition, both positive nuclear and high cytoplasmic UCHL5-immunoexpression associated with better prognosis in PDAC. Positive UCHL5-immunoexpression was also linked to enhanced survival in the subgroups of gastric cancer patients with small tumors ( |
