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Type: Thesis
Title: The role of the piRNA pathway genes in ovarian and prostate cancer progression
Author: Lee, Eunice Hsiu Yee
Issue Date: 2020
School/Discipline: School of Biological Sciences
Abstract: The PIWI-interacting RNA (piRNA) pathway consists of small noncoding RNAs (piRNAs) and pathway genes that play an intricate role in maintaining genomic stability through repressing transposable elements (TEs). The pathway genes are involved in piRNA biogenesis and TE repression through primary and secondary pathways. More recently, deregulated expression and implication in pro-cancer pathways were reported for several piRNA pathway genes (PIWIL1-4, DDX4, MAEL and TDRD1) in various cancers. However, discrepancies in expression changes and effects from manipulating piRNA pathway gene expression in different cancers were observed. Here, we investigated expression of a broader set of piRNA pathway genes and their effects on migration and invasion in two hormone-sensitive cancers, high grade serous ovarian (HGSOC) and prostate (PCa) cancer. We showed dissimilar expression of 10 piRNA pathway genes (PIWIL1- 4, DDX4, HENMT1, MAEL, PLD6, TDRD1 and TDRD9) in clinical HGSOC and PCa samples. In HGSOC, we discovered that genes involved in the primary and secondary pathway were differentially expressed, suggesting differential regulation of these pathways in HGSOC. Notably, their expression change in PCa occurred between benign and malignant samples indicating potential contribution to PCa development. Additionally, their different expression profile in low grade ovarian cancer, HGSOC and PCa demonstrated possible cancerspecific expression. Aberrant expression of certain piRNA pathway genes showed significant association with progression-free and overall survival when clinical data and samples from HGSOC and PCa patients were analysed. This hints at their clinical relevance and potential as novel cancer biomarkers. Preliminary studies on chemoresistant HGSOC and relapsed PCa patient samples also revealed dissimilar trends in expression patterns of the 10 piRNA pathway genes. In particular, we observed PIWIL3 expression in chemosensitive but not chemoresistant primary HGSOC cells. This points towards their potential involvement in the development of resistance in HGSOC and PCa. Addressing the hormone-sensitive aspect of HGSOC and PCa, HGSOC cells treated with high dose follicle stimulating hormone showed significantly upregulated PIWIL2 expression. PCa cells engineered to have reduced androgen receptor activity showed different trends in piRNA pathway gene expression. These pilot studies demonstrated possible hormonal regulation of piRNA pathway genes. Next, we assessed the motility and invasion of HGSOC and PCa cells overexpressing piRNA pathway genes in vitro and in vivo. In contrast to procancer effects observed in other cancers, we demonstrated that their overexpression decreased motility and invasion of HGSOC and PCa. We propose that this discrepancy may be related to the unusually high (~100%) TP53 mutation in HGSOC and the prevalent TMPRSS2:ERG fusion in PCa. Therefore, the piRNA pathway genes may have a protective effect on HGSOC and PCa through maintaining genomic stability. The previously reported PIWIL1 and PIWIL2 mutants with truncated domains postulated to have impaired endonuclease activity and piRNA binding respectively raised questions about heightened effects compared to wildtype. Surprisingly, overexpression of PIWIL1 and PIWIL2 mutants showed increased motility (HGSOC and PCa) and invasion (HGSOC) compared to wildtype. Altogether, this work broadened our understanding of the piRNA pathway genes in cancer and provided novel perspectives on how they may be functioning in different cancers. It is clear from the literature and this study that the piRNA pathway genes play a role in cancer development. This research reinforces the role of the piRNA pathway genes but also highlights the possibility of opposing effects depending on the malignancy.
Advisor: Grutzner, Frank
Oehler, Martin
Ricciardelli, Carmela
Lokman, Noor Alia
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2021
Keywords: Ovarian cancer
prostate cancer
piRNA pathway
patient survival
expression study
Provenance: This thesis is currently under Embargo and is not available.
Appears in Collections:Research Theses

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