Characterization of Novel Long Noncoding RNAs in Prostate Cancer

Cancer is the second leading cause of death globally, and the number of diagnosed cancer cases continues to grow, thus exerting substantial physical, emotional, and financial burdens on society as a whole. In men, prostate cancer (PC) is the most diagnosed cancer and the third leading cause of cancer death in Europe and the second most lethal cancer in Finland. While the majority of patients with PC are cured, 11–26% of PCs clinically relapse and eventually progress to lethal PC. Current diagnostic methods, most notably prostate-specific antigen (PSA), are very efficient at detecting PCs to the point where even nonthreatening, indolent PCs are diagnosed and treated. However, these treatments can cause unnecessary harm to patients and burden the health care system. Therefore, more specific and effective ways to diagnose and treat aggressive PCs are needed.

Long noncoding RNAs (lncRNAs) are a relatively recently identified group of RNAs that do not encode proteins. They participate in the regulation of genes in cells, including in cancers. LncRNAs are typically expressed specifically in certain tissues and cellular contexts, and many of them are aberrantly expressed in cancers. In addition, several lncRNAs have been shown to play roles in cancer development and progression. These attributes make lncRNAs ideal as prospective biomarkers and therapeutic targets in cancers.

The aim of this dissertation was to discover novel, unexplored lncRNAs that are specifically expressed in PC and to study their regulatory, functional, and biomarker potential in PC models. For this purpose, multiple next-generation sequencing datasets, both publicly available and produced by us, and several molecular, cellular, and biotechnological methods were used to evaluate both in vitro and clinical patient material. These methods were utilized to study the expression profiles of novel lncRNAs in different sample types and to understand the detailed molecular mechanisms underlying their aberrant expression and function. In total, we identified more than one hundred novel PC-associated lncRNAs, called Tampere PCATs (TPCATs). The aberrant expression of most TPCATs is caused by the dysregulation of PC-specific transcription factors, most notably androgen receptors. High expression levels of three TPCATs were independently associated with PC progression. The prognostic TPCATs include EPCART, which is androgen regulated and associated with TMPRSS2-ERG fusion, the most common genetic alteration in PC. The functional role of EPCART was studied in more detail in PC cells, and EPCART was found to promote PC cell proliferation and migration through the regulation of protein translation via the PI3K/AKT/mTORC1 pathway. Overall, the findings in this dissertation revealed novel diagnostic and prognostic biomarker candidates for PC and identified new molecular pathways and potential therapeutic targets for PC treatment.