Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Hasenöhrl, C.
Differential roles of G protein-coupled receptors GPR55 and CB1 in colorectal cancer
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Schicho Rudolf
- Schuligoi Rufina
- Altmetrics:
- Abstract:
- Colorectal cancer (CRC) is a common malignancy in the Western world that is not only linked to lifestyle factors such as diet, smoking, and alcohol consumption but also to inflammatory bowel disease. Although tremendous advances have been made in detection and treatment of the disease, it is still the third most leading cause of cancer death in the United States. In recent years, the endocannabinoid system has become of interest in cancer research since several of its constituents have been observed to be differentially expressed under many pathophysiological conditions including cancer. While the cannabinoid receptor 1 (CB1) has been reported to suppress intestinal tumor growth, the role of lysophospholipid and atypical cannabinoid receptor GPR55 in the development of gastrointestinal cancers is not yet elucidated. GPR55 is involved in many physiological and pathological processes of the gastrointestinal tract and has been shown to play a tumor-promoting role in various cancers. It has recently been reported to exert a pro-inflammatory role in gastrointestinal inflammation via mechanisms involving leukocyte infiltration. This thesis aims at elucidating the hitherto unknown functions of GPR55 in the development and progression of colorectal cancer. Additionally, the involvement of CB1 in colorectal carcinogenesis has been investigated. Using azoxymethane and dextran sulfate sodium-driven CRC mouse models, GPR55 was found to play a tumor-promoting role that is likely based on alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor microenvironment. Concomitantly, the expression levels of tumor promoting factors cyclooxygenase-2 and signal transducer and activator of transcription 3 were reduced in tumor tissue of GPR55 knockout (GPR55-/-) mice, indicating reduced presence of tumor-promoting factors in the microenvironment. By employing the experimental CRC models to CB1 knockout (CB1-/-) and CB1/GPR55 double knockout (CB1-/-GPR55-/-) mice, it was further observed that GPR55 plays an opposing role to CB1. Furthermore, GPR55 and CB1 mRNA expression were differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 (the gene coding for CB1) and GPR55 was also differentially regulated in human CRC tissue compared to control samples. Collectively, the data presented in this thesis suggest that GPR55 and CB1 play opposing roles in colorectal carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. These findings are of importance when developing strategies to target the endocannabinoid system for the therapy of CRC.