Date of Award
2024
Document Type
Thesis - ECU Access Only
Publisher
Edith Cowan University
Degree Name
Doctor of Philosophy
School
School of Medical and Health Sciences
First Supervisor
Wei Wang
Second Supervisor
Hu Wang
Third Supervisor
Lois Balmer
Fourth Supervisor
Manshu Song
Abstract
Osteosarcoma is the most prevalent primary bone cancer, posing challenges due to its high aggressiveness and propensity for chemotherapy resistance. Circular RNAs (circRNAs) can function as competing endogenous RNAs (ceRNAs), playing a crucial role in cancer progression, including invasion, metastasis and chemotherapy resistance. The expression profile and role of circRNAs in osteosarcoma remain unclear. Thus, my PhD identified dysregulated circRNAs and investigated their potential regulatory mechanisms in the pathogenesis of osteosarcoma.
An updated systematic review and meta-analysis was conducted based on articles published from January 2010 to September 2023 across eight databases (PubMed, EMBASE, Cochrane Library, Web of Science, Wanfang, Sinomed, CNKI, Vip) to identify consistently reported circRNAs as potential biomarkers in osteosarcoma. A total of 58 dysregulated circRNAs (52 upregulated and 6 downregulated) were identified, with 11 of them exhibiting dysregulation in both osteosarcoma tissues and cell lines. Among the dysregulated circRNAs, hsa_circ_0005721 showed potential as a circulating biomarker in osteosarcoma, and hsa_circ_0001821 was the most reported circRNA.
The in vitro experiments were performed to explore the potential mechanism underlying hsa_circ_0001821, also known as circPVT1. CircPVT1 was highly expressed in osteosarcoma cells and facilitated cells’ capability of migration and invasion. Mechanistically, circPVT1 modulated the expression of HAVCR2 by acting as a miR-490-5p sequester, in which overexpression of miR-490-5p resulted in a significant reduction of migration and invasion of osteosarcoma cells, whereas HAVCR2 overexpression had the opposite effect.
High-throughput RNA sequencing was employed on doxorubicin sensitivity and resistant osteosarcoma cell lines. The bioinformatics analysis revealed that 163 circRNAs exhibited differential expression, with 57 being upregulated and 106 downregulated in doxorubicin resistant osteosarcoma cells. Based on the prediction from various databases, a ceRNA network consisting of 6 circRNAs, 8 miRNAs and 16 mRNAs was constructed, including 9 circRNA-miRNA-mRNA axes all sharing miR-188-3p, which were deemed potentially crucial in the development of doxorubicin resistance in osteosarcoma.
My PhD project identified pivotal roles for circRNAs in the pathogenesis of osteosarcoma and expanded comprehension of circRNA expression profiles and their underlying regulatory mechanisms in osteosarcoma.
DOI
10.25958/29gt-vt41
Access Note
Access to this thesis is embargoed until 26th November 2027
Recommended Citation
Zhou, C. (2024). Investigating the expression and role of circular RNAs in the pathogenesis of osteosarcoma. Edith Cowan University. https://doi.org/10.25958/29gt-vt41