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Chong, Zhi Xiong (2024) Unravelling the tumour- and cancer stem cell (CSC)-regulatory roles of miR-3934-5p in human breast cancer. PhD thesis, University of Nottingham.

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Abstract

MicroRNA (miRNA) is a small non-coding RNA. It can interact with the untranslated region of messenger RNA (mRNA) to suppress protein translation. It can also attach to gene promoters to enhance gene transcription. The published work from our group previously showed that cisplatin resistant cancer stem cells (CSCs) isolated from a triple-negative breast cancer (TNBC) cell line (MDA-MB-231) displayed significant upregulation of exosomal miR-3934-5p. However, the underlying mechanism that explains this cellular phenomenon is unclear. Besides, it would also be intriguing to evaluate whether miR-3934-5p affects the development of other breast cancers, like luminal A (ER- and PR-positive) breast cancer (MCF-7). To narrow this gap in the literature, this study aimed to evaluate the cancer- and CSC-controlling role of miR-3934-5p in MDA-MB-231 and MCF-7 using an in vitro functional study approach.

Two varieties of immortal human breast cancer cell lines, MDA-MB-231 and MCF-7 cell lines, were stably transfected with various plasmids in order to carry out the study plan. The miR-3934-5p precursor sequence, miR-3934-5p inhibitor sequence, or scrambled control sequences are present in each of these plasmids. To evaluate the impact of miR-3934-5p modification on cancer development and stemness, several in vitro cellular experiments were then performed on both untransfected and distinct groups of stably transfected cancer cells. Afterward, transcriptomic and protein studies were performed to determine the potential downstream targets and pathways regulated by miR-3934-5p.

Upregulating miR-3934-5p enhanced (p<0.05) breast tumour cell growth, aggression, and stemness in vitro. Besides, this miRNA also promoted cancer cell resistance to anti-cancer therapy. Transcriptomic sequencing (NGS), quantitative real-time polymerase chain reaction (qPCR), and immunoblotting assays revealed that miR-3934-5p considerably (p<0.05) promoted MMP9 and PRDM1 levels in MDA-MB-231 and MCF-7. Conversely, this miRNA suppressed EYA4 and ADM expressions. Additionally, enhanced metalloproteinase activities of miR-3934-5p-overexpressing cells suggested MMP9 as the potential target of this miRNA. Pathway and bioinformatics studies further revealed the association of cancer development and stemness to miR-3934-5p overexpression. Hence, miR-3934-5p can be used to predict clinical outcomes in breast cancer patients. Administration of miR-3934-5p inhibitor could possibly halt breast cancer progression. However, this needs to be supported with in-depth in vivo or clinical studies.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Ho, Wan Yong Yeap, Swee Keong Fang, Chee Mun
Keywords:	breast cancer, miR-3934-5p, cancer stem cell, tumour-regulation
Subjects:	Q Science > QH Natural history. Biology > QH573 Cytology
Faculties/Schools:	University of Nottingham, Malaysia > Faculty of Science and Engineering — Science > School of Pharmacy
Item ID:	77108
Depositing User:	Chong, Zhi
Date Deposited:	09 Mar 2024 04:40
Last Modified:	11 Mar 2024 01:54
URI:	https://eprints.nottingham.ac.uk/id/eprint/77108

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