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Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Assistant Professor Eda Yildirim, Duke University School of Medicine, US
- Second opponent: Professor Christian Beisland, University of Bergen, Norway
- Third member and chair of the evaluation committee: Professor Kristin Austlid Taskén, University of Oslo
Chair of the Defence
Professor Arnljot Tveit, University of Oslo
Principal Supervisor
Senior Research Investigator Rune Ougland, Bærum sykehus, Vestre Viken
Summary
Urothelial carcinoma of the bladder (BLCA) is a disease of high occurrence globally. A high recurrence frequency often necessitates lifelong control schemes of invasive examinations and harsh treatment, reducing the life quality of patients.
Several RNA-modifying proteins have been associated with BLCA, and a link between transfer RNA (tRNA) modifications and the disease has been proposed. N1-methyladenosine (m1A) is a highly abundant tRNA modification, and it has been suggested that m1A and m1A-regulatory proteins contribute to tumour development and progression, yet the contribution in BLCA pathogenesis remains elusive.
The aims of the thesis were to profile the abundance and m1A modification status of non-micro smallRNAs in BLCA primary tumours to gain a deeper insight into the non-micro smallRNA landscape in BLCA, and to further determine the function of m1A base modification in regulation of mRNA functions.
An updated workflow of small RNA-sequencing using a reverse transcriptase more prone to read through the m1A modification (TGIRT-based sRNA-Seq) was applied in the thesis. TGIRT-based sRNA-Seq of surgical specimens of non-muscle invasive BLCA revealed that non-micro sRNAs are abundantly expressed in BLCA. Particularly in one class of non-micro smallRNAs, tRNA-derived fragments (tRFs), the m1A modification is highly prevalent and dependent on the methyltransferase complex TRMT6/TRMT61A which is upregulated in BLCA.
The m1A modification level in a subset of tRFs was found to prevent the tRFs from silencing target genes involved in the unfolded protein response pathway in BLCA cells, resulting in increased expression of those genes promoting cell survival. This proposes a mechanism by which the elevation of TRMT6/TRMT61A can impact gene expression through RNA base modification.
Investigations of the biological role of TRMT6/TRMT61A in BLCA cell lines suggested that the m1A methyltransferase complex plays an oncogenic role in BLCA by being involved in desensitising BLCA cells against cellular stress.
The results raises the possibility that inhibiting the TRMT6/TRMT61A enzyme or reversing the aberrant m1A modification in target tRFs may be a new approach to treat BLCA. The findings present tRFs as potential candidates for BLCA targeting strategy requiring further research. Collectively, these findings support that continued efforts in understanding the role of m1A modification status in small RNAs could present opportunities for future therapeutic and diagnostic strategies.
Additional information
Contact the research support staff.